Celiac disease is a chronic, immune-mediated systemic disorder primarily affecting the small intestine. It develops in genetically susceptible individuals following exposure to gluten, a complex mixture of storage proteins found mainly in wheat, barley and rye. The disease is characterised by an abnormal immune response to specific gluten-derived peptides, resulting in inflammation and structural damage to the small intestinal mucosa. The characteristic pathological changes include villous atrophy, crypt hyperplasia and increased infiltration of intraepithelial lymphocytes. These alterations progressively impair the absorptive capacity of the intestine and may produce nutritional deficiencies and a wide range of gastrointestinal and extraintestinal manifestations.
Although celiac disease was traditionally considered primarily a gastrointestinal disorder associated with chronic diarrhoea and malabsorption, modern immunological research has established that it is a systemic autoimmune-associated disease with manifestations involving several organ systems. Some patients develop severe intestinal symptoms, while others present with relatively nonspecific complaints such as fatigue, anaemia, osteoporosis, neurological abnormalities or reproductive problems. A proportion of affected individuals may remain apparently asymptomatic despite having characteristic intestinal lesions. Consequently, the disease can remain undiagnosed for years, particularly when its manifestations are predominantly extraintestinal.
Celiac disease is scientifically significant because it provides a well-characterised example of how genetic susceptibility, environmental exposure, molecular modification of dietary proteins and dysregulated immune recognition can interact to produce chronic inflammatory disease. Its pathogenesis demonstrates the importance of molecular structure in antigen recognition and the role of adaptive and innate immune mechanisms in maintaining or disrupting tissue homeostasis.
Gluten is a protein complex present in wheat and related cereals. Its principal components include gliadins and glutenins. Barley contains related proteins called hordeins, while rye contains secalins. These proteins contain relatively high concentrations of proline and glutamine, which make certain peptide sequences resistant to complete degradation by gastrointestinal digestive enzymes.
Under normal digestive conditions, dietary proteins are progressively broken down into smaller peptides and amino acids through the combined action of gastric, pancreatic and intestinal enzymes. However, some gluten-derived peptides resist complete enzymatic digestion because their amino acid composition makes them relatively resistant to proteolysis. Consequently, immunologically active peptide fragments can persist within the intestinal environment.
One particularly important peptide is a 33-amino-acid fragment derived from alpha-gliadin, commonly referred to as the immunodominant gliadin peptide. Such gluten-derived peptides can cross the intestinal epithelial barrier through several possible pathways and become accessible to antigen-presenting cells in the underlying intestinal tissue. Their interaction with genetically determined immune-recognition molecules is central to the initiation of celiac disease.
The presence of gluten alone, however, is insufficient to produce celiac disease. Most people consume wheat and other gluten-containing foods throughout their lives without developing this disorder. Disease development requires an appropriate genetic background and an abnormal immune response to gluten-derived antigens. This explains why celiac disease occurs only in a relatively small proportion of the population despite widespread exposure to gluten.
The strongest known genetic association with celiac disease involves the human leukocyte antigen system, particularly HLA-DQ2 and HLA-DQ8. These molecules belong to the major histocompatibility complex class II family and play an essential role in presenting extracellularly derived antigens to CD4-positive T lymphocytes.
Approximately 90–95% of patients with celiac disease carry HLA-DQ2.5, while most of the remaining patients carry HLA-DQ8 or certain other permissive HLA-DQ2 variants. These molecules possess specific structural characteristics that allow them to bind deamidated gluten peptides with relatively high affinity.
The genetic association is important because antigen recognition is dependent not simply on the presence of a foreign protein but also on the molecular compatibility between the antigenic peptide and the antigen-presenting molecule. HLA-DQ2 and HLA-DQ8 provide the molecular framework through which specific gluten-derived peptides can be presented to T lymphocytes.
However, carrying these genetic variants does not necessarily result in disease. HLA-DQ2 and HLA-DQ8 are relatively common in the general population, whereas only a small proportion of carriers develop celiac disease. Therefore, additional genetic, environmental and immunological factors must contribute to disease initiation and progression. Several non-HLA genetic loci associated with immune regulation and intestinal barrier function have also been implicated.
One of the most important molecular events in celiac disease is the modification of gluten-derived peptides by an enzyme called tissue transglutaminase 2, commonly abbreviated as TG2 or tTG.
Tissue transglutaminase is normally present in various tissues and participates in several biological processes, including protein cross-linking and extracellular matrix organisation. In the intestinal environment, it can modify selected glutamine residues in gliadin peptides through a process known as deamidation. During this reaction, certain glutamine residues are converted into negatively charged glutamate residues.
This modification changes the physicochemical properties of the peptide and increases its affinity for HLA-DQ2 and HLA-DQ8 molecules. Consequently, deamidated gliadin peptides can be presented more efficiently to gluten-specific CD4-positive T lymphocytes.
This molecular modification is a crucial step in the development of the adaptive immune response. It illustrates how an enzymatic alteration of a dietary protein can transform its antigen-presenting properties and increase its capacity to stimulate an immune reaction in genetically susceptible individuals.
The same tissue transglutaminase molecule also becomes an important target of the autoimmune response. Patients frequently develop antibodies against tissue transglutaminase, which form the basis of the widely used anti-tTG diagnostic test. Thus, TG2 has a dual significance in celiac disease: it participates in the modification of gluten peptides and serves as a major autoantigen recognised by the immune system.
Following deamidation, gluten-derived peptides bind to HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells, particularly dendritic cells. These antigen-presenting cells display the peptide-HLA complexes to CD4-positive T lymphocytes.
In genetically susceptible individuals, the interaction between the peptide-HLA complex and the T-cell receptor activates gluten-specific T lymphocytes. This initiates an antigen-specific adaptive immune response involving the production of inflammatory cytokines and the activation of other immune cells.
Activated CD4-positive T lymphocytes produce several cytokines, including interferon-gamma, which contributes significantly to intestinal inflammation. Other inflammatory mediators participate in the recruitment and activation of immune cells and influence epithelial function. This immune response is not merely directed towards the presence of gluten in the intestinal lumen; it produces a sustained inflammatory environment within the intestinal mucosa.
The activation of gluten-specific T lymphocytes also contributes to the generation of B-cell responses. B lymphocytes differentiate into antibody-producing plasma cells and produce antibodies against deamidated gliadin peptides and tissue transglutaminase. These antibodies are important diagnostic markers, although the direct mechanisms through which they contribute to intestinal tissue damage are more complex and are not considered the principal drivers of villous destruction.
The adaptive immune response therefore establishes a connection between dietary antigen recognition, genetic susceptibility, inflammatory signalling and the development of autoantibodies.
Although adaptive immunity is central to the antigen-specific response in celiac disease, innate immune mechanisms are equally important in producing intestinal epithelial injury.
One of the major molecules involved in this process is interleukin-15 (IL-15). Its expression increases in the intestinal mucosa of affected individuals, particularly in the epithelial compartment. IL-15 promotes the activation, survival and cytotoxic potential of intraepithelial lymphocytes.
These lymphocytes are normally present between intestinal epithelial cells and contribute to mucosal immune surveillance. Under normal conditions, they help protect the intestinal barrier against invading microorganisms and abnormal cells. In celiac disease, however, inflammatory signalling alters their behaviour and promotes excessive cytotoxic activity.
Activated intraepithelial lymphocytes express cytotoxic molecules, including natural killer cell receptors such as NKG2D. These receptors recognise stress-associated molecules expressed by intestinal epithelial cells. Their interaction promotes epithelial cell injury and destruction.
The resulting damage involves the progressive loss of mature absorptive epithelial cells and disruption of the normal organisation of the intestinal mucosa. The combined effects of adaptive immune activation and innate immune-mediated cytotoxicity produce the characteristic pathological changes of celiac disease.
Thus, intestinal injury is not simply a consequence of direct toxicity from gluten. It results from an abnormal immune response in which antigen-specific T-cell activation and innate cytotoxic mechanisms interact to damage the body’s own intestinal tissue.
The small intestine is specialised for nutrient absorption through its extensive mucosal surface. Its inner lining contains numerous finger-like projections called villi, which considerably increase the available absorptive area. Each villus contains epithelial cells, blood vessels and lymphatic structures involved in the absorption and transportation of nutrients.
In celiac disease, chronic inflammation progressively alters this architecture. The most characteristic histopathological changes are villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes.
Villous atrophy refers to the shortening, flattening or complete disappearance of the intestinal villi. This reduces the surface area available for nutrient absorption. Crypt hyperplasia represents an increase in the depth and proliferative activity of the intestinal crypts, reflecting an attempt by the intestinal epithelium to replace damaged cells. Increased intraepithelial lymphocytes indicate the presence of an abnormal immune-cell population within the epithelial layer.
These changes are commonly evaluated using the Marsh classification, which grades the severity of intestinal abnormalities according to lymphocyte infiltration, crypt changes and villous architecture.
The loss of normal villous structure produces varying degrees of malabsorption. Iron, folate, calcium, vitamin D and other nutrients may become deficient. In more advanced cases, protein and fat absorption can also be significantly impaired.
The severity of histological abnormalities does not always correspond directly to the severity of clinical symptoms. Some individuals with substantial villous atrophy experience relatively mild symptoms, while others with less extensive structural abnormalities may report significant gastrointestinal disturbances.
The clinical manifestations of celiac disease are highly variable. Classical presentations include chronic diarrhoea, abdominal distension, excessive flatulence, abdominal pain, weight loss and steatorrhoea. These symptoms arise primarily from intestinal inflammation and impaired nutrient absorption.
Steatorrhoea occurs when fat absorption is significantly impaired, resulting in bulky, greasy and sometimes foul-smelling stools. Chronic malabsorption may produce weight loss, muscle wasting and general nutritional deficiencies.
However, many patients do not present with the classical gastrointestinal picture. Some develop persistent iron-deficiency anaemia due to impaired absorption of iron, which normally occurs predominantly in the duodenum and proximal jejunum. Others may develop folate deficiency, vitamin B12 deficiency, chronic fatigue or unexplained weakness.
Bone health can also be affected. Impaired calcium and vitamin D absorption may lead to secondary hyperparathyroidism, reduced bone mineral density, osteopenia and osteoporosis. In some individuals, bone pain or recurrent fractures may be the first indication of an underlying intestinal disorder.
Celiac disease can also produce neurological manifestations, including peripheral neuropathy, ataxia and certain forms of cognitive disturbance. The mechanisms may involve nutritional deficiencies, immune-mediated effects and other systemic consequences of the disease.
Dermatitis herpetiformis is a particularly important extraintestinal manifestation. It is a chronic, intensely itchy skin disorder characterised by grouped papules and vesicles, commonly affecting the elbows, knees, buttocks and scalp. It is associated with gluten sensitivity and granular deposition of IgA in the dermal papillae. Its presence should raise strong suspicion of celiac disease, even when gastrointestinal symptoms are absent.
Reproductive abnormalities, including infertility and certain pregnancy complications, have also been associated with untreated celiac disease. The underlying mechanisms may involve nutritional deficiencies, chronic inflammation and systemic immune effects.
Celiac disease is associated with an increased prevalence of other autoimmune conditions. Type 1 diabetes mellitus and autoimmune thyroid disorders are among the most recognised associations.
The relationship with type 1 diabetes is particularly interesting because both diseases involve genetically influenced immune dysregulation. In type 1 diabetes, immune mechanisms destroy insulin-producing pancreatic beta cells, whereas in celiac disease, immune mechanisms damage the intestinal mucosa in response to gluten exposure.
Autoimmune thyroiditis, autoimmune liver diseases and certain connective tissue disorders have also been reported more frequently among individuals with celiac disease.
These associations suggest that genetic susceptibility and abnormalities in immune regulation may create a broader predisposition to autoimmune disease. However, the presence of one autoimmune disorder does not automatically imply that another will develop.
Celiac disease is frequently confused with irritable bowel syndrome because both conditions can produce abdominal pain, bloating, excessive gas, diarrhoea and altered bowel habits. However, their underlying biological mechanisms are fundamentally different.
Celiac disease is an immune-mediated disorder characterised by an abnormal response to gluten and, in established disease, structural injury to the small intestinal mucosa. IBS, in contrast, is classified as a disorder of gut-brain interaction. It involves disturbances in intestinal motility, visceral sensitivity, gastrointestinal sensory processing and communication between the enteric nervous system and the central nervous system.
In IBS, patients may experience considerable abdominal discomfort even though there is no characteristic villous atrophy or celiac-type immune-mediated intestinal destruction. Changes in intestinal microbiota, altered intestinal permeability, post-infectious changes and visceral hypersensitivity may contribute to symptoms in different patients.
An important complication is that some individuals with IBS-like symptoms may actually have undiagnosed celiac disease. Therefore, celiac screening should be considered in appropriate patients, particularly those with chronic diarrhoea, unexplained iron-deficiency anaemia, weight loss or a family history of celiac disease.
Another condition that must be distinguished from both is non-celiac gluten sensitivity. Individuals with this condition report symptoms associated with gluten consumption but do not demonstrate the characteristic autoimmune response or intestinal histopathology of celiac disease. Furthermore, in some individuals, symptoms attributed to gluten may actually result from sensitivity to other wheat components, particularly fermentable carbohydrates known as fructans.
Consequently, improvement following a gluten-free diet alone cannot establish a diagnosis of celiac disease.
The diagnosis of celiac disease is based on a combination of clinical assessment, serological investigations and, in most adults, histopathological examination of duodenal tissue.
The preferred initial blood test is the measurement of immunoglobulin A antibodies against tissue transglutaminase, commonly called anti-tTG IgA. This test has high diagnostic sensitivity and specificity when performed in individuals consuming adequate quantities of gluten.
Total serum IgA should also be measured because selective IgA deficiency is more common among patients with celiac disease than in the general population. In individuals with IgA deficiency, IgA-based antibody tests may produce false-negative results. In such cases, IgG-based tests, including deamidated gliadin peptide IgG and tTG IgG, are useful alternatives.
Endomysial antibodies of the IgA class are another highly specific serological marker. They are directed against tissue structures containing tissue transglutaminase and are particularly useful in selected diagnostic situations.
Upper gastrointestinal endoscopy with multiple biopsies from the duodenum is generally recommended for confirmation in adults. The biopsy demonstrates the characteristic combination of increased intraepithelial lymphocytes, crypt hyperplasia and villous atrophy.
Genetic testing for HLA-DQ2 and HLA-DQ8 can help resolve diagnostic uncertainty. The absence of the relevant permissive HLA variants makes celiac disease very unlikely. However, their presence alone cannot establish the diagnosis because many healthy individuals carry these genetic variants.
An essential diagnostic precaution is that patients should continue consuming gluten until the appropriate investigations have been completed. Starting a gluten-free diet before testing can reduce antibody concentrations and allow intestinal tissue to recover, potentially resulting in misleading negative findings.
The established treatment for celiac disease is a strict, lifelong gluten-free diet. At present, dietary exclusion of gluten remains the standard treatment because it removes the antigenic stimulus responsible for initiating the abnormal immune response.
Patients must avoid wheat, barley and rye, including foods prepared using flour derived from these cereals. This includes ordinary bread, biscuits, pasta, cakes, many processed foods and certain sauces or food additives containing gluten.
Fortunately, many commonly consumed foods are naturally gluten-free. Rice, maize, tapioca, potatoes, pulses, fruits, vegetables, fish, meat, eggs and unprocessed dairy products can generally be included in the diet, provided they are not contaminated with gluten during preparation or processing.
In the Indian context, rice, ragi, jowar, bajra, maize and tapioca offer several dietary alternatives. However, cross-contamination during milling, storage, cooking and food preparation must be prevented. Even relatively small quantities of gluten can provoke an immune response in susceptible individuals.
Oats require particular attention because commercial oats are frequently contaminated with wheat or barley during cultivation and processing. Certified gluten-free oats may be suitable for some patients, although a minority may react to avenin, an oat protein.
Nutritional deficiencies should be corrected according to laboratory findings. Iron, folate, vitamin B12, calcium and vitamin D supplementation may be necessary in selected patients. Bone mineral density assessment should be considered when there are significant risk factors or evidence of prolonged malabsorption.
Dietary counselling by a qualified dietitian familiar with celiac disease is valuable because an unnecessarily restrictive diet can itself produce nutritional deficiencies.
When gluten is removed from the diet, the inflammatory stimulus gradually diminishes. Antibody concentrations generally decline, intestinal inflammation improves and the damaged villous architecture begins to recover.
The rate of recovery varies considerably between individuals. Gastrointestinal symptoms may improve within weeks or months, whereas complete histological recovery can take considerably longer, particularly in older adults or those with severe intestinal damage.
Long-term monitoring is important. Clinical symptoms, nutritional status, celiac antibody concentrations and relevant biochemical parameters should be evaluated periodically. Persistent symptoms despite strict gluten avoidance require further investigation for accidental gluten exposure, lactose intolerance, microscopic colitis, pancreatic insufficiency, small intestinal bacterial overgrowth or other associated conditions.
A small proportion of patients develop refractory celiac disease, in which intestinal abnormalities and symptoms persist despite prolonged adherence to a strict gluten-free diet. This is a serious condition requiring specialist evaluation because some forms are associated with an increased risk of intestinal lymphoma.
Untreated celiac disease is associated with certain malignancies, particularly enteropathy-associated T-cell lymphoma and some small intestinal adenocarcinomas. Nevertheless, these complications are uncommon, and the overall prognosis is generally excellent when the disease is correctly diagnosed and managed.
From the perspective of molecular biology, celiac disease offers an especially informative example of the relationship between molecular structure, genetic susceptibility and immune recognition. Its pathogenesis demonstrates how a dietary protein can acquire pathological significance through enzymatic modification and interaction with genetically determined antigen-presenting molecules.
The process begins with the persistence of certain gluten-derived peptides following incomplete gastrointestinal digestion. Tissue transglutaminase modifies selected peptide sequences through deamidation, changing their charge characteristics and increasing their affinity for HLA-DQ2 and HLA-DQ8. The resulting peptide-HLA complexes are recognised by specific T-cell receptors, initiating an antigen-specific immune response.
This recognition process is followed by the production of inflammatory cytokines, activation of intraepithelial lymphocytes, epithelial cell destruction and progressive alteration of intestinal tissue architecture. The disease therefore involves a sequence of molecular interactions extending from dietary protein structure to genetic antigen presentation, immune-cell activation and tissue-level pathology.
An important distinction is that the immune response is not directed exclusively against a foreign dietary substance. The inflammatory process also involves the body’s own tissue structures, and autoantibodies against tissue transglutaminase become prominent diagnostic markers. Celiac disease thus illustrates how an immune response initiated by an external antigen can become associated with autoimmunity and chronic tissue injury.
It also demonstrates that the biological effects of a molecule depend not merely on its chemical composition but on its molecular structure, modification, recognition and interaction with specific biological systems. The same gluten proteins that are harmless to most individuals can become potent immunological triggers in a genetically susceptible individual because of the particular molecular conditions governing antigen presentation and immune activation.
Celiac disease is much more than a dietary intolerance or a simple digestive disorder. It is a genetically influenced, gluten-triggered, immune-mediated disease involving a complex interaction between dietary proteins, enzymatic modification, antigen-presenting molecules, T lymphocytes, inflammatory cytokines and intestinal epithelial cells. Its characteristic intestinal lesions result from the combined effects of adaptive immune activation and innate immune-mediated cytotoxicity.
The disease provides a clear demonstration of how molecular recognition can determine the difference between physiological tolerance and pathological immune activation. It also illustrates how a disturbance originating at the molecular and immunological levels can produce structural damage, nutritional deficiencies and systemic clinical manifestations.
The availability of reliable serological tests, histopathological investigations and an effective gluten-free dietary treatment makes celiac disease one of the better-understood immune-mediated intestinal disorders. Early diagnosis and strict dietary management can prevent progressive intestinal injury, correct nutritional deficiencies and substantially improve long-term health.
Ultimately, understanding celiac disease requires an integrated approach combining molecular biology, genetics, immunology, gastrointestinal physiology and clinical medicine. It is an important model for studying the mechanisms through which environmental molecules interact with genetically determined biological systems to produce disease.
Pathophysiology of Celiac Disease: Molecular, Genetic, Immunological and Cellular Mechanisms
Celiac disease is a chronic, gluten-dependent, immune-mediated systemic disorder in which dietary proteins initiate an abnormal immune response in genetically susceptible individuals. The principal site of pathological involvement is the small intestinal mucosa, where persistent immune activation produces inflammation, epithelial injury, villous atrophy and impaired nutrient absorption. The disease is particularly significant from a molecular biological perspective because its development involves a complex sequence of interactions between dietary protein molecules, digestive enzymes, tissue transglutaminase, genetically determined antigen-presenting molecules, T lymphocytes, B lymphocytes, inflammatory cytokines and intestinal epithelial cells. The resulting pathological changes are not caused by the direct toxic effects of gluten on intestinal tissue but by an abnormal immune response against gluten-derived peptides and the subsequent activation of mechanisms that damage the body’s own intestinal epithelium.
The pathogenesis of celiac disease involves two closely interconnected immunological processes. The first is an adaptive immune response directed specifically against gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules. The second is an innate immune response involving inflammatory signalling, particularly interleukin-15, and the activation of cytotoxic intraepithelial lymphocytes. The adaptive response establishes antigen-specific immune recognition and produces inflammatory mediators, whereas the innate immune response contributes directly to epithelial destruction. Their interaction creates a sustained inflammatory environment that progressively alters the normal architecture and functional organisation of the intestinal mucosa.
The pathological process begins with the ingestion of gluten-containing foods. Gluten is a complex mixture of storage proteins found predominantly in wheat, with related proteins occurring in barley and rye. Its principal components are gliadins and glutenins. Gliadins are particularly important in celiac disease because they contain relatively high concentrations of proline and glutamine residues. These amino acids influence the susceptibility of protein sequences to enzymatic degradation. Under normal physiological conditions, dietary proteins undergo progressive digestion through the combined action of gastric pepsin, pancreatic proteases and intestinal peptidases. However, certain gluten-derived sequences resist complete degradation because human gastrointestinal enzymes have limited capacity to cleave peptide bonds adjacent to proline residues. Consequently, relatively large peptide fragments remain in the intestinal lumen. One particularly important fragment is a 33-amino-acid peptide derived from alpha-gliadin, which contains several immunologically active sequences capable of stimulating gluten-specific immune responses. Such incomplete digestion also occurs in healthy individuals, but it does not normally produce disease. The development of celiac disease requires additional genetic and immunological conditions that permit these peptides to initiate an abnormal immune response.
The next important event involves the passage of gluten-derived peptides across the intestinal epithelial barrier. The intestinal epithelium consists primarily of a single layer of specialised cells connected by intercellular structures known as tight junctions. These junctions regulate the movement of molecules between adjacent epithelial cells and help maintain the selective permeability of the intestinal barrier. Gluten-derived peptides can reach the underlying mucosal immune compartment through paracellular and transcellular pathways. Paracellular transport involves movement between adjacent epithelial cells, whereas transcellular transport involves passage through epithelial cells by cellular uptake and transport mechanisms. Changes in epithelial barrier function may influence the accessibility of gluten peptides to the immune system. Zonulin, a protein associated with the regulation of tight-junction function, has been investigated in relation to intestinal permeability and celiac disease, although its precise contribution to human disease remains under investigation. Once gluten-derived peptides reach the lamina propria, the connective tissue layer beneath the intestinal epithelium, they encounter dendritic cells, macrophages and other immune cells capable of antigen processing and presentation.
One of the most important biochemical events in the pathogenesis of celiac disease is the enzymatic modification of gluten-derived peptides by tissue transglutaminase 2, commonly called TG2 or tTG. This enzyme belongs to the transglutaminase family and normally participates in several physiological processes, including protein cross-linking, extracellular matrix organisation, tissue repair and cellular signalling. In the intestinal mucosa, TG2 modifies selected glutamine residues in gliadin peptides through a reaction known as deamidation. During this process, the neutral glutamine side chain is converted into a negatively charged glutamate side chain. This modification changes the physicochemical properties of the peptide and increases its affinity for HLA-DQ2 and HLA-DQ8 molecules. The importance of deamidation lies in the fact that these HLA molecules possess peptide-binding grooves that favour negatively charged amino acid residues at particular positions. Consequently, deamidated gliadin peptides bind more effectively to HLA-DQ2 and HLA-DQ8 than many corresponding non-deamidated peptides. In this manner, an enzymatic modification transforms certain dietary protein fragments into more effective immunological antigens. TG2 can also catalyse transamidation, a distinct reaction involving the formation of covalent bonds between glutamine residues and primary amines, but deamidation is particularly important in enhancing the immunogenicity of gluten peptides.
The ability of deamidated gluten peptides to initiate an adaptive immune response depends substantially on genetic susceptibility. The strongest genetic association with celiac disease involves the human leukocyte antigen system, particularly HLA-DQ2 and HLA-DQ8. These molecules belong to the major histocompatibility complex class II family and are expressed primarily by professional antigen-presenting cells. Their physiological function is to bind peptides derived from extracellular proteins and present them to CD4-positive T lymphocytes. HLA-DQ2 and HLA-DQ8 consist of alpha and beta protein chains that together form a peptide-binding groove. The molecular structure of this groove determines which peptide sequences can bind effectively. Deamidated gliadin peptides possess particular amino acid sequences that fit favourably into these binding grooves, allowing them to be presented efficiently to gluten-specific T lymphocytes. Approximately 90–95% of patients with celiac disease carry HLA-DQ2.5, while most of the remaining patients carry HLA-DQ8 or other permissive HLA-DQ2 variants. However, the presence of these genetic variants does not automatically produce disease. They establish susceptibility by permitting effective presentation of particular gluten-derived peptides, while additional genetic and environmental factors influence whether an abnormal immune response actually develops.
Following antigen processing, dendritic cells and other antigen-presenting cells display deamidated gliadin peptides bound to HLA-DQ2 or HLA-DQ8 molecules on their surfaces. These peptide-HLA complexes are recognised by specific T-cell receptors present on CD4-positive T lymphocytes. The interaction between the antigen-presenting complex and the T-cell receptor, together with appropriate costimulatory signals, activates gluten-specific T lymphocytes. These cells proliferate and differentiate into effector populations that produce several inflammatory mediators, including interferon-gamma, tumour necrosis factor-alpha and interleukin-21. Interferon-gamma plays a particularly important role in promoting inflammation within the intestinal mucosa and influencing the functional behaviour of epithelial and immune cells. Tumour necrosis factor-alpha contributes to inflammatory signalling, cellular stress and tissue injury, while interleukin-21 supports adaptive immune responses and interactions between T lymphocytes and B lymphocytes. The combined activity of these cytokines creates an inflammatory environment that recruits additional immune cells and amplifies mucosal inflammation. Thus, the recognition of deamidated gluten peptides by genetically restricted antigen-presenting molecules initiates an antigen-specific adaptive immune response that becomes a major driving force in disease progression.
Although adaptive immunity is essential to the pathogenesis of celiac disease, the direct destruction of intestinal epithelial cells involves another important immunological mechanism associated with innate immunity. Among the molecules involved, interleukin-15 is particularly significant. IL-15 is a cytokine produced by several cell types, including intestinal epithelial cells and antigen-presenting cells. Its expression and signalling become abnormally increased in the intestinal mucosa of affected individuals. IL-15 promotes the survival, proliferation and cytotoxic activity of intraepithelial lymphocytes, which are immune cells normally located between the epithelial cells lining the intestinal mucosa. Under physiological conditions, these lymphocytes participate in immune surveillance and help protect the intestinal barrier against invading microorganisms and abnormal cells. In celiac disease, however, increased IL-15 signalling alters their functional behaviour and promotes enhanced cytotoxic activity. These lymphocytes express receptors associated with natural killer cell activity, particularly NKG2D, which recognises stress-associated ligands such as MICA and MICB expressed by intestinal epithelial cells. Inflammatory and cellular stress can increase the expression of these ligands, making epithelial cells more susceptible to immune-mediated destruction. The interaction between NKG2D and its ligands activates cytotoxic mechanisms within intraepithelial lymphocytes, resulting in the release of perforin, granzyme B and other molecules involved in cellular killing. Perforin facilitates the delivery of granzymes into target cells, where they activate intracellular pathways leading to cell death. Consequently, intestinal epithelial cells undergo apoptosis and other forms of cellular injury. This mechanism provides a direct link between inflammatory signalling and the progressive destruction of intestinal tissue.
The activation of B lymphocytes and the production of autoantibodies constitute another important component of celiac disease pathophysiology. Gluten-specific CD4-positive helper T lymphocytes provide signals that support B-cell activation, proliferation and differentiation into antibody-producing plasma cells. Some B lymphocytes recognise deamidated gliadin peptides through their surface immunoglobulin receptors, internalise these antigens, process them and present gliadin-derived peptides to gluten-specific helper T cells. This interaction provides the necessary T-cell help for antibody production. The resulting antibodies include those directed against deamidated gliadin peptides and tissue transglutaminase. Anti-tTG antibodies are particularly important because tissue transglutaminase is a major autoantigen in celiac disease. An interesting molecular mechanism involves the formation of complexes between gliadin and tissue transglutaminase. B lymphocytes recognising TG2 can internalise complexes containing both TG2 and gliadin and subsequently present gliadin-derived peptides to gluten-specific helper T lymphocytes. This provides a mechanism through which an immune response directed against a foreign dietary antigen can generate antibodies against a self-protein. This phenomenon is known as linked recognition. The resulting anti-TG2 antibodies are important diagnostic biomarkers, although their precise contribution to intestinal tissue destruction remains incompletely understood. The principal mechanisms responsible for villous injury are attributed primarily to cellular immune responses involving inflammatory T lymphocytes and cytotoxic intraepithelial lymphocytes.
The development of celiac disease also involves abnormalities in the mechanisms responsible for maintaining immune tolerance. Under normal physiological conditions, the immune system must distinguish between potentially harmful antigens and harmless dietary or environmental molecules. The gastrointestinal immune system is continuously exposed to numerous dietary proteins and microbial antigens, yet it normally prevents unnecessary destructive immune responses against these substances. Regulatory T lymphocytes, particularly CD4-positive CD25-positive FOXP3-positive cells, contribute to this process by suppressing excessive immune activation. Tolerogenic antigen-presenting cells and anti-inflammatory cytokines also participate in maintaining intestinal immune homeostasis. In celiac disease, gluten-specific immune responses escape normal regulation and become sustained. The precise mechanisms responsible for this loss of tolerance are not completely understood, but genetic susceptibility, antigen presentation, epithelial stress, inflammatory signalling and alterations in regulatory immune mechanisms may all contribute. Importantly, celiac disease is not simply a generalised failure of immune tolerance. It is a highly specific immune-mediated disorder in which particular gluten-derived peptides initiate an adaptive immune response, while associated innate immune mechanisms contribute to the destruction of intestinal tissue.
As the disease progresses, a complex network of inflammatory cytokines sustains and amplifies mucosal inflammation. Interferon-gamma, tumour necrosis factor-alpha, interleukin-15 and interleukin-21 are among the important mediators involved, although their relative contributions vary according to the cellular compartment and stage of disease. Interferon-gamma produced by activated gluten-specific T lymphocytes promotes inflammatory responses in the intestinal mucosa and influences epithelial and antigen-presenting cell functions. IL-15 activates intraepithelial lymphocytes and enhances their cytotoxic potential, thereby connecting the adaptive immune response with direct epithelial destruction. TNF-alpha contributes to inflammatory activity, cellular stress and alterations in epithelial function, while IL-21 supports adaptive immune responses, including B-cell differentiation and antibody production. Other chemokines and inflammatory mediators promote the recruitment of additional immune cells into the intestinal mucosa. These cytokines interact through interconnected signalling pathways, producing a sustained inflammatory environment that interferes with normal epithelial function and tissue regeneration. Consequently, the pathological process becomes self-amplifying as epithelial injury generates further cellular stress and inflammatory signalling.
The cumulative effects of inflammation, epithelial apoptosis and abnormal cellular regeneration produce the characteristic histopathological changes of celiac disease. The three major abnormalities are increased intraepithelial lymphocytes, crypt hyperplasia and villous atrophy. Under normal physiological conditions, the small intestinal mucosa contains numerous finger-like projections called villi, which considerably increase the available absorptive surface area. The intestinal crypts contain stem cells and proliferating epithelial precursor cells responsible for continuously replacing damaged or shed epithelial cells. Newly generated cells migrate towards the villus tips, differentiate into specialised absorptive enterocytes and eventually undergo normal cellular shedding. In celiac disease, persistent immune-mediated epithelial destruction increases the demand for cellular replacement. Consequently, crypt cells undergo increased proliferation, producing crypt hyperplasia. However, the continuing inflammatory environment interferes with normal epithelial differentiation and maturation. At the same time, activated intraepithelial lymphocytes accumulate within the epithelial layer, reflecting ongoing immune activity. Progressive epithelial injury and abnormal mucosal regeneration eventually result in shortening, flattening or complete disappearance of intestinal villi, a pathological change known as villous atrophy. In severe cases, the normal finger-like architecture of the intestinal mucosa becomes almost completely flattened. These structural changes can be classified using the Marsh-Oberhuber system, which describes the severity of lymphocytic infiltration, crypt hyperplasia and villous atrophy.
The destruction of normal villous architecture has profound consequences for intestinal absorption because the absorptive capacity of the small intestine depends on the extensive surface area and specialised metabolic functions of its epithelial cells. Enterocytes, the principal absorptive cells, possess numerous microvilli on their luminal surfaces, forming the brush border. These structures further increase the effective surface area and contain digestive enzymes and membrane transport proteins required for nutrient absorption. When villous architecture is damaged and epithelial differentiation becomes abnormal, several digestive and absorptive functions are impaired. Reduced brush-border enzyme activity can produce secondary lactose intolerance, particularly because lactase is expressed on mature villous enterocytes. Impaired fat absorption can result in steatorrhoea and deficiencies of fat-soluble vitamins. Iron absorption is particularly affected because it occurs predominantly in the duodenum and proximal jejunum, regions commonly involved in celiac disease. Damage to these regions can also reduce folate absorption and produce folate deficiency. Impaired calcium and vitamin D absorption can disturb bone metabolism, contributing to reduced bone mineral density and osteoporosis. More extensive intestinal injury may produce deficiencies of several other vitamins, minerals and nutrients, depending on the severity and duration of disease.
The consequences of celiac disease are not confined to the intestinal tract. Nutritional deficiencies and systemic immune effects can influence several organ systems. Iron deficiency may produce anaemia, fatigue, weakness and reduced exercise tolerance. Folate and vitamin B12 deficiencies can interfere with normal blood-cell production and neurological function. Calcium and vitamin D deficiency may impair bone mineralisation and stimulate secondary hyperparathyroidism as the body attempts to maintain normal circulating calcium concentrations. Neurological manifestations, including peripheral neuropathy and cerebellar ataxia, have been associated with celiac disease and may involve nutritional, metabolic and potentially immune-mediated mechanisms. Dermatitis herpetiformis is an important extraintestinal manifestation characterised by intensely itchy grouped papules and vesicles, commonly affecting the elbows, knees, buttocks and scalp. It is associated with IgA deposition in the dermal papillae and has a strong relationship with gluten exposure. Celiac disease is also associated with an increased prevalence of certain autoimmune disorders, particularly type 1 diabetes mellitus and autoimmune thyroiditis. These associations indicate that genetic predisposition and abnormalities in immune regulation may contribute to susceptibility to multiple autoimmune conditions.
Alterations in intestinal microbiota have also been investigated in relation to celiac disease. The intestinal microbiota consists of a complex community of microorganisms that participate in digestion, metabolism, immune regulation and maintenance of epithelial integrity. Differences in microbial composition have been reported between individuals with celiac disease and healthy controls. These alterations, commonly described as dysbiosis, may influence gluten peptide degradation, epithelial barrier function and mucosal immune signalling. However, their exact contribution to disease initiation remains uncertain. Dysbiosis may act as a contributing factor in some individuals, develop as a consequence of intestinal inflammation or represent a combination of both processes. Therefore, alterations in microbiota should not be regarded as an established primary cause of celiac disease.
The development of celiac disease is influenced by interactions among genetic and environmental factors. Although HLA-DQ2 and HLA-DQ8 represent the strongest genetic susceptibility factors, several non-HLA genes involved in immune regulation, T-cell activation, cytokine signalling and epithelial biology also contribute to disease susceptibility. Environmental influences, including gastrointestinal infections and factors affecting intestinal microbiota and immune maturation, have been investigated as potential modifiers of disease development. Certain infections may influence intestinal barrier function and mucosal immune responses, although no single infectious agent has been established as a universal trigger. The disease may become clinically apparent during childhood, adolescence or adulthood, indicating that genetic susceptibility does not determine the exact time of onset. Rather, celiac disease develops when dietary antigen exposure interacts with a permissive genetic background and an abnormal immune response.
The relationship between celiac disease and irritable bowel syndrome is particularly important in clinical practice because both conditions can produce abdominal pain, bloating, excessive gas and altered bowel habits. However, their underlying biological mechanisms are fundamentally different. Celiac disease is an immune-mediated disorder involving gluten-specific adaptive immunity and characteristic intestinal tissue injury. IBS is classified as a disorder of gut-brain interaction involving abnormalities in intestinal motility, visceral sensitivity, gastrointestinal sensory processing and communication between the enteric nervous system and the central nervous system. Patients with IBS may experience considerable abdominal discomfort despite the absence of characteristic villous atrophy or celiac-type immune-mediated intestinal destruction. Changes in intestinal microbiota, visceral hypersensitivity, altered intestinal permeability and post-infectious disturbances may contribute to IBS symptoms in different individuals. Some patients initially diagnosed with IBS may actually have undetected celiac disease, particularly when they present with chronic diarrhoea, unexplained iron-deficiency anaemia, weight loss or a family history of celiac disease. Non-celiac gluten sensitivity must also be distinguished from both conditions because individuals with this disorder report symptoms associated with gluten consumption without demonstrating the characteristic autoimmune response or intestinal histopathology of celiac disease. In some cases, symptoms attributed to gluten may instead be related to other wheat components, particularly fermentable carbohydrates called fructans.
The diagnosis of celiac disease reflects its underlying immunological mechanisms. The preferred initial serological investigation is the measurement of immunoglobulin A antibodies against tissue transglutaminase, commonly called anti-tTG IgA. Total serum IgA should also be measured because selective IgA deficiency is more prevalent among individuals with celiac disease and may produce false-negative results with IgA-based tests. In patients with IgA deficiency, IgG-based tests, including deamidated gliadin peptide IgG and tTG IgG, are useful alternatives. Endomysial IgA antibodies are another highly specific diagnostic marker. Upper gastrointestinal endoscopy with multiple duodenal biopsies is generally used to confirm the diagnosis in adults. The biopsy demonstrates increased intraepithelial lymphocytes, crypt hyperplasia and varying degrees of villous atrophy. Genetic testing for HLA-DQ2 and HLA-DQ8 can help resolve diagnostic uncertainty because the absence of the relevant permissive variants makes celiac disease very unlikely, although their presence alone cannot establish the diagnosis. An important precaution is that patients should continue consuming gluten until diagnostic investigations have been completed, because premature gluten withdrawal can reduce antibody concentrations and allow intestinal tissue to recover, potentially producing false-negative findings.
The established treatment for celiac disease is a strict, lifelong gluten-free diet. Removing gluten eliminates the principal dietary antigen responsible for initiating the abnormal immune response. When gluten exposure stops, stimulation of gluten-specific T lymphocytes gradually decreases, inflammatory cytokine production declines and the cytotoxic activity of intraepithelial lymphocytes progressively normalises. As the inflammatory environment subsides, the intestinal epithelium begins recovering through the normal processes of stem-cell proliferation, epithelial differentiation and cellular migration. Newly generated epithelial cells gradually replace damaged cells, crypt hyperplasia decreases and villous architecture begins to recover. Gastrointestinal symptoms may improve within weeks or months, although complete histological recovery can take considerably longer, particularly in older adults or individuals with severe intestinal damage. Follow-up evaluation includes clinical assessment, nutritional investigations and measurement of celiac antibody concentrations. Iron, folate, vitamin B12, calcium and vitamin D deficiencies should be corrected when present. In the Indian context, naturally gluten-free foods such as rice, ragi, jowar, bajra, maize, tapioca, pulses, vegetables, fish, meat and eggs can form the foundation of a balanced diet, provided cross-contamination with gluten-containing cereals is prevented.
A small proportion of patients continue to have symptoms and intestinal villous atrophy despite prolonged adherence to a strict gluten-free diet. This condition is called refractory celiac disease. Before making this diagnosis, clinicians must exclude continued inadvertent gluten exposure, an incorrect original diagnosis and other causes of persistent intestinal symptoms, including lactose intolerance, microscopic colitis, pancreatic insufficiency and small intestinal bacterial overgrowth. Refractory celiac disease requires specialist investigation because certain forms are associated with an increased risk of enteropathy-associated T-cell lymphoma. Untreated celiac disease is also associated with an increased risk of certain intestinal malignancies, particularly enteropathy-associated T-cell lymphoma and small intestinal adenocarcinoma, although these complications are uncommon.
From the perspective of molecular biology, celiac disease provides an especially informative example of the relationship between molecular structure, genetic susceptibility and immune recognition. Its pathogenesis demonstrates how a dietary protein can acquire pathological significance through enzymatic modification and interaction with genetically determined antigen-presenting molecules. The process begins with the persistence of certain gluten-derived peptides following incomplete gastrointestinal digestion. Tissue transglutaminase modifies selected peptide sequences through deamidation, changing their charge characteristics and increasing their affinity for HLA-DQ2 and HLA-DQ8. The resulting peptide-HLA complexes are recognised by specific T-cell receptors and initiate an antigen-specific immune response. This is followed by inflammatory cytokine production, activation of intraepithelial lymphocytes, epithelial cell destruction and progressive alteration of intestinal tissue architecture. The disease therefore involves a continuous sequence of molecular interactions extending from dietary protein structure to genetic antigen presentation, immune-cell activation and tissue-level pathology.
An important scientific distinction is that the immune response in celiac disease is not directed exclusively against a foreign dietary substance. The inflammatory process also involves the body’s own tissue structures, and autoantibodies against tissue transglutaminase become prominent diagnostic markers. Celiac disease thus illustrates how an immune response initiated by an external antigen can become associated with autoimmunity and chronic tissue injury. It also demonstrates that the biological effects of a molecule depend not merely on its chemical composition but on its molecular structure, modification, recognition and interaction with specific biological systems. The same gluten proteins that are harmless to most individuals can become potent immunological triggers in genetically susceptible individuals because of the particular molecular conditions governing antigen presentation and immune activation.
Ultimately, celiac disease is much more than a dietary intolerance or a simple digestive disorder. It is a genetically influenced, gluten-triggered, immune-mediated disease involving a complex interaction between dietary proteins, enzymatic modification, antigen-presenting molecules, T lymphocytes, inflammatory cytokines and intestinal epithelial cells. Its characteristic intestinal lesions result from the combined effects of adaptive immune activation and innate immune-mediated cytotoxicity. The disease provides a clear demonstration of how molecular recognition determines the difference between physiological tolerance and pathological immune activation, and how disturbances originating at the molecular and immunological levels can produce structural tissue damage, nutritional deficiencies and systemic clinical manifestations. Understanding its pathophysiology therefore requires an integrated approach combining molecular biology, genetics, immunology, gastrointestinal physiology and clinical medicine.
Role of Genetic Factors in Celiac Disease
Genetic factors play a fundamental role in the development of celiac disease by determining an individual’s susceptibility to an abnormal immune response against gluten-derived peptides. Celiac disease is not caused simply by the consumption of wheat, barley or rye. Millions of people consume these cereals throughout their lives without developing the disease. It occurs predominantly in individuals whose genetic constitution permits specific gluten-derived peptides to be recognised and presented to the immune system in a manner that initiates pathological inflammation. The genetic basis of celiac disease is particularly interesting because it demonstrates how variations in genes encoding immune-recognition molecules can influence the biological response to an otherwise harmless dietary protein. The most important genetic determinants are the human leukocyte antigen (HLA) class II molecules HLA-DQ2 and HLA-DQ8. These molecules determine the capacity of antigen-presenting cells to bind and present particular gluten-derived peptides to CD4-positive T lymphocytes. However, HLA genes do not explain the entire genetic susceptibility. Several non-HLA genes involved in T-cell activation, immune regulation, cytokine signalling, epithelial barrier function and inflammatory responses also contribute. The interaction of these genetic factors with environmental influences determines whether gluten exposure produces immune tolerance or pathological immune activation.
The strongest genetic association with celiac disease is found in the major histocompatibility complex region on chromosome 6, particularly the genes encoding HLA-DQ molecules. HLA molecules are cell-surface proteins involved in antigen presentation. Their principal function is to display peptide fragments derived from proteins to T lymphocytes, enabling the immune system to recognise foreign antigens and initiate appropriate immune responses. HLA-DQ molecules belong to the MHC class II family. Each molecule consists of two protein chains, an alpha chain and a beta chain, encoded by separate genes. These chains combine to form a molecular structure containing a peptide-binding groove. The structure and amino acid composition of this groove determine which peptide sequences can bind to the HLA molecule. This is particularly important in celiac disease because certain HLA-DQ variants possess a strong binding affinity for deamidated gluten peptides.
The two principal susceptibility molecules are HLA-DQ2 and HLA-DQ8. Approximately 90–95% of patients with celiac disease carry HLA-DQ2.5, while most of the remaining patients carry HLA-DQ8 or other permissive HLA-DQ2 variants. The importance of these molecules lies in their ability to present gluten-derived peptides to specific T-cell receptors. Without an appropriate HLA molecule, the characteristic gluten-specific adaptive immune response is extremely unlikely to develop. Nevertheless, the presence of these molecules indicates genetic susceptibility rather than an inevitable development of disease.
HLA-DQ2.5 is the most important genetic susceptibility variant associated with celiac disease. It is encoded by the combination of two alleles, HLA-DQA1*05, which encodes the alpha chain, and HLA-DQB1*02, which encodes the beta chain. The proteins produced by these genes combine to form the HLA-DQ2.5 molecule. The peptide-binding groove of HLA-DQ2.5 possesses particular structural properties that favour the binding of negatively charged amino acid residues at specific positions within gluten-derived peptides. This becomes especially important following the action of tissue transglutaminase 2 (TG2). TG2 converts selected glutamine residues in gliadin peptides into glutamate residues through deamidation. The resulting negatively charged peptides bind more effectively to HLA-DQ2.5. The peptide-HLA complexes are then recognised by gluten-specific CD4-positive T lymphocytes, initiating an adaptive immune response.
HLA-DQ2.5 can be inherited through different genetic arrangements. Individuals carrying the relevant alpha- and beta-chain alleles on the same chromosome have a cis configuration, while individuals inheriting them on different chromosomes may have a trans configuration. The number and arrangement of HLA-DQ2.5-associated alleles can influence susceptibility. Individuals carrying two copies of HLA-DQB1*02, particularly in certain genetic configurations, generally have a higher risk of developing celiac disease than individuals carrying a single copy. This illustrates how differences in the quantity and configuration of antigen-presenting molecules can influence the strength of gluten-specific immune responses.
HLA-DQ8 is the second major susceptibility molecule associated with celiac disease. It is generally encoded by HLA-DQA1*03, which produces the alpha chain, and HLA-DQB1*03:02, which produces the beta chain. Like HLA-DQ2.5, HLA-DQ8 can bind deamidated gluten-derived peptides and present them to CD4-positive T lymphocytes. Although its peptide-binding properties differ from those of HLA-DQ2.5, it is capable of presenting immunologically important gliadin sequences. The resulting activation of gluten-specific T lymphocytes initiates inflammatory cytokine production and contributes to the pathological immune response. HLA-DQ8 is particularly important because it explains the genetic susceptibility of a proportion of patients who do not carry the classical HLA-DQ2.5 combination. Other HLA-DQ2 configurations can also confer susceptibility, although their associated risks differ.
The relationship between HLA-DQ2, HLA-DQ8 and celiac disease can be understood through the molecular process of antigen presentation. In a genetically susceptible individual, gluten-derived peptides enter the intestinal mucosa and undergo modification by tissue transglutaminase. The modified peptides are taken up by antigen-presenting cells and loaded onto HLA-DQ2 or HLA-DQ8 molecules. The resulting peptide-HLA complexes are displayed on the cell surface, where they can be recognised by specific T-cell receptors. This recognition activates gluten-specific CD4-positive T lymphocytes, which proliferate and release inflammatory cytokines such as interferon-gamma and interleukin-21. These inflammatory mediators contribute to intestinal inflammation and interact with other immune mechanisms, particularly IL-15-dependent activation of cytotoxic intraepithelial lymphocytes. The result is progressive epithelial injury, crypt hyperplasia and villous atrophy.
Therefore, the primary genetic contribution of HLA-DQ2 and HLA-DQ8 is to establish the molecular conditions necessary for effective presentation of gluten-derived antigens to the adaptive immune system. It is important to recognise that these molecules do not directly cause intestinal injury. They establish susceptibility by determining the antigen-presenting properties of the immune system.
Although HLA genes account for the largest proportion of the genetic association with celiac disease, they explain only part of its overall heritability. Genome-wide association studies have identified numerous non-HLA genetic variants associated with disease susceptibility. Many of these genes participate in immune-cell development, T-cell activation, cytokine signalling, immune tolerance and intestinal epithelial function. Their contribution is generally smaller than that of HLA genes, but collectively they influence the probability that a genetically susceptible individual will develop the disease.
One important group of susceptibility genes involves the IL2 and IL21 region. IL-2 is essential for the proliferation and survival of activated T lymphocytes and for maintaining regulatory T-cell function. Regulatory T cells help prevent excessive immune activation and maintain tolerance towards harmless antigens. Genetic variations affecting IL2-related pathways may influence the balance between inflammatory T-cell responses and immune regulation. IL-21 is an important cytokine involved in T-cell and B-cell communication. It promotes B-cell differentiation and antibody production and contributes to the regulation of adaptive immune responses. Variations in the IL2/IL21 region may therefore influence the intensity and regulation of the immune response associated with celiac disease.
Another important gene is CTLA4, which encodes cytotoxic T-lymphocyte-associated protein 4, an inhibitory receptor expressed by activated T cells and regulatory T cells. CTLA-4 acts as a negative regulator of T-cell activation by competing with the stimulatory receptor CD28 for binding to CD80 and CD86 molecules on antigen-presenting cells. This inhibitory mechanism helps prevent excessive immune responses and maintains immune homeostasis. Genetic variations affecting CTLA4 expression or function may influence the effectiveness of immune regulation and contribute to susceptibility to autoimmune disorders, including celiac disease.
The PTPN22 gene is another important immune-regulatory susceptibility locus. It encodes a protein tyrosine phosphatase involved in regulating signalling through T-cell and B-cell receptors. By modifying the intensity of receptor-mediated signalling, PTPN22 influences lymphocyte activation and immune tolerance. Certain genetic variants of PTPN22 have been associated with several autoimmune conditions. Their relationship with celiac disease is more modest and population-dependent than the principal HLA associations, but they illustrate the importance of genetically controlled immune-cell signalling.
The SH2B3 gene, which encodes the adaptor protein LNK, also contributes to immune regulation. This protein participates in signalling pathways associated with haematopoietic cells and cytokine receptors. Variations in SH2B3 can influence immune-cell activation and inflammatory responses. Its association with celiac disease provides further evidence that susceptibility involves a network of genes regulating the behaviour of immune cells rather than a single antigen-presentation mechanism.
Genes involved in T-cell differentiation and cytokine signalling also contribute to disease susceptibility. Variations in genes associated with the IL-12 and IL-23 signalling pathways, for example, may influence the differentiation and functional behaviour of inflammatory T-cell populations. These pathways help regulate cytokine production and interactions between innate and adaptive immunity. Genetic variation affecting such mechanisms may modify the intensity and persistence of gluten-induced intestinal inflammation.
Genetic susceptibility is not limited to immune-cell function. Genes influencing intestinal epithelial biology and barrier integrity may also modify disease risk. The intestinal epithelium forms the first major biological barrier separating dietary antigens and microorganisms in the intestinal lumen from the underlying immune system. Its permeability, cellular integrity and capacity for repair influence the extent to which antigens gain access to mucosal immune cells.
Genes involved in epithelial differentiation, cellular adhesion, tight-junction regulation and tissue repair may therefore influence the local environment in which gluten-specific immune responses develop. Genetic variations affecting these functions could modify antigen accessibility, inflammatory signalling and the ability of the intestinal mucosa to recover from injury. However, no single epithelial barrier gene has been established as a primary determinant comparable to HLA-DQ2 and HLA-DQ8. The contribution of these genetic pathways is more complex and generally involves multiple interacting variants.
An important feature of celiac disease is the failure to maintain normal immune tolerance towards gluten-derived peptides. Under physiological conditions, the intestinal immune system must continuously distinguish between harmless dietary antigens and potentially dangerous foreign substances. This process involves regulatory T lymphocytes, tolerogenic antigen-presenting cells, anti-inflammatory cytokines and specialised mechanisms that prevent excessive lymphocyte activation.
Genetic variations affecting these regulatory mechanisms may reduce the ability of the immune system to suppress inappropriate inflammatory responses. For example, alterations in pathways involving IL-2, CTLA-4 and other immune-regulatory proteins may influence regulatory T-cell development, survival and suppressive activity. When these regulatory mechanisms are insufficient, gluten-specific immune activation may become sustained.
The interaction between antigen presentation and immune regulation is particularly important. HLA-DQ2 and HLA-DQ8 determine which gluten-derived peptides can be efficiently presented to T lymphocytes, while other genetic factors influence how strongly these lymphocytes respond and how effectively their activity is controlled. Consequently, the development of celiac disease reflects the combined effects of antigen recognition and the genetic regulation of immune responses.
Celiac disease demonstrates a significant familial and hereditary tendency. First-degree relatives of affected individuals, including parents, siblings and children, have a considerably higher risk of developing the disease than the general population. The risk is particularly elevated among siblings who share relevant susceptibility genes.
However, celiac disease does not follow a simple Mendelian inheritance pattern. It is a polygenic disorder in which multiple genetic variants contribute to susceptibility, and their effects are modified by environmental exposure and immune-system characteristics.
The inheritance of HLA-DQ2 or HLA-DQ8 does not guarantee that an individual will develop celiac disease. Many people carry these variants without ever developing the disorder. Conversely, almost all individuals with established celiac disease possess a permissive HLA background. Therefore, HLA testing is more useful for excluding celiac disease than for confirming it.
The familial distribution of celiac disease reflects the inheritance of susceptibility genes, particularly HLA variants, together with other genetic factors that influence immune regulation and intestinal function.
Although genetic susceptibility is essential, environmental exposure is also necessary for the development of celiac disease. Gluten is the principal environmental antigen responsible for initiating the characteristic immune response. Without exposure to gluten, the disease-specific immune reaction cannot be sustained.
Other environmental influences may modify the risk of developing the disease. Gastrointestinal infections, changes in intestinal microbiota and factors influencing epithelial barrier function have been investigated as possible contributors. Some infections may alter intestinal immune responses or epithelial permeability, potentially influencing the presentation of gluten-derived peptides to the immune system. However, the precise contribution of these factors to disease initiation remains under investigation.
The relationship between genes and environmental factors is therefore dynamic. Genetic variants establish the biological susceptibility, while environmental exposure provides the antigenic stimulus. The final outcome depends on how these factors interact with the individual’s immune regulatory mechanisms.
HLA-DQ2 and HLA-DQ8 testing has an important role in selected diagnostic situations. Because nearly all individuals with celiac disease carry permissive HLA variants, the absence of HLA-DQ2 and HLA-DQ8 makes the diagnosis extremely unlikely. This gives genetic testing a particularly high negative predictive value.
However, the presence of either genetic variant does not establish the diagnosis because these variants are relatively common in the general population. Genetic testing therefore cannot replace serological investigations or duodenal biopsy when these are indicated.
HLA testing can be particularly useful when previous investigations are inconclusive, when a patient has already started a gluten-free diet before diagnostic testing, or when there is uncertainty about whether an individual with a family history has the genetic susceptibility associated with celiac disease.
It is also useful in assessing selected individuals with other autoimmune conditions or unexplained gastrointestinal and nutritional abnormalities, although routine genetic screening of everyone carrying HLA-DQ2 or HLA-DQ8 is not generally recommended.
Genetic factors may influence not only the probability of developing celiac disease but also certain aspects of its clinical and immunological expression. The dosage and configuration of HLA-DQ2-associated alleles can influence the strength of gluten peptide presentation and the magnitude of the antigen-specific T-cell response. Individuals carrying two copies of HLA-DQB1*02 generally have a greater genetic susceptibility than those carrying a single copy.
However, the relationship between genotype and clinical severity is not straightforward. The extent of villous atrophy, degree of malabsorption, age of onset and extraintestinal manifestations cannot be reliably predicted from HLA genotype alone. These characteristics are influenced by additional genetic factors, gluten exposure, immune regulation, environmental influences and the duration of untreated disease.
Thus, genetic susceptibility determines an important part of the biological foundation of celiac disease, but it does not independently determine the complete clinical outcome.
Genetic factors play a central role in celiac disease by determining the molecular conditions under which gluten-derived peptides can initiate an abnormal immune response. HLA-DQ2 and HLA-DQ8 are the principal susceptibility molecules because their peptide-binding properties permit efficient presentation of deamidated gliadin peptides to gluten-specific CD4-positive T lymphocytes. This initiates adaptive immune activation, inflammatory cytokine production and interactions with innate immune mechanisms that ultimately damage the intestinal mucosa.
Beyond HLA genes, several non-HLA genetic variants involving IL2, IL21, CTLA4, PTPN22, SH2B3 and other immune-regulatory pathways contribute to the disease’s polygenic architecture. These genes influence lymphocyte activation, immune tolerance, cytokine signalling and inflammatory regulation. Additional genetic influences on intestinal epithelial function may also modify susceptibility.
The most important scientific conclusion is that celiac disease does not arise from a single defective gene. It develops through the interaction of multiple susceptibility genes with environmental gluten exposure and the biological mechanisms governing immune recognition and regulation. HLA genes determine the capacity for disease-specific antigen presentation, while other genetic factors influence the intensity, persistence and regulation of the resulting immune response. This makes celiac disease an important model of gene-environment interaction and genetically determined immune-mediated pathology.
A fundamental distinction: HLA-DQ2 and HLA-DQ8 are genetic susceptibility factors, not disease-causing mutations in the conventional sense. Their presence establishes a permissive molecular environment for gluten-specific immune activation, but additional genetic, immunological and environmental conditions are required for clinical disease to develop.
Role of Autoimmunity in Celiac Disease
Autoimmunity plays a central role in the pathogenesis of celiac disease, although the disease has a distinctive immunological characteristic: its autoimmune response is initiated by exposure to an external dietary antigen, namely gluten. Celiac disease is a chronic, gluten-dependent, immune-mediated disorder in which genetically susceptible individuals develop an abnormal immune response against gluten-derived peptides. This response involves both antigen-specific adaptive immunity and innate immune mechanisms, resulting in inflammation and destruction of the small intestinal mucosa. The autoimmune nature of celiac disease is particularly evident from the production of antibodies against tissue transglutaminase 2 (TG2), an enzyme naturally present in human tissues. The development of these autoantibodies demonstrates that an immune response initially directed against a foreign dietary protein becomes associated with recognition of a self-protein. However, the pathological process is more complex than conventional antibody-mediated autoimmune diseases. The principal mechanism responsible for intestinal villous destruction involves cellular immune responses, particularly gluten-specific CD4-positive T lymphocytes and cytotoxic intraepithelial lymphocytes. Therefore, celiac disease provides an important example of how an immune response against an environmental antigen can become associated with autoimmunity, loss of immunological tolerance and chronic destruction of the body’s own tissues.
Under normal physiological conditions, the immune system distinguishes between foreign antigens and the body’s own molecular structures. This capacity, known as immunological tolerance, prevents the immune system from mounting destructive responses against normal tissues. In celiac disease, this regulatory balance is disturbed. The initiating antigen is gluten, particularly certain gliadin-derived peptides. These peptides are not themselves components of human tissues. However, their interaction with tissue transglutaminase and the genetically determined antigen-presentation system initiates an abnormal immune response that eventually includes the production of autoantibodies against TG2.
This is an important distinction because the primary antigenic stimulus is dietary gluten, whereas tissue transglutaminase becomes a major target of the autoimmune response. The disease therefore involves two related but distinguishable immunological processes. The first is an adaptive immune response against gluten-derived peptides, and the second is an autoimmune response involving recognition of self-antigens, particularly tissue transglutaminase. The interaction between these processes contributes to chronic intestinal inflammation and tissue damage.
Tissue transglutaminase 2, commonly called TG2 or tTG, is a calcium-dependent enzyme belonging to the transglutaminase family. It is expressed in several human tissues and participates in biological processes such as extracellular matrix organisation, protein cross-linking, cellular signalling and tissue repair. In celiac disease, TG2 has a particularly important function because it modifies gluten-derived gliadin peptides through a reaction called deamidation. During this process, selected glutamine residues in gliadin are converted into negatively charged glutamate residues. This molecular modification increases the affinity of certain gliadin peptides for HLA-DQ2 and HLA-DQ8 molecules. Consequently, deamidated gliadin peptides are presented more efficiently to gluten-specific CD4-positive T lymphocytes.
The same enzyme that modifies gluten peptides subsequently becomes a target of the immune response. This is the molecular connection between gluten exposure and autoimmunity. TG2 participates in the generation of immunologically active gluten peptides, while the resulting immune response includes the production of antibodies against TG2 itself. It is important to recognise that TG2 is not an abnormal protein or a foreign substance. It is a normal human enzyme. Its recognition by the immune system as an autoantigen represents a breakdown of normal immunological tolerance.
One of the most characteristic features of celiac disease is the production of antibodies against tissue transglutaminase. These antibodies are predominantly of the IgA class and are commonly measured through the anti-tTG IgA blood test. They are among the most useful serological markers for diagnosing celiac disease. The development of these antibodies involves cooperation between B lymphocytes and gluten-specific CD4-positive helper T lymphocytes.
Certain B lymphocytes possess surface immunoglobulin receptors capable of recognising TG2. When TG2 is associated with gliadin peptides, these B lymphocytes can internalise the antigen complex. Inside the B lymphocyte, the complex undergoes processing, and gliadin-derived peptides are subsequently presented on HLA-DQ2 or HLA-DQ8 molecules to gluten-specific helper T lymphocytes. The activated T lymphocytes provide stimulatory signals and cytokines that promote B-cell proliferation and differentiation into plasma cells. These plasma cells produce antibodies directed against TG2.
This mechanism is known as linked recognition. The B lymphocyte recognises one component of an antigen complex, namely TG2, while the helper T lymphocyte recognises a peptide derived from another component, namely gliadin. The interaction allows an immune response against a foreign dietary antigen to support the production of antibodies against a normal self-protein. This is one of the most important molecular explanations for the development of autoimmunity in celiac disease.
The development of autoimmune responses involves abnormalities in the mechanisms that normally maintain tolerance towards self-antigens. Under physiological conditions, the immune system uses several mechanisms to prevent autoreactive lymphocytes from producing destructive immune responses. These include central tolerance, peripheral tolerance, regulatory T lymphocytes and inhibitory immune signalling pathways. Central tolerance develops during the maturation of T and B lymphocytes. Autoreactive lymphocytes are eliminated or modified through selection mechanisms in the thymus and bone marrow. Peripheral tolerance controls potentially autoreactive lymphocytes that escape central selection. Regulatory T lymphocytes, particularly CD4-positive CD25-positive FOXP3-positive cells, suppress excessive immune activation. Inhibitory receptors such as CTLA-4 also help regulate T-cell responses.
In celiac disease, gluten-specific immune responses become sustained despite the regulatory mechanisms that normally prevent unnecessary intestinal inflammation. The precise mechanisms responsible for this failure of tolerance are not completely understood. However, genetic susceptibility, antigen presentation, inflammatory signalling and abnormalities in regulatory immune responses all appear to contribute. An important feature is that the loss of tolerance is not necessarily a generalised breakdown of immune regulation. It is associated with a highly specific response to gluten-derived peptides and the subsequent development of autoantibodies against TG2.
Genetic susceptibility is essential to the development of the characteristic immune response. HLA-DQ2 and HLA-DQ8 are major histocompatibility complex class II molecules responsible for presenting extracellularly derived peptides to CD4-positive T lymphocytes. Their molecular structures allow them to bind deamidated gliadin peptides with relatively high affinity. When these peptides are presented to gluten-specific T lymphocytes, the cells become activated and produce inflammatory cytokines, including interferon-gamma, tumour necrosis factor and interleukin-21. These cytokines promote inflammation and support B-cell activation and antibody production.
Thus, HLA-DQ2 and HLA-DQ8 provide the genetic foundation for gluten-specific immune activation, while the subsequent interaction between B cells and helper T cells contributes to the development of autoantibodies against TG2. The presence of these HLA molecules alone does not produce autoimmunity. Gluten exposure and the appropriate immunological conditions are also necessary.
B lymphocytes are responsible for the antibody-producing component of the autoimmune response. In celiac disease, activated B cells differentiate into plasma cells that produce several classes of antibodies. The principal antibodies include anti-tTG IgA, endomysial IgA and antibodies against deamidated gliadin peptides. Anti-tTG antibodies are particularly important because they are directed against a normal human enzyme. Endomysial antibodies are also highly specific for celiac disease and are closely associated with the presence of antibodies recognising tissue transglutaminase.
These antibodies can be detected in the blood and provide evidence of an ongoing gluten-dependent immune response. However, the presence of autoantibodies does not mean that celiac disease is primarily an antibody-mediated tissue-destructive disorder. Although anti-TG2 antibodies may influence certain cellular and extracellular processes, the major mechanisms responsible for intestinal epithelial destruction involve T-cell-mediated inflammation and cytotoxic intraepithelial lymphocytes. This distinction is important when comparing celiac disease with autoimmune diseases in which autoantibodies directly interfere with receptor function or destroy target cells.
T lymphocytes are central to the tissue-destructive component of celiac disease. Gluten-specific CD4-positive T lymphocytes recognise deamidated gliadin peptides presented by HLA-DQ2 or HLA-DQ8 molecules. Their activation produces inflammatory cytokines, particularly interferon-gamma. These cytokines establish an inflammatory environment within the intestinal mucosa and promote the activation of other immune cells.
At the same time, interleukin-15 expression increases in the intestinal epithelium and underlying mucosal tissue. IL-15 promotes the activation and cytotoxic potential of intraepithelial lymphocytes. These lymphocytes express natural killer cell-associated receptors, particularly NKG2D, which recognise stress-associated ligands such as MICA and MICB on intestinal epithelial cells. The interaction activates cytotoxic pathways involving perforin and granzymes. These molecules damage epithelial cells and promote their death. The resulting epithelial destruction produces the characteristic histopathological abnormalities of celiac disease, including increased intraepithelial lymphocytes, crypt hyperplasia and villous atrophy. Thus, the autoimmune-associated tissue damage is primarily mediated by cellular immune mechanisms rather than by direct antibody attack alone.
The autoimmune and inflammatory processes in celiac disease are maintained by an interconnected network of cytokines. Interferon-gamma is one of the major inflammatory mediators produced by gluten-specific T lymphocytes. It promotes mucosal inflammation and influences the functional behaviour of epithelial and immune cells. Interleukin-15 plays an especially important role in innate immune activation by increasing the survival and cytotoxic activity of intraepithelial lymphocytes. Tumour necrosis factor-alpha contributes to inflammation and epithelial injury, while interleukin-21 supports adaptive immune responses and B-cell differentiation.
These cytokines interact through several intracellular signalling pathways, creating an inflammatory environment that promotes further immune-cell recruitment and epithelial damage. The persistence of gluten exposure continuously supplies the antigenic stimulus that maintains this response. Consequently, chronic inflammation continues until the principal dietary trigger is removed.
The interaction between adaptive immunity, autoantibody production and innate cytotoxic mechanisms eventually produces structural changes in the small intestinal mucosa. The normal intestinal mucosa contains numerous finger-like projections called villi, which increase the surface area available for nutrient absorption. In celiac disease, inflammatory cytokines and cytotoxic intraepithelial lymphocytes damage the epithelial cells covering these villi. As epithelial cells are destroyed, the intestinal crypts increase their proliferative activity in an attempt to replace the damaged cells. This produces crypt hyperplasia.
However, persistent inflammation interferes with normal epithelial differentiation and regeneration. The villi gradually become shortened and flattened, producing villous atrophy. The resulting reduction in absorptive surface area causes malabsorption of iron, folate, calcium, vitamin D, fats and other nutrients. The pathological changes therefore represent the cumulative consequences of chronic immune-mediated epithelial injury.
Autoimmunity and extraintestinal manifestations
Although the principal autoimmune-associated pathology occurs in the small intestine, celiac disease can produce manifestations in several other organs. Dermatitis herpetiformis is one of the most important extraintestinal manifestations. It is associated with granular IgA deposition in the dermal papillae, predominantly involving epidermal transglutaminase 3 (TG3). Patients develop intensely itchy grouped papules and vesicles, commonly on the elbows, knees, buttocks and scalp.
Neurological manifestations, including peripheral neuropathy and cerebellar ataxia, have also been associated with celiac disease. Their mechanisms may involve nutritional deficiencies, immune-mediated effects and other systemic consequences of chronic inflammation. Celiac disease is also associated with other autoimmune conditions, particularly type 1 diabetes mellitus and autoimmune thyroiditis. These associations suggest shared genetic and immunological susceptibility rather than necessarily indicating that celiac disease directly causes those disorders. The systemic manifestations demonstrate that the immune consequences of celiac disease are not confined to the intestinal mucosa.
This question deserves particular scientific consideration. Celiac disease is generally classified as an immune-mediated disease with a well-established autoimmune component. It has several features commonly associated with autoimmune disorders, including genetic susceptibility, antigen-specific T-cell responses, loss of tolerance towards a self-antigen and the production of autoantibodies.
However, it differs from many conventional autoimmune diseases because its principal initiating antigen is an external dietary protein. In classical autoimmune diseases such as autoimmune thyroiditis, the immune response is primarily directed against self-antigens. In celiac disease, gluten-derived peptides initiate the immune response, while tissue transglutaminase becomes an important target of the associated autoimmune response. Furthermore, the disease is dependent on continued gluten exposure. Removal of gluten generally leads to a decline in antibody levels and gradual recovery of the intestinal mucosa.
Therefore, the most scientifically appropriate description is that celiac disease is a gluten-dependent, immune-mediated systemic disorder characterised by a highly specific autoimmune response. It is not simply an ordinary food intolerance, nor is it identical to conventional organ-specific autoimmune diseases.
It is important to distinguish the autoimmune mechanism of celiac disease from other adverse reactions to wheat and gluten. In wheat allergy, the immune response is generally mediated by allergen-specific IgE antibodies. Exposure can produce immediate hypersensitivity reactions, including urticaria, respiratory symptoms, gastrointestinal disturbances and, in severe cases, anaphylaxis. The mechanism involves allergic recognition rather than the characteristic HLA-restricted autoimmune response of celiac disease.
In non-celiac gluten sensitivity, individuals experience symptoms associated with gluten-containing foods but lack the characteristic serological and histopathological findings of celiac disease. Its underlying mechanisms remain incompletely understood and may involve gluten, wheat fructans or other dietary components. Celiac disease differs from both because it involves gluten-specific T-cell activation, an autoimmune response against tissue transglutaminase and characteristic small intestinal mucosal injury.
The dependence of celiac disease on gluten exposure is particularly important in understanding its autoimmune mechanism. When gluten is eliminated from the diet, the supply of immunologically active gliadin peptides decreases. Consequently, the stimulation of gluten-specific T lymphocytes progressively diminishes. As the antigenic stimulus declines, inflammatory cytokine production decreases and the activation of cytotoxic intraepithelial lymphocytes gradually subsides.
The production of anti-tTG antibodies also declines over time. Existing antibody-producing plasma cells and circulating antibodies may persist for some time, so the autoimmune response does not disappear immediately. With the reduction in inflammatory activity, intestinal epithelial cells begin to recover. Crypt hyperplasia gradually decreases, villous architecture is restored and nutrient absorption improves. However, complete histological recovery may take months or longer, particularly in adults and older patients. The recovery following gluten withdrawal provides strong evidence that gluten is the principal environmental antigen sustaining the pathological immune response. Patients with confirmed celiac disease must nevertheless maintain a strict lifelong gluten-free diet, even if their symptoms disappear and their antibody levels become normal.
The pathogenesis of celiac disease can be understood as a sequence of interconnected immunological events. The process begins when incompletely digested gluten-derived peptides enter the intestinal mucosa. Tissue transglutaminase modifies selected gliadin peptides through deamidation, increasing their affinity for HLA-DQ2 or HLA-DQ8 molecules. These modified peptides are presented to gluten-specific CD4-positive T lymphocytes, which become activated and produce inflammatory cytokines.
The activated T cells also provide help to B lymphocytes, which recognise TG2-gliadin complexes and differentiate into plasma cells producing antibodies against tissue transglutaminase. Simultaneously, increased IL-15 signalling activates cytotoxic intraepithelial lymphocytes, which damage intestinal epithelial cells through perforin- and granzyme-mediated mechanisms. The combined effects of adaptive immune activation, autoantibody production and innate cytotoxicity result in chronic mucosal inflammation, crypt hyperplasia and villous atrophy.
This sequence illustrates how an immune response initiated by an external antigen can become associated with autoimmunity and the destruction of the body’s own tissue.
Autoimmunity is an essential component of celiac disease pathophysiology. Its development begins with an abnormal immune response to gluten-derived peptides in genetically susceptible individuals and subsequently involves the recognition of tissue transglutaminase as a self-antigen. The production of anti-tTG antibodies represents an important manifestation of this autoimmune process, while the principal mechanisms of intestinal tissue destruction involve gluten-specific CD4-positive T lymphocytes, inflammatory cytokines and cytotoxic intraepithelial lymphocytes.
The disease therefore demonstrates a complex relationship between external antigen exposure, genetic susceptibility, antigen presentation, loss of immune tolerance, autoantibody production and cellular tissue destruction. Unlike many conventional autoimmune diseases, its principal environmental trigger is identifiable and can be eliminated through dietary intervention.
The most important scientific insight is that celiac disease is not merely an autoimmune reaction against a self-protein, nor is it simply an immune reaction against a dietary protein. It represents an integrated pathological process in which an external antigen initiates a genetically restricted immune response that becomes associated with autoimmunity and chronic destruction of intestinal tissue.
Role of Phytochemicals in Celiac Disease
Phytochemicals are biologically active chemical compounds produced by plants that participate in their growth, defence and interaction with the environment. Many of these compounds possess antioxidant, anti-inflammatory, immunomodulatory, antimicrobial and cytoprotective properties. In recent years, their potential role in several chronic inflammatory and immune-mediated diseases has attracted considerable scientific interest. Celiac disease is one condition in which phytochemicals deserve investigation because its pathogenesis involves multiple interconnected processes, including gluten-induced immune activation, oxidative stress, inflammatory cytokine production, intestinal epithelial injury, altered intestinal permeability and disturbances in mucosal immune regulation.
Celiac disease is a genetically influenced, gluten-dependent immune-mediated disorder characterised by an abnormal response to gluten-derived peptides in individuals carrying permissive HLA-DQ2 or HLA-DQ8 molecules. The disease involves activation of gluten-specific CD4-positive T lymphocytes, production of inflammatory cytokines, activation of cytotoxic intraepithelial lymphocytes and the development of autoantibodies against tissue transglutaminase. These mechanisms ultimately produce intestinal inflammation, crypt hyperplasia and villous atrophy. Although a strict lifelong gluten-free diet remains the established treatment, the persistence of inflammation, nutritional deficiencies and incomplete mucosal recovery in some patients has stimulated interest in complementary therapeutic approaches. Phytochemicals are being investigated for their potential to influence several molecular pathways involved in intestinal inflammation and tissue injury. Their possible benefits include suppression of inflammatory signalling, reduction of oxidative stress, modulation of immune-cell activity, protection of intestinal epithelial cells and regulation of the intestinal microbiota.
However, an important distinction must be maintained between established clinical treatment and experimental therapeutic possibilities. At present, no phytochemical has been demonstrated to replace gluten exclusion or reliably prevent the autoimmune response to gluten in patients with celiac disease. Most evidence concerning phytochemicals comes from cell cultures, experimental animal models and broader studies of intestinal inflammation rather than definitive clinical trials in celiac disease.
One of the major pathological features of celiac disease is chronic inflammation of the small intestinal mucosa. The inflammatory response develops following the presentation of deamidated gluten peptides by HLA-DQ2 or HLA-DQ8 molecules to gluten-specific CD4-positive T lymphocytes. Activated T cells release inflammatory cytokines, particularly interferon-gamma, tumour necrosis factor-alpha and interleukin-21. At the same time, increased interleukin-15 signalling promotes the activation of cytotoxic intraepithelial lymphocytes, which damage intestinal epithelial cells.
Several phytochemicals possess the capacity to influence intracellular signalling pathways involved in inflammatory cytokine production. Particularly important are the nuclear factor kappa B pathway, commonly called NF-κB, and the mitogen-activated protein kinase pathways, including p38 MAPK, JNK and ERK. These signalling systems regulate the expression of inflammatory cytokines, chemokines, adhesion molecules and other mediators involved in tissue inflammation. Certain plant-derived polyphenols have demonstrated the ability to suppress excessive activation of NF-κB and reduce the expression of inflammatory mediators in experimental systems. Such actions could theoretically reduce the inflammatory environment in the intestinal mucosa. However, suppressing general inflammatory signalling is not equivalent to eliminating the gluten-specific immune response. The antigen-specific T-cell response that characterises celiac disease may persist even if some downstream inflammatory pathways are modified.
Flavonoids constitute a large group of plant polyphenols present in fruits, vegetables, tea, herbs and medicinal plants. Important members include quercetin, luteolin, apigenin, kaempferol and catechins. These compounds possess antioxidant and anti-inflammatory properties and have been investigated for their effects on immune-cell signalling.
Quercetin is present in onions, apples, berries and several vegetables. Experimental studies have demonstrated that it can influence NF-κB activation, inflammatory cytokine production and oxidative stress pathways. It may also influence mast-cell activity and certain immune-cell responses. In the context of celiac disease, these properties provide a theoretical basis for investigating its ability to reduce secondary intestinal inflammation. However, direct evidence that quercetin prevents gluten-specific T-cell activation or reverses celiac-associated villous atrophy in humans is insufficient.
Luteolin and apigenin, found in several vegetables, herbs and plant leaves, have also demonstrated anti-inflammatory effects in experimental models. They can influence inflammatory signalling pathways and the expression of cytokines involved in immune responses. Their possible relevance to celiac disease lies in their capacity to modulate inflammatory processes rather than their ability to eliminate the initiating gluten antigen.
Catechins, particularly epigallocatechin gallate (EGCG) from green tea, have been studied for their antioxidant and anti-inflammatory activities. Experimental research indicates that EGCG can influence NF-κB signalling, oxidative stress and cellular survival pathways. These actions may be relevant to the protection of intestinal epithelial cells against inflammatory injury, although clinical efficacy in celiac disease has not been established.
Curcumin is a polyphenolic compound derived from the rhizome of turmeric (Curcuma longa), a plant widely used in Indian traditional medicine and cuisine. It has attracted considerable scientific attention because of its antioxidant, anti-inflammatory and immunomodulatory properties. Curcumin influences several molecular signalling pathways, including NF-κB, MAPK and certain inflammatory enzyme systems. Experimental studies have shown that it can reduce the expression of inflammatory mediators such as TNF-alpha, IL-1 beta and IL-6 in different models of inflammation.
Another important property is its ability to influence oxidative stress by modifying the activity of cellular antioxidant systems. Curcumin has been investigated for its effects on nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates the expression of several antioxidant and cytoprotective proteins. In the context of celiac disease, these mechanisms suggest a possible role in reducing secondary inflammatory injury and protecting intestinal epithelial cells. However, there is no convincing clinical evidence that curcumin suppresses the fundamental gluten-specific autoimmune response or restores intestinal villi in patients with celiac disease. Its poor absorption, rapid metabolism and variable bioavailability also limit the translation of experimental findings into clinical treatment.
Resveratrol is a polyphenolic compound found in grapes, berries, peanuts and certain other plants. It has been extensively investigated for its antioxidant, anti-inflammatory and metabolic effects. One of its important molecular targets is the sirtuin family of proteins, particularly SIRT1, which participates in cellular metabolism, stress responses, mitochondrial function and inflammatory regulation. Resveratrol has also been investigated for its effects on AMPK, NF-κB and Nrf2-related signalling pathways.
In experimental systems, resveratrol can influence oxidative stress, inflammatory cytokine production and cellular survival. These properties suggest possible relevance to the protection of intestinal epithelial cells against chronic inflammatory injury. However, its role in celiac disease remains experimental. There is insufficient clinical evidence to establish that resveratrol improves intestinal histology, reduces anti-tTG antibody concentrations or prevents disease progression in affected individuals.
Sulforaphane is an isothiocyanate derived from glucoraphanin, a compound found particularly in broccoli sprouts and other cruciferous vegetables. Its most important biological action involves activation of the Nrf2 pathway. Under normal conditions, Nrf2 is regulated by the protein KEAP1, which promotes its degradation. Certain electrophilic compounds, including sulforaphane, modify the KEAP1 regulatory system, allowing Nrf2 to accumulate and activate antioxidant-response genes.
These genes promote the production of several protective enzymes, including glutathione-related enzymes, NAD(P)H quinone dehydrogenase 1 and heme oxygenase-1. Through this mechanism, sulforaphane can enhance the cellular capacity to manage oxidative stress and protect tissues against inflammatory injury. Oxidative stress may contribute to intestinal epithelial damage in celiac disease, particularly through the production of reactive oxygen species by activated immune cells. Therefore, Nrf2 activation represents an interesting potential mechanism for reducing secondary tissue injury. Nevertheless, the ability of sulforaphane to improve celiac disease outcomes has not been established through adequate clinical trials.
Oxidative stress is another biological process that may contribute to intestinal tissue injury in celiac disease. It develops when the production of reactive oxygen species exceeds the capacity of cellular antioxidant defence mechanisms. Activated inflammatory cells can generate reactive oxygen species, which interact with cellular lipids, proteins and nucleic acids. Excessive oxidative stress can damage cellular membranes, alter mitochondrial function, influence intracellular signalling and promote epithelial cell death.
Several phytochemicals possess antioxidant properties that may influence this process. Polyphenols from fruits, vegetables, tea and medicinal plants can act through different mechanisms, including modulation of antioxidant enzymes, regulation of Nrf2 signalling, reduction of inflammatory ROS production and interaction with cellular redox systems. An important example is the relationship between polyphenols and glutathione metabolism. Glutathione is one of the major intracellular antioxidant molecules. It participates in the neutralisation of reactive oxygen species and the maintenance of cellular redox balance. Some phytochemicals influence the expression of enzymes involved in glutathione synthesis and recycling, potentially strengthening the antioxidant capacity of intestinal epithelial cells.
However, antioxidant activity observed in laboratory experiments does not necessarily translate into therapeutic efficacy in celiac disease. Reactive oxygen species also participate in normal immune signalling, and indiscriminate suppression of oxidative processes could interfere with physiological immune functions. The therapeutic objective would therefore be the regulation of excessive oxidative stress rather than the complete elimination of reactive oxygen species.
Anthocyanins are water-soluble flavonoid pigments responsible for the red, purple and blue colours of many fruits and vegetables. They are particularly abundant in blueberries, blackberries, black grapes, cherries, purple cabbage and certain varieties of coloured rice. Anthocyanins have demonstrated antioxidant and anti-inflammatory properties in several experimental models. They can influence inflammatory signalling pathways, regulate oxidative stress and modify the activity of certain enzymes involved in cellular protection.
One area of interest is their potential effect on intestinal epithelial integrity. Experimental studies suggest that some anthocyanins and their metabolites can influence tight-junction proteins, epithelial inflammatory signalling and intestinal barrier function. The intestinal barrier is particularly important in celiac disease because it regulates the interaction between dietary antigens and the underlying mucosal immune system. Maintaining epithelial integrity may help limit secondary tissue injury and preserve normal intestinal homeostasis. However, the relationship between anthocyanins and gluten-induced intestinal immune activation remains insufficiently investigated. There is no established evidence that anthocyanin consumption prevents the characteristic autoimmune response in celiac disease.
Terpenoids constitute a large group of plant-derived compounds found in essential oils, herbs, spices and medicinal plants. Carotenoids such as beta-carotene, lutein and lycopene are particularly important because of their antioxidant properties. They occur in carrots, tomatoes, green leafy vegetables and other coloured plant foods. Lycopene has been investigated for its ability to regulate oxidative stress and inflammatory signalling. Lutein and beta-carotene contribute to antioxidant defence and may influence cellular responses to oxidative injury.
Some other terpenoids, including ursolic acid and oleanolic acid, have also demonstrated anti-inflammatory effects in experimental models. They can influence NF-κB and MAPK signalling pathways and may modify inflammatory cytokine production. In celiac disease, the possible relevance of these compounds lies mainly in their potential to protect intestinal cells from secondary inflammatory and oxidative damage. Nevertheless, their disease-specific therapeutic effects have not been established.
Garlic, onions and several other edible plants contain organosulfur compounds that possess antioxidant and biological signalling activities. Allicin and related sulfur-containing compounds derived from garlic have been investigated for their antimicrobial, antioxidant and anti-inflammatory properties. Some experimental studies indicate that these compounds can influence inflammatory signalling, oxidative stress and microbial growth.
Sulforaphane, discussed earlier, is another important organosulfur-related phytochemical derived from cruciferous vegetables. Its ability to activate Nrf2-mediated antioxidant defence makes it particularly interesting from the perspective of cellular protection. In celiac disease, these compounds may theoretically influence secondary inflammatory processes and intestinal microbial ecology. However, there is no established clinical evidence that garlic-derived organosulfur compounds or sulforaphane can prevent gluten-induced immune activation or replace a gluten-free diet.
One of the potentially important areas of phytochemical research in celiac disease is the regulation of intestinal epithelial barrier function. The intestinal epithelium is maintained by a complex network of tight-junction proteins, including occludin, claudins and zonula occludens proteins. These structures regulate the movement of substances between adjacent epithelial cells. In celiac disease, inflammatory mediators and epithelial stress can alter intestinal barrier function. This may facilitate the interaction of gluten-derived peptides with the underlying mucosal immune system.
Certain phytochemicals have demonstrated the capacity to influence tight-junction protein expression and epithelial integrity in experimental models. Quercetin, curcumin, resveratrol and some anthocyanins have been investigated in this context. Their potential effects involve the regulation of intracellular signalling pathways, reduction of oxidative stress and modulation of inflammatory cytokines. By influencing these mechanisms, phytochemicals may help preserve epithelial integrity under inflammatory conditions. However, the intestinal barrier abnormalities observed in celiac disease should not be regarded as the sole cause of the disorder. Genetic antigen presentation and gluten-specific adaptive immunity are fundamental to its pathogenesis. Improving epithelial barrier function alone would not eliminate the disease-specific immune response.
The intestinal microbiota plays an important role in digestion, metabolism, immune regulation and maintenance of intestinal homeostasis. It consists of a complex community of bacteria and other microorganisms that interact continuously with intestinal epithelial cells and mucosal immune mechanisms. Alterations in microbial composition, commonly called dysbiosis, have been reported in individuals with celiac disease. However, it is not yet clear whether these alterations are primary contributors to disease development or secondary consequences of gluten-induced intestinal inflammation, dietary changes and other factors.
Many phytochemicals interact with the intestinal microbiota. Some polyphenols are poorly absorbed in the upper gastrointestinal tract and reach the colon, where intestinal microorganisms metabolise them into smaller biologically active compounds. Conversely, the microbiota can modify the chemical structure and biological availability of phytochemicals. This creates a bidirectional relationship between plant-derived compounds and intestinal microorganisms.
Certain polyphenols may influence the relative abundance of microbial populations, microbial metabolic activity and the production of short-chain fatty acids. These fatty acids, particularly butyrate, are important for colonocyte metabolism, epithelial barrier function and regulatory immune mechanisms. Butyrate can also influence histone deacetylase activity and promote regulatory T-cell differentiation under appropriate biological conditions. This relationship provides a possible mechanism through which dietary phytochemicals may influence intestinal immune homeostasis. Nevertheless, the relevance of these effects to the gluten-specific autoimmune response in celiac disease requires further investigation.
Regulatory T lymphocytes are essential for maintaining immunological tolerance and preventing excessive immune responses. They are characterised by the expression of CD4, CD25 and the transcription factor FOXP3. Their principal function is to suppress inappropriate immune activation through several mechanisms, including inhibitory cytokine production, modulation of antigen-presenting cells and suppression of effector T-cell activity. In celiac disease, gluten-specific T lymphocytes become activated despite the mechanisms that normally maintain tolerance towards dietary antigens.
Some phytochemicals have demonstrated immunomodulatory properties that may influence regulatory T-cell activity in experimental systems. Curcumin, resveratrol and certain flavonoids have been investigated for their effects on regulatory T cells, inflammatory T-cell differentiation and cytokine production. For example, resveratrol can influence SIRT1-related signalling, while curcumin can modify several inflammatory pathways. Certain polyphenols may also influence the balance between inflammatory T-cell populations and regulatory T-cell activity.
These findings raise the possibility that phytochemicals could influence the immunological environment associated with celiac disease. However, it has not been established that any of these compounds can restore gluten-specific immune tolerance in affected patients. This distinction is crucial because increasing regulatory immune activity in a general experimental model does not necessarily mean that the specific pathological immune response against gluten will disappear.
NF-κB is one of the most important transcriptional regulators of inflammatory responses. It controls the expression of numerous genes involved in cytokine production, cellular survival, immune activation and inflammatory signalling. In resting cells, NF-κB is generally retained in the cytoplasm through its association with inhibitory proteins called IκBs. Inflammatory stimulation activates the IκB kinase complex, resulting in phosphorylation and degradation of IκB proteins. NF-κB can then enter the nucleus and regulate the transcription of inflammatory genes.
Several phytochemicals have demonstrated the ability to influence this pathway. Curcumin, quercetin, EGCG and resveratrol have all been investigated for their effects on NF-κB signalling in experimental systems. Their actions may involve inhibition of upstream signalling molecules, modification of oxidative stress pathways and regulation of inflammatory gene expression. Because NF-κB participates in the production of inflammatory mediators, its modulation may help reduce secondary intestinal inflammation. However, NF-κB also participates in normal immune defence, cell survival and tissue repair. Therefore, its complete inhibition would not be desirable. The potential therapeutic objective would be selective regulation of excessive inflammatory signalling while preserving normal immune and epithelial functions.
The Nrf2 pathway is another important molecular target of phytochemicals. Nrf2 is a transcription factor that regulates the expression of genes involved in antioxidant defence, detoxification and cellular protection. Under normal conditions, Nrf2 is controlled by KEAP1, which promotes its degradation. When cells encounter certain oxidative or electrophilic stresses, the KEAP1 regulatory mechanism is modified, allowing Nrf2 to accumulate and enter the nucleus. It then binds to antioxidant response elements in DNA and promotes the expression of protective genes.
These genes include those encoding heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 and several enzymes involved in glutathione metabolism. Sulforaphane, curcumin and certain polyphenols have been investigated as modulators of this pathway. In celiac disease, Nrf2 activation is potentially relevant because intestinal epithelial cells are exposed to inflammatory and oxidative stress. Increasing cellular antioxidant capacity could theoretically improve resistance to secondary inflammatory injury. However, Nrf2 activation cannot be considered a treatment for the primary gluten-dependent autoimmune mechanism.
Restoration of intestinal villous architecture is an important objective in the management of celiac disease. The intestinal epithelium possesses a remarkable regenerative capacity. Stem cells located within the crypts continuously produce new epithelial cells, which migrate towards the villi and differentiate into specialised absorptive cells. In celiac disease, persistent inflammatory injury interferes with this process. Crypt hyperplasia develops as a compensatory response, while the normal differentiation and maturation of epithelial cells become disturbed.
Certain phytochemicals have demonstrated cytoprotective and tissue-repair-related effects in experimental models. Their actions may involve modulation of oxidative stress, mitochondrial function, inflammatory signalling and epithelial survival pathways. However, it is important to distinguish general epithelial protection from actual restoration of celiac-associated villous atrophy. There is currently insufficient clinical evidence that phytochemicals independently restore normal villous architecture in patients who continue to consume gluten. The primary requirement for intestinal healing remains the removal of gluten from the diet.
Several phytochemical groups are of particular interest because of their biological effects on inflammation, oxidative stress and epithelial protection. Quercetin, found in onions, apples and berries, has been investigated for its antioxidant properties and its ability to influence NF-κB signalling. Curcumin from turmeric has demonstrated anti-inflammatory and Nrf2-related activities in experimental systems. Resveratrol, found in grapes and berries, influences SIRT1, AMPK and inflammatory signalling pathways. Epigallocatechin gallate from green tea possesses antioxidant and anti-inflammatory properties. Sulforaphane from broccoli sprouts activates Nrf2-mediated cellular defence. Luteolin and apigenin from vegetables and herbs have been investigated for their effects on inflammatory signalling and immune regulation. Anthocyanins from blueberries, black grapes and purple vegetables have demonstrated antioxidant and epithelial-protective properties, while lycopene from tomatoes contributes to antioxidant defence. Ursolic acid, found in apple peel and several medicinal plants, has also shown experimental anti-inflammatory activity.
These compounds should be understood as research candidates rather than established treatments for celiac disease. Their biological activities are not necessarily specific to gluten-induced autoimmunity, and the concentrations producing beneficial effects in experimental systems may not be achievable through ordinary dietary consumption.
Phytochemicals offer an interesting field of investigation in celiac disease because they can influence several biological pathways involved in intestinal inflammation, oxidative stress, immune regulation, epithelial barrier function and microbial homeostasis. Compounds such as quercetin, curcumin, resveratrol, epigallocatechin gallate, sulforaphane and anthocyanins have demonstrated various antioxidant, anti-inflammatory and cytoprotective properties in experimental systems. Their potential relevance lies primarily in modifying secondary pathological processes associated with gluten-induced intestinal injury.
From a molecular perspective, their possible actions involve modulation of NF-κB and MAPK inflammatory signalling, activation of Nrf2-mediated antioxidant defence, regulation of glutathione metabolism, influence on regulatory T-cell activity and interactions with the intestinal microbiota. These mechanisms provide several scientifically plausible avenues for future investigation.
Nevertheless, it is essential to distinguish the modulation of inflammation from the elimination of its initiating cause. Celiac disease is fundamentally a gluten-dependent, genetically restricted immune-mediated disorder. Phytochemicals may potentially influence the severity of secondary inflammation and support cellular protection, but there is currently no reliable clinical evidence that they can suppress the specific gluten-driven autoimmune response or replace strict gluten exclusion.
The most promising direction for future research is therefore to investigate whether selected phytochemicals, used alongside a strict gluten-free diet, can improve intestinal epithelial recovery, reduce oxidative stress, support immune homeostasis and enhance long-term mucosal health. Such research should combine molecular investigations, controlled experimental models and properly designed clinical trials before any therapeutic recommendations are made.
Role of Vitamins in Celiac Disease
Vitamins play an important role in the development, clinical manifestations, recovery and long-term management of celiac disease. Although celiac disease is primarily an immune-mediated disorder triggered by gluten, its consequences extend far beyond the intestinal immune system. The characteristic inflammation and structural damage of the small-intestinal mucosa interfere with the absorption of several essential nutrients, particularly vitamins. Consequently, vitamin deficiencies may become important contributors to the systemic manifestations of celiac disease, including anaemia, osteoporosis, neurological disturbances, muscle weakness, impaired immunity, skin abnormalities and reproductive problems.
The relationship between celiac disease and vitamins is bidirectional in a broader physiological sense. Intestinal damage causes vitamin malabsorption, while deficiencies of certain vitamins can further compromise epithelial integrity, immune regulation, antioxidant protection, bone metabolism and tissue repair. Correcting these deficiencies is therefore an important component of comprehensive treatment. However, vitamin supplementation cannot eliminate the underlying gluten-dependent immune reaction. The fundamental treatment remains a strict, lifelong gluten-free diet.
The principal mechanism responsible for vitamin deficiencies in celiac disease is damage to the small-intestinal mucosa. In healthy individuals, the inner surface of the small intestine contains numerous finger-like projections called villi. These structures, together with microscopic microvilli on the surface of epithelial cells, greatly increase the absorptive surface area. Nutrients released during digestion are absorbed through this extensive epithelial surface and transported into the blood or lymphatic circulation.
In active celiac disease, gluten-derived peptides initiate an immune reaction involving tissue transglutaminase, HLA-DQ2 or HLA-DQ8, gluten-specific CD4+ T lymphocytes, inflammatory cytokines and intraepithelial lymphocytes. This immune response produces inflammation, crypt hyperplasia and progressive villous atrophy. The resulting reduction in absorptive surface area interferes with the uptake of nutrients.
The extent of malabsorption depends partly on the distribution and severity of intestinal injury. Celiac disease frequently affects the proximal small intestine, particularly the duodenum and upper jejunum. This is especially important because iron, folate and several other nutrients are absorbed predominantly in these regions. More extensive intestinal involvement can also impair the absorption of vitamin B12 and fat-soluble vitamins.
Fat malabsorption is particularly relevant to vitamins A, D, E and K. These vitamins require normal fat digestion, incorporation into mixed micelles and subsequent intestinal absorption. When intestinal inflammation and impaired fat absorption interfere with these processes, deficiencies of fat-soluble vitamins may develop.
Vitamin deficiencies may also arise from reduced dietary intake, chronic diarrhoea, altered intestinal metabolism and increased nutritional requirements during recovery. In some patients, deficiencies persist temporarily even after gluten is eliminated because the intestinal mucosa requires time to recover.
Vitamin D is one of the most clinically important vitamins in celiac disease because of its central role in calcium and phosphate metabolism, bone mineralisation and skeletal health. Vitamin D facilitates intestinal calcium absorption and contributes to the maintenance of normal blood calcium concentrations. It also regulates phosphate metabolism and supports the normal functioning of bone-forming and bone-resorbing cells.
In active celiac disease, intestinal damage can reduce the absorption of vitamin D and calcium. When calcium absorption becomes inadequate, the body attempts to maintain blood calcium levels by increasing parathyroid hormone secretion. This process, known as secondary hyperparathyroidism, stimulates the mobilisation of calcium from bone and increases renal conservation of calcium. Persistent disturbances can produce reduced bone mineral density, osteopenia and osteoporosis.
In children, severe or prolonged vitamin D deficiency may contribute to rickets, while adults may develop osteomalacia, osteoporosis and an increased risk of fractures. Bone pain, muscle weakness and generalised fatigue may accompany severe deficiency.
Vitamin D also has immunological functions. Its active metabolite, calcitriol, interacts with the vitamin D receptor, which is expressed in several immune-cell populations. Through this receptor, vitamin D can influence the activity of dendritic cells, macrophages, T lymphocytes and regulatory T cells. Experimental studies suggest that vitamin D can promote a more regulatory immune environment and influence inflammatory cytokine production.
These immunological effects are scientifically interesting in celiac disease because the disease involves an abnormal gluten-specific immune response. However, it has not been demonstrated that vitamin D supplementation can independently suppress the pathogenic gluten-specific immune reaction or reverse celiac disease. Its established therapeutic importance is primarily the correction of deficiency and protection of bone health.
Vitamin A is essential for the maintenance of epithelial tissues, cellular differentiation, vision, reproduction and immune function. It is particularly important for maintaining the normal structure and function of mucosal surfaces, including the intestinal epithelium.
Vitamin A and its active metabolites, especially retinoic acid, regulate the differentiation of intestinal epithelial cells and influence immune-cell development. Retinoic acid also participates in the regulation of mucosal immune responses, including the development and function of regulatory T cells.
In celiac disease, vitamin A deficiency may develop when fat absorption is significantly impaired. Since vitamin A is fat-soluble, its intestinal absorption depends on normal lipid digestion and absorption. Severe deficiency can produce night blindness, dryness of the conjunctiva and cornea, impaired epithelial integrity and increased susceptibility to infections.
Vitamin A also participates in the maintenance of intestinal mucosal immunity. It influences the differentiation and migration of immune cells and helps maintain appropriate immune responses at mucosal surfaces. These functions are relevant to the intestinal inflammatory environment in celiac disease.
Nevertheless, there is insufficient clinical evidence to conclude that additional vitamin A supplementation modifies the gluten-induced autoimmune process. Supplementation should be directed towards demonstrated deficiency or a clear nutritional indication. Excessive preformed vitamin A can be toxic, particularly when taken in high doses for prolonged periods.
Vitamin E is a group of fat-soluble compounds, of which alpha-tocopherol is the principal form maintained in human tissues. Its most important biological function is antioxidant protection, particularly the prevention of lipid peroxidation in cellular membranes.
The intestinal inflammation associated with celiac disease can increase the production of reactive oxygen species by activated immune cells and damaged epithelial tissues. Excessive oxidative stress can contribute to membrane injury, mitochondrial dysfunction, protein modification and cellular damage.
Vitamin E protects polyunsaturated fatty acids in cell membranes from oxidative damage by interrupting lipid-peroxidation reactions. It therefore contributes to the protection of epithelial cells and other tissues against oxidative stress.
In severe celiac disease involving extensive fat malabsorption, vitamin E deficiency may develop. Deficiency can affect the nervous system and produce peripheral neuropathy, impaired coordination, muscle weakness and other neurological abnormalities. Such manifestations are uncommon in ordinary, promptly diagnosed celiac disease but may occur in severe or prolonged malabsorption.
Although the antioxidant properties of vitamin E are relevant to inflammatory intestinal injury, there is no convincing clinical evidence that vitamin E supplementation alone can prevent or reverse the gluten-specific immune response. Its principal role is the correction of deficiency and maintenance of normal antioxidant function.
Vitamin K is essential for the activation of several proteins involved in blood coagulation. It is also required for the normal functioning of proteins involved in bone metabolism, including osteocalcin and matrix Gla protein.
Vitamin K deficiency can develop in celiac disease when fat malabsorption is sufficiently severe to interfere with its intestinal absorption. Since vitamin K is fat-soluble, prolonged intestinal dysfunction can reduce its availability.
The most clinically significant consequence is impaired activation of coagulation factors II, VII, IX and X, which may produce an increased tendency to bleed. Laboratory abnormalities can include prolongation of the prothrombin time and an increased international normalised ratio.
Vitamin K also participates in bone metabolism by supporting the carboxylation of osteocalcin, a protein produced by osteoblasts. Its role in skeletal health is therefore relevant to the increased risk of reduced bone density in celiac disease, although vitamin D and calcium deficiencies are generally more central to the bone complications associated with the disease.
Vitamin K deficiency is not present in every patient with celiac disease. It is more likely in individuals with severe or prolonged fat malabsorption.
Vitamin B12, or cobalamin, is essential for DNA synthesis, red blood cell production, normal neurological function and the metabolism of certain amino acids and fatty acids.
Vitamin B12 absorption occurs primarily in the terminal ileum, the final portion of the small intestine. It requires binding to intrinsic factor, a protein secreted by gastric parietal cells. The vitamin B12–intrinsic factor complex is subsequently absorbed through specialised receptors in the terminal ileum.
Since celiac disease predominantly affects the proximal small intestine, vitamin B12 deficiency is not necessarily as common as folate deficiency. However, it can occur when the disease involves more extensive regions of the small intestine or when other factors interfere with B12 absorption. Dietary insufficiency, autoimmune gastritis, pernicious anaemia and certain medications can also contribute independently.
Vitamin B12 deficiency can produce megaloblastic anaemia, fatigue, weakness, numbness, tingling sensations, impaired balance and neurological dysfunction. A particularly important feature is that neurological manifestations can occur even when anaemia is absent.
Vitamin B12 is also involved in the conversion of homocysteine to methionine. Deficiency can therefore increase blood homocysteine concentrations, although elevated homocysteine is not specific to B12 deficiency and can also occur with folate or vitamin B6 deficiency.
In patients with celiac disease, vitamin B12 deficiency should be investigated when there is unexplained anaemia, neuropathy, cognitive disturbance or persistent fatigue.
Folate is one of the vitamins most directly associated with proximal small-intestinal injury in celiac disease. It is absorbed predominantly in the upper small intestine, particularly the duodenum and jejunum. Since these are common sites of celiac-related mucosal damage, folate absorption can be substantially reduced.
Folate participates in one-carbon metabolism, DNA synthesis, amino-acid metabolism and the formation of normal red blood cells. It is necessary for the production of nucleotides required for cell division. Consequently, rapidly dividing tissues, especially bone marrow and intestinal epithelial cells, are particularly sensitive to folate deficiency.
Folate deficiency can cause megaloblastic anaemia, characterised by the production of abnormally large red blood cell precursors and enlarged circulating red blood cells. Clinical manifestations include fatigue, weakness, pallor, breathlessness and reduced exercise tolerance.
Folate is also involved in homocysteine metabolism. Inadequate folate availability can increase homocysteine concentrations, especially when vitamin B12 or vitamin B6 deficiency is also present.
Folate deficiency is particularly important in untreated celiac disease because it can contribute to anaemia independently of iron deficiency. In some patients, iron deficiency and folate deficiency may coexist, producing a mixed pattern of anaemia in which the typical red blood cell changes are less obvious.
Folate supplementation can correct deficiency, but vitamin B12 status should be considered before treating suspected megaloblastic anaemia with folic acid alone. Folic acid may improve the blood abnormalities of B12 deficiency while allowing neurological injury to progress undetected.
Vitamin B6, particularly in its active form pyridoxal-5-phosphate, functions as a coenzyme in numerous metabolic reactions. It is involved in amino-acid metabolism, neurotransmitter synthesis, haemoglobin production and the regulation of homocysteine metabolism.
In celiac disease, inadequate dietary intake, intestinal malabsorption and broader nutritional disturbances may contribute to vitamin B6 deficiency. Deficiency can cause dermatitis, inflammation of the tongue, microcytic or sideroblastic anaemia in certain circumstances, peripheral neuropathy and disturbances in immune function.
Vitamin B6 is also involved in the synthesis of neurotransmitters such as serotonin, dopamine and gamma-aminobutyric acid. Therefore, severe deficiency can affect neurological functioning.
The relationship between vitamin B6 and celiac disease is relevant because some patients experience neurological symptoms that cannot be explained solely by intestinal manifestations. However, neurological symptoms in celiac disease are multifactorial and may involve immune-mediated mechanisms, nutritional deficiencies and other associated conditions.
Excessive vitamin B6 supplementation can itself cause sensory neuropathy. Therefore, high-dose supplementation should not be used routinely without a medical indication.
Vitamin B1, or thiamine, is essential for carbohydrate metabolism and energy production. It functions as a coenzyme in several important biochemical pathways, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase reactions.
Severe malabsorption, prolonged diarrhoea, inadequate dietary intake and general malnutrition may contribute to thiamine deficiency in advanced celiac disease.
Thiamine deficiency can produce peripheral neuropathy, muscle weakness, fatigue and cardiovascular abnormalities. In severe cases, it may cause beriberi or neurological syndromes associated with impaired brain energy metabolism.
Although thiamine deficiency is not among the most characteristic nutritional abnormalities of uncomplicated celiac disease, it should be considered in patients with severe malnutrition, prolonged vomiting or diarrhoea and unexplained neurological symptoms.
Other B-complex vitamins also contribute to normal metabolism and tissue function. Riboflavin (B2) is required for flavoprotein-dependent oxidation-reduction reactions and energy metabolism. Niacin (B3) is a precursor of NAD and NADP, which participate in numerous cellular metabolic reactions. Biotin (B7) functions as a coenzyme in carboxylation reactions, while pantothenic acid (B5) is a component of coenzyme A.
Severe malnutrition and extensive malabsorption may affect the availability of these vitamins. However, individual deficiencies are less consistently recognised as characteristic features of celiac disease than folate, vitamin B12 and vitamin D deficiencies.
A balanced gluten-free diet generally provides these vitamins when it includes adequate quantities of vegetables, fruits, legumes, nuts, dairy products, eggs, fish, meat and appropriately fortified gluten-free foods.
The importance of vitamins in celiac disease extends beyond their conventional nutritional functions. Several vitamins participate directly in the regulation of immune responses, epithelial integrity, antioxidant defence and cellular repair.
Vitamin D influences immune-cell differentiation and inflammatory signalling. Vitamin A and retinoic acid regulate mucosal immune tolerance and the differentiation of regulatory T cells. Vitamin E protects cellular membranes against oxidative damage, while folate and vitamin B12 support DNA synthesis and normal cellular proliferation. These functions are important for the maintenance and regeneration of intestinal epithelial tissues.
The intestinal epithelium undergoes continuous renewal. Stem cells located in the intestinal crypts produce new epithelial cells, which migrate towards the villous surface and eventually undergo programmed cell death. This process is essential for maintaining the intestinal barrier and absorptive function. Adequate nutritional availability, including vitamins and minerals, is necessary for normal epithelial regeneration.
In celiac disease, however, the primary pathological mechanism is not simply nutritional deficiency or oxidative stress. It is the gluten-dependent immune reaction involving antigen presentation, gluten-specific T lymphocytes, inflammatory cytokines and cytotoxic intraepithelial lymphocytes. Vitamin supplementation may support normal physiological processes, but it has not been shown to eliminate this fundamental immunological mechanism.
A strict gluten-free diet is the essential treatment for celiac disease. Once gluten exposure is eliminated, the inflammatory response gradually subsides, and intestinal epithelial regeneration begins. Villous architecture can progressively recover, although the time required varies considerably between individuals.
During this recovery period, correction of vitamin deficiencies is important because the regenerating intestinal mucosa requires adequate nutritional support. Vitamin A contributes to epithelial differentiation, vitamin D supports calcium metabolism and immune regulation, vitamin E protects cellular membranes, and folate and vitamin B12 support DNA synthesis and cellular proliferation.
Vitamin deficiencies may improve naturally as intestinal absorption recovers. Nevertheless, some patients require temporary or prolonged supplementation, depending on the severity of deficiency and the extent of intestinal damage.
Clinical improvement does not always indicate complete histological recovery. Symptoms may disappear before the intestinal mucosa has fully healed. Persistent deficiencies after treatment should therefore prompt assessment of dietary adequacy, continued gluten exposure, incomplete mucosal recovery and other possible causes of malabsorption.
The assessment of vitamin status should be guided by the patient’s symptoms, clinical severity, dietary history and laboratory findings. Testing every vitamin in every patient is not always necessary, but nutritional assessment is particularly important at diagnosis and when symptoms suggest malabsorption.
Vitamin D status is generally evaluated by measuring serum 25-hydroxyvitamin D. Folate and vitamin B12 measurements are useful when anaemia, neurological symptoms or nutritional deficiencies are suspected. Vitamin A, vitamin E and vitamin K assessment may be appropriate in patients with significant fat malabsorption, prolonged diarrhoea or unexplained bleeding and neurological manifestations.
Vitamin B12 testing may require additional interpretation when the serum concentration is borderline. Methylmalonic acid can help identify functional B12 deficiency, although kidney dysfunction can also elevate this marker. Homocysteine may be elevated in folate, B12 or B6 deficiency and is therefore less specific.
The evaluation of nutritional status should also include haemoglobin, red blood cell indices, ferritin, iron studies, calcium, phosphate and parathyroid hormone when clinically indicated. These are important because vitamin deficiencies frequently coexist with mineral deficiencies in celiac disease.
The most effective long-term strategy for preventing vitamin deficiencies in celiac disease is strict adherence to a nutritionally balanced gluten-free diet. The diet should include adequate quantities of vegetables, fruits, legumes, nuts, seeds, eggs, dairy products, fish and meat according to individual dietary preferences and tolerance.
Gluten-free diets are not automatically nutritionally complete. Many commercially available gluten-free breads, biscuits and processed foods contain less fibre and may contain lower quantities of iron, folate and certain B vitamins than their conventional fortified wheat-based equivalents. Some gluten-free products are also relatively high in refined starch, sugar or fat. Therefore, dietary quality is as important as gluten exclusion.
Supplementation should be based on demonstrated deficiency, substantial clinical risk or a specific medical indication. Vitamin D may be required in patients with deficiency or reduced bone mineral density. Folate and vitamin B12 may be necessary in patients with documented deficiencies. Vitamins A, E and K may be required in severe fat malabsorption, but supplementation should be medically supervised because excessive intake can cause toxicity.
It is particularly important to distinguish between correcting a deficiency and taking high doses in the hope of modifying the autoimmune process. There is currently no convincing clinical evidence that high-dose vitamin combinations can replace gluten exclusion or independently cure celiac disease.
Vitamins have a significant role in the clinical course and nutritional management of celiac disease. The immune-mediated destruction of the small-intestinal mucosa interferes with the absorption of essential nutrients, producing deficiencies that may contribute to anaemia, osteoporosis, neurological abnormalities, impaired epithelial integrity and general nutritional deterioration. Folate deficiency is particularly associated with proximal small-intestinal injury, while vitamin B12 deficiency may occur with more extensive intestinal involvement or additional absorption problems. Vitamin D deficiency is especially important because of its consequences for calcium metabolism and bone health. Deficiencies of vitamins A, E and K may occur when fat absorption is substantially impaired.
Beyond their nutritional functions, vitamins participate in immune regulation, antioxidant protection, epithelial differentiation and tissue regeneration. These biological activities make them relevant to the recovery of intestinal function after gluten withdrawal. Nevertheless, the distinction between nutritional support and disease-modifying treatment is essential. Vitamins can correct deficiencies and support physiological recovery, but they do not remove the gluten-dependent immunological trigger responsible for celiac disease. A strict lifelong gluten-free diet, appropriate nutritional assessment and targeted correction of deficiencies remain the foundations of effective management.
An important scientific distinction: Vitamin deficiencies in celiac disease are primarily consequences of intestinal injury and malabsorption. Although several vitamins have immunomodulatory properties, there is not sufficient clinical evidence to recommend vitamin supplementation as a treatment for the underlying gluten-specific autoimmune response.
Role of Microelements in Celiac Disease
Microelements, also called trace elements, are essential inorganic nutrients required by the human body in very small quantities. Despite their relatively low concentrations, they participate in an enormous range of biological processes, including enzyme activation, cellular respiration, antioxidant defence, DNA synthesis, immune regulation, hormone production, epithelial integrity and tissue repair. Iron, zinc, copper, selenium, manganese, iodine, chromium and molybdenum are among the important trace elements involved in human physiology.
The relationship between microelements and celiac disease is particularly significant because the disease affects the small intestine, the principal organ responsible for the absorption of most dietary minerals. Celiac disease is a gluten-dependent, immune-mediated disorder in which gluten exposure triggers an abnormal immune response in genetically susceptible individuals, particularly those carrying HLA-DQ2 or HLA-DQ8. The resulting inflammation produces villous atrophy, crypt hyperplasia and damage to the intestinal absorptive surface. These structural changes interfere with the absorption of several trace elements, producing nutritional deficiencies that may contribute to the systemic manifestations of the disease.
Microelement deficiencies are not merely secondary nutritional abnormalities. Certain trace elements are essential for maintaining intestinal epithelial integrity, regulating oxidative stress, supporting immune-cell function and facilitating tissue regeneration. Their deficiency may therefore aggravate some physiological disturbances associated with active celiac disease. However, it is important to distinguish between established clinical consequences of deficiency and experimental hypotheses about the ability of trace elements to modify the underlying gluten-specific immune reaction. At present, correcting deficiencies is an important part of treatment, but trace-element supplementation cannot replace strict gluten exclusion.
Iron deficiency is one of the most frequent nutritional abnormalities associated with celiac disease. Iron is essential for haemoglobin synthesis, oxygen transport, mitochondrial energy production, cellular respiration and numerous enzymatic reactions. The human body does not have an efficient regulated mechanism for eliminating excess iron, so intestinal absorption is tightly controlled according to physiological requirements.
Dietary iron occurs in two major forms: haem iron, obtained mainly from animal foods, and non-haem iron, obtained from plant foods and other dietary sources. Iron absorption occurs predominantly in the duodenum and proximal jejunum. These regions are frequently affected in celiac disease, making iron deficiency a particularly important consequence of the intestinal injury.
In healthy individuals, non-haem ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺) at the intestinal brush border and transported into enterocytes through divalent metal transporter 1 (DMT1). Haem iron is absorbed through separate pathways, after which iron is released within the enterocyte. Iron may be stored as ferritin or exported into the circulation through ferroportin. Hephaestin helps oxidise exported ferrous iron so that it can bind to transferrin for transport.
In active celiac disease, villous atrophy and damage to duodenal enterocytes reduce the absorptive capacity for iron. Chronic intestinal inflammation may also influence iron metabolism through hepcidin, a liver-derived hormone that regulates ferroportin. In inflammatory states, increased hepcidin can reduce intestinal iron absorption and trap iron within storage cells. Thus, iron deficiency in celiac disease may result from both impaired absorption and inflammatory disturbances of iron regulation.
The most important clinical consequence is iron-deficiency anaemia. Patients may experience fatigue, weakness, pallor, breathlessness, palpitations, reduced exercise tolerance and impaired concentration. Iron deficiency can sometimes be the only apparent manifestation of celiac disease, even in individuals without prominent diarrhoea or abdominal symptoms. Unexplained or treatment-resistant iron-deficiency anaemia should therefore prompt consideration of celiac disease.
Iron deficiency can also exist without anaemia. In such cases, serum ferritin may be reduced while haemoglobin remains within the normal range. This can still contribute to fatigue and reduced physical performance.
A strict gluten-free diet allows intestinal recovery and may gradually improve iron absorption. However, iron supplementation is often required when deficiency is substantial. Persistent iron deficiency despite dietary treatment should lead to an assessment of continued gluten exposure, incomplete mucosal recovery, blood loss and other possible causes.
Zinc is one of the most biologically important trace elements in celiac disease. It is required for the activity of hundreds of enzymes and participates in DNA synthesis, protein synthesis, cell division, gene expression, antioxidant defence and immune regulation. It is particularly important for rapidly renewing tissues, including the intestinal epithelium.
Zinc absorption occurs mainly in the small intestine, especially the proximal small intestine, through transport proteins such as ZIP4, which facilitates zinc uptake into intestinal epithelial cells. Intracellular zinc is then regulated by zinc transporters and metallothioneins, which control its storage and distribution.
In active celiac disease, villous atrophy and epithelial damage can reduce zinc absorption. Chronic diarrhoea, reduced food intake and increased intestinal losses may further aggravate the deficiency. Zinc deficiency can itself produce gastrointestinal disturbances, including diarrhoea and impaired epithelial repair, potentially creating a cycle in which intestinal disease and nutritional deficiency reinforce one another.
Zinc has an important role in maintaining the intestinal barrier. It supports the structure and function of epithelial cells and influences tight-junction proteins that regulate the movement of substances between adjacent cells. Adequate zinc availability is necessary for normal epithelial regeneration and wound healing. Deficiency may therefore impair the recovery of intestinal tissues after inflammatory injury.
Zinc is also essential for normal immune function. It influences the development and activity of T lymphocytes, B lymphocytes, natural killer cells and other immune populations. It participates in the regulation of cytokine production and helps maintain appropriate immune responses. Severe zinc deficiency can impair immune defence and increase susceptibility to infections.
Clinically, zinc deficiency may produce dermatitis, hair loss, delayed wound healing, impaired taste and smell, reduced appetite, diarrhoea and increased susceptibility to infections. In children, prolonged deficiency may impair growth and development.
Zinc is therefore particularly relevant during the recovery phase of celiac disease. Nevertheless, although zinc supports epithelial integrity and normal immune function, there is no convincing clinical evidence that zinc supplementation independently suppresses the gluten-specific immune reaction. Supplementation is indicated when deficiency is demonstrated or strongly suspected, rather than as a substitute for gluten exclusion.
Copper is an essential trace element involved in iron metabolism, mitochondrial energy production, antioxidant defence, connective-tissue formation and nervous system function. It acts as a cofactor for several enzymes, including cytochrome c oxidase, superoxide dismutase, lysyl oxidase and ceruloplasmin.
Copper is absorbed mainly in the stomach and proximal small intestine. Although copper deficiency is less common than iron or zinc deficiency in celiac disease, it can occur in patients with severe or prolonged malabsorption.
One of copper’s most important functions is its participation in iron metabolism. Ceruloplasmin and hephaestin are copper-dependent enzymes that facilitate the oxidation of ferrous iron to ferric iron, enabling iron to bind to transferrin and circulate in the blood. Copper deficiency can therefore interfere with iron utilisation and produce anaemia even when iron stores are not markedly depleted.
Copper deficiency may cause anaemia, neutropenia and, in more severe cases, neurological abnormalities. Its neurological manifestations can resemble those of vitamin B12 deficiency, including impaired coordination, sensory disturbances and gait abnormalities. This distinction is clinically important because unexplained neurological symptoms in a patient with celiac disease should not automatically be attributed to vitamin B12 deficiency.
Copper also participates in the formation and maintenance of connective tissue through lysyl oxidase, which supports the cross-linking of collagen and elastin. It contributes to antioxidant defence through copper-zinc superoxide dismutase, an enzyme that converts superoxide radicals into less reactive products.
Copper deficiency is uncommon in uncomplicated celiac disease, but it should be considered when anaemia, neutropenia or neurological symptoms persist despite correction of more common deficiencies. Excessive zinc supplementation can also induce copper deficiency by increasing intestinal metallothionein, which binds copper and reduces its absorption. This is an important reason to avoid prolonged high-dose zinc supplementation without medical supervision.
Selenium is an essential trace element incorporated into specialised proteins known as selenoproteins. These proteins participate in antioxidant defence, thyroid hormone metabolism, redox regulation and immune function.
Several selenoproteins are particularly important in protecting cells against oxidative damage. Glutathione peroxidases reduce hydrogen peroxide and lipid hydroperoxides, while thioredoxin reductases maintain the cellular thioredoxin system. These enzymes help regulate the intracellular redox environment and protect cellular components from excessive oxidative stress.
Oxidative stress is relevant to celiac disease because activated immune cells and inflamed intestinal tissues can generate reactive oxygen species. Excessive production of these molecules may contribute to lipid peroxidation, protein modification, mitochondrial dysfunction and epithelial injury. Selenium-dependent antioxidant enzymes participate in controlling this oxidative burden.
Selenium deficiency has been reported in some individuals with active celiac disease, particularly in association with malabsorption and poor nutritional intake. However, selenium status varies according to dietary patterns, soil selenium concentrations, food sources and geographical conditions. Deficiency is not universal in celiac disease, and its clinical significance varies between populations.
Selenium also participates in thyroid hormone metabolism. The enzymes responsible for converting thyroxine (T4) into the more active triiodothyronine (T3), and for inactivating thyroid hormones, include selenium-dependent deiodinases. This is relevant because autoimmune thyroid disease occurs more frequently in people with celiac disease than in the general population. Nevertheless, selenium supplementation has not been established as a treatment for celiac-associated thyroid autoimmunity.
Selenium is therefore important for antioxidant protection and normal thyroid physiology, but there is insufficient evidence to recommend routine high-dose selenium supplementation as a disease-modifying treatment for celiac disease. Excess selenium can cause toxicity, including hair and nail abnormalities, gastrointestinal symptoms and neurological effects.
Manganese is required in small quantities for the activity of several enzymes involved in metabolism, antioxidant defence, bone formation and cellular regulation. One of its most important functions is as a cofactor for mitochondrial manganese superoxide dismutase, commonly known as MnSOD or SOD2.
Mitochondria are major sites of cellular energy production and also generate reactive oxygen species during normal metabolism. Manganese-dependent superoxide dismutase converts mitochondrial superoxide radicals into hydrogen peroxide, which can subsequently be broken down by other antioxidant enzymes. This mechanism is important for maintaining mitochondrial integrity.
Manganese also participates in enzymes involved in amino-acid metabolism, carbohydrate metabolism and the synthesis of connective-tissue components. It contributes to bone development and normal neurological function.
The intestine absorbs manganese through regulated transport mechanisms, but the clinical relationship between manganese deficiency and celiac disease is not well established. There is insufficient evidence to identify manganese deficiency as a frequent or characteristic complication of the disease. Most patients obtain adequate manganese from a varied diet containing whole grains that are gluten-free, legumes, nuts, seeds and vegetables.
Manganese is therefore biologically relevant to cellular antioxidant defence, but routine manganese supplementation is not justified in celiac disease unless a specific deficiency or medical indication is identified. Excessive manganese exposure can be harmful, particularly to the nervous system.
Iodine is an essential trace element required for the synthesis of thyroid hormones, thyroxine (T4) and triiodothyronine (T3). These hormones regulate basal metabolic activity, growth, development, thermogenesis, cardiovascular function and nervous system activity.
Iodine is absorbed mainly in the stomach and upper small intestine, and its availability depends substantially on dietary intake. Celiac disease does not generally produce a characteristic iodine-deficiency syndrome, but severe malabsorption and restricted dietary intake may contribute to inadequate iodine availability in some individuals.
The thyroid gland uses iodine to produce thyroid hormones through a process involving the sodium-iodide symporter, thyroid peroxidase and thyroglobulin. Insufficient iodine can impair thyroid hormone synthesis and cause increased thyroid-stimulating hormone secretion, thyroid enlargement and, in more severe cases, hypothyroidism.
An important consideration is the association between celiac disease and autoimmune thyroid disorders, particularly autoimmune thyroiditis. This association reflects shared genetic susceptibility and immune-regulatory factors rather than a simple consequence of iodine deficiency. The presence of autoimmune thyroid disease should therefore not be interpreted as evidence that iodine supplementation is necessary.
Both iodine deficiency and excessive iodine intake can disturb thyroid function. Consequently, iodine supplements should not be prescribed routinely to patients with celiac disease unless dietary assessment or clinical evaluation indicates a need. Iodised salt and an appropriate balanced diet are sufficient for most individuals.
Chromium has traditionally been described as a trace element involved in glucose metabolism and insulin action. However, the essentiality and precise physiological role of chromium in humans remain subjects of scientific debate. Evidence for a specific requirement for chromium supplementation in otherwise healthy individuals is limited.
Some studies have examined chromium status in gastrointestinal disorders and metabolic conditions, but there is no strong evidence that chromium deficiency is a common or defining feature of celiac disease.
Celiac disease can coexist with type 1 diabetes, an autoimmune condition. This association is related to shared genetic susceptibility and immune mechanisms, not to a demonstrated chromium deficiency. Chromium supplementation has not been shown to prevent or treat the autoimmune processes responsible for either disease.
There is therefore no established role for routine chromium supplementation in celiac disease. Patients with diabetes should manage glucose metabolism according to established diabetes care rather than relying on chromium preparations.
Molybdenum is an essential trace element required for the function of several enzymes, including sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase and mitochondrial amidoxime-reducing component.
These enzymes participate in the metabolism of sulphur-containing amino acids, purines and certain other compounds. Molybdenum is incorporated into a specialised molybdenum cofactor that is necessary for the catalytic activity of these enzymes.
Dietary molybdenum is absorbed in the small intestine, but clinically significant deficiency is extremely rare under ordinary dietary conditions. There is no convincing evidence that molybdenum deficiency is a common complication of celiac disease.
Consequently, molybdenum is important in general human metabolism but has no established specific therapeutic role in celiac disease. Routine supplementation is unnecessary in the absence of an unusual medical indication.
Although magnesium, calcium and phosphorus are often discussed alongside trace elements in nutritional studies of celiac disease, they are technically classified as macrominerals because the body requires them in comparatively large quantities.
Magnesium participates in hundreds of enzymatic reactions, including ATP-dependent energy metabolism, protein synthesis, DNA replication and neuromuscular function. Severe intestinal malabsorption and chronic diarrhoea can reduce magnesium availability. Deficiency may cause muscle cramps, weakness, tremors, cardiac rhythm disturbances and, in severe cases, neurological symptoms.
Calcium is essential for bone mineralisation, muscle contraction, nerve transmission and intracellular signalling. In celiac disease, calcium deficiency can result from impaired intestinal absorption, vitamin D deficiency and inadequate dietary intake. Chronic calcium deficiency may contribute to secondary hyperparathyroidism and reduced bone mineral density.
Phosphorus is required for ATP production, nucleic acid synthesis, phospholipid formation and bone mineralisation. Significant deficiency may occur in severe malnutrition or during certain forms of nutritional recovery, although it is not a typical isolated manifestation of celiac disease.
These minerals should be assessed when clinically indicated, particularly in patients with prolonged diarrhoea, severe malabsorption, muscle weakness, osteoporosis or evidence of generalised nutritional deficiency.
The intestinal mucosa is a metabolically active tissue undergoing continuous renewal. Epithelial cells are generated from stem cells located in the crypts and migrate towards the villous surface, where they mature and eventually undergo programmed cell death. This continuous process maintains the absorptive surface and intestinal barrier.
Trace elements participate in several stages of this process. Zinc is required for DNA synthesis, protein synthesis and cellular proliferation. Iron supports mitochondrial energy production and oxygen-dependent metabolism. Copper is involved in mitochondrial respiration and connective-tissue formation. Selenium-dependent enzymes protect cells against oxidative damage, while manganese-dependent superoxide dismutase helps regulate mitochondrial reactive oxygen species.
When these elements are deficient, normal cellular functions may become impaired. Epithelial regeneration, antioxidant protection and immune-cell activity may be affected. In this way, micronutrient deficiencies can contribute to the persistence of general physiological disturbances during recovery from intestinal injury.
However, this does not mean that deficiencies are the primary cause of celiac disease or that correcting them will independently reverse villous atrophy. The initiating pathological process remains the gluten-dependent immune response. Removal of gluten is essential for controlling that process, while nutritional correction supports the restoration of normal intestinal function.
Trace elements are important regulators of innate and adaptive immunity. Their influence extends to immune-cell development, antigen presentation, cytokine production, oxidative signalling and the maintenance of immune tolerance.
Zinc is particularly important for T-lymphocyte development and function. It influences intracellular signalling pathways, transcription factors and the balance between different T-cell populations. Selenium-dependent enzymes regulate cellular redox conditions and can influence inflammatory signalling. Iron is required for the proliferation and metabolic activity of immune cells, while copper-dependent enzymes contribute to cellular respiration and antioxidant defence.
In celiac disease, these functions are relevant because the disease involves an abnormal adaptive immune response against gluten-derived peptides. Gluten-specific CD4+ T cells recognise deamidated gluten peptides presented by HLA-DQ2 or HLA-DQ8 molecules. Inflammatory cytokines and cytotoxic intraepithelial lymphocytes contribute to epithelial injury.
Nutritional deficiencies can disturb normal immune function, but the relationship is not simply that more trace elements produce better immune regulation. Both deficiency and excessive intake can be harmful. Iron, for example, is essential for immune-cell metabolism, but excessive iron can promote oxidative reactions and may support the growth of certain pathogens. Zinc deficiency impairs immune function, whereas excessive zinc can interfere with copper absorption. Selenium deficiency can compromise antioxidant defence, but excessive selenium causes toxicity.
Therefore, maintaining physiological concentrations of trace elements is more important than indiscriminately increasing their intake.
Oxidative stress results when the production of reactive oxygen species exceeds the capacity of antioxidant defence systems. In inflamed intestinal tissues, activated immune cells can generate reactive oxygen species as part of their inflammatory activity. Excessive oxidative stress can damage membrane lipids, proteins, nucleic acids and mitochondrial structures.
Several trace elements participate in antioxidant defence, although they do so through different biochemical mechanisms. Selenium is incorporated into glutathione peroxidases and thioredoxin reductases. Copper and zinc are components of cytosolic superoxide dismutase, while manganese is required for the mitochondrial form of superoxide dismutase.
These enzymes form part of an integrated antioxidant network. Superoxide dismutases convert superoxide radicals into hydrogen peroxide, which is subsequently detoxified by catalase and glutathione peroxidases. The selenium-dependent glutathione peroxidase system is especially important in reducing lipid hydroperoxides.
In celiac disease, adequate availability of these trace elements supports normal antioxidant defence. Nevertheless, the presence of oxidative stress does not establish that antioxidant supplementation will modify the disease. Clinical trials have not demonstrated that selenium, zinc, copper or manganese supplementation can replace gluten exclusion or reliably suppress the pathogenic immune response.
Nutritional assessment is an important part of celiac disease management, particularly at diagnosis and in patients with severe symptoms, prolonged malabsorption, anaemia, unexplained fatigue, neurological abnormalities or poor recovery.
Iron status is commonly assessed using a complete blood count, serum ferritin, transferrin saturation and other iron studies. Ferritin is particularly useful for identifying depleted iron stores, although inflammation can increase ferritin and make interpretation more difficult.
Zinc assessment may be appropriate when there is unexplained dermatitis, hair loss, poor wound healing, persistent diarrhoea or evidence of general malnutrition. Serum or plasma zinc can provide useful information, but the result is influenced by inflammation, fasting status, recent food intake and albumin concentration.
Copper and ceruloplasmin measurements may be considered in patients with unexplained anaemia, neutropenia or neurological abnormalities, especially when prolonged high-dose zinc supplementation has been used.
Selenium testing is generally reserved for selected patients with substantial malabsorption or suspected deficiency. Manganese, iodine, chromium and molybdenum do not normally require routine testing in celiac disease. Their assessment should be based on specific clinical circumstances rather than indiscriminate screening.
The interpretation of trace-element measurements requires caution. Inflammation can alter circulating concentrations independently of total body stores. Albumin concentrations, dietary intake, liver function, kidney function and recent supplementation can also influence laboratory results.
A well-planned gluten-free diet can provide adequate quantities of most essential trace elements. The principal challenge is ensuring that gluten exclusion does not result in an unnecessarily restricted or nutritionally unbalanced diet.
Iron can be obtained from meat, fish, poultry, eggs, legumes and dark-green vegetables. Haem iron from animal foods is generally absorbed more efficiently than non-haem iron from plant foods. Vitamin C-rich foods, such as citrus fruits, guava and amla, can improve the absorption of non-haem iron.
Zinc is present in meat, seafood, eggs, dairy products, legumes, nuts and seeds. Copper is available from nuts, seeds, cocoa, legumes, seafood and organ meats. Selenium sources include fish, eggs, meat and some nuts, although the selenium content of plant foods varies according to soil composition. Manganese is found in nuts, legumes, seeds and many vegetables. Iodine is supplied mainly through iodised salt, seafood, dairy products and eggs, depending on dietary patterns and food sources.
Some gluten-free products are not fortified to the same extent as conventional wheat-based foods. Consequently, individuals with celiac disease should not assume that a gluten-free diet is automatically nutritionally adequate. Dietary planning should include naturally nutrient-rich gluten-free foods and, where appropriate, fortified products.
Supplementation should be based on confirmed deficiency, clinical risk or a specific medical indication. Iron, zinc, copper and selenium supplements should not be taken in high doses without appropriate assessment. Prolonged excessive zinc intake can cause copper deficiency, while excessive selenium can produce selenosis. Excess iron can cause gastrointestinal adverse effects and, in susceptible individuals, iron overload.
Patients with persistent deficiencies despite a gluten-free diet should be evaluated for ongoing gluten exposure, incomplete intestinal healing, poor dietary intake, blood loss or other causes of malabsorption.
Microelements have important roles in the pathophysiology, clinical manifestations and nutritional recovery of celiac disease. Their significance arises from the fact that the small intestine, which is damaged by the gluten-dependent immune response, is also the principal site of absorption of many essential trace elements. Iron deficiency is particularly common and may present as otherwise unexplained anaemia. Zinc deficiency can affect epithelial integrity, immune function and tissue repair. Copper deficiency may contribute to anaemia, neutropenia and neurological abnormalities, while selenium deficiency can compromise antioxidant defence. Manganese, iodine, chromium and molybdenum have important physiological functions, but their deficiencies are not established as frequent or characteristic complications of celiac disease.
The broader biological significance of these elements lies in their participation in cellular metabolism, antioxidant defence, immune regulation and intestinal epithelial regeneration. Adequate trace-element availability supports the restoration of normal physiological functions after gluten withdrawal. Nevertheless, microelements should not be considered direct treatments for the underlying disease. The primary therapeutic intervention remains strict lifelong gluten exclusion, accompanied by nutritional assessment and targeted correction of deficiencies.
The most important clinical priorities are iron, zinc, copper and selenium, with the strength of evidence and frequency of deficiency differing among them. Calcium, magnesium and phosphorus also deserve attention in nutritional assessment, although they are macrominerals rather than trace elements.
Role of Diet and Lifestyle in Celiac Disease
Diet and lifestyle have a fundamental role in the management of celiac disease because the disorder is directly triggered by the consumption of gluten-containing foods. Unlike many gastrointestinal conditions in which dietary modification primarily reduces symptoms, celiac disease requires the complete and lifelong elimination of gluten to prevent the underlying immune-mediated intestinal injury. Dietary management is therefore not simply a method of controlling diarrhoea, abdominal discomfort or indigestion; it is the principal therapeutic intervention that prevents continued exposure to the antigen responsible for the disease.
Celiac disease is a chronic immune-mediated disorder occurring in genetically susceptible individuals, particularly those carrying HLA-DQ2 or HLA-DQ8. Gluten proteins present in wheat, barley and rye contain peptide sequences that resist complete digestion in the gastrointestinal tract. These peptides can cross the intestinal epithelial barrier and interact with tissue transglutaminase 2 (TG2), which modifies certain glutamine residues through deamidation. The resulting peptides bind efficiently to HLA-DQ2 or HLA-DQ8 molecules and activate gluten-specific CD4+ T lymphocytes. This initiates an inflammatory cascade involving cytokines, B lymphocytes, autoantibody production and cytotoxic intraepithelial lymphocytes, eventually producing villous atrophy, crypt hyperplasia and impaired nutrient absorption.
A strict gluten-free diet removes the principal environmental trigger and allows the intestinal inflammatory response to subside. However, successful long-term management involves more than avoiding wheat, barley and rye. It requires nutritional balance, prevention of cross-contamination, appropriate food selection, correction of deficiencies, maintenance of bone health, healthy physical activity, adequate sleep and attention to psychological and social well-being. These factors collectively determine the patient’s nutritional recovery and quality of life.
The essential dietary requirement in celiac disease is the complete and lifelong exclusion of gluten. Gluten is a complex mixture of storage proteins found principally in wheat, barley and rye. Wheat contains gliadins and glutenins, while barley contains hordeins and rye contains secalins. These proteins contain immunologically active peptide sequences capable of stimulating the celiac immune response.
Wheat and its related varieties must be avoided, including durum wheat, semolina, spelt, farro, einkorn, emmer, bulgur, couscous and products made from ordinary wheat flour. Barley and rye must also be excluded. Foods prepared using these grains can contain sufficient gluten to maintain intestinal inflammation even when the patient experiences no immediate symptoms.
The exclusion of gluten is necessary even when symptoms are mild or absent. Some individuals with celiac disease have very few gastrointestinal symptoms despite continuing intestinal damage. Others may have predominantly extraintestinal manifestations such as anaemia, osteoporosis, fatigue, infertility or neurological abnormalities. Therefore, symptom improvement alone is not a reliable indication that gluten exposure has stopped or that the intestinal mucosa has healed.
Oats require particular consideration. Pure uncontaminated oats do not contain wheat, barley or rye gluten, and many people with celiac disease can tolerate them. However, ordinary commercial oats are frequently contaminated during cultivation, transportation, storage or processing. Only oats specifically labelled or certified gluten-free should be considered. A minority of patients may react to oat avenin, and some may develop symptoms or persistent intestinal abnormalities. Oats should therefore be introduced cautiously, with clinical monitoring where appropriate.
The term gluten-free does not mean that a food must be completely free of every analytically detectable gluten molecule. International standards commonly use a threshold of less than 20 parts per million (ppm) for foods labelled gluten-free. This standard is intended to make gluten exposure sufficiently low for most people with celiac disease. However, strict avoidance of intentional gluten-containing ingredients and prevention of cross-contamination remain essential.
A gluten-free diet should not be understood as a diet consisting mainly of specially manufactured gluten-free products. Many ordinary, minimally processed foods are naturally gluten-free and can provide a nutritionally complete foundation for long-term management.
Rice is an important staple food in many parts of India and is naturally gluten-free. Both white and brown rice can be included according to individual nutritional requirements. Millets such as ragi, foxtail millet, little millet, kodo millet, barnyard millet and pearl millet are also naturally gluten-free, provided they have not been contaminated during harvesting, storage or processing. Corn, sorghum and buckwheat can also be included. Despite its name, buckwheat is not a type of wheat and does not contain wheat gluten.
In the Kerala dietary context, rice, ragi, tapioca, millets, pulses, vegetables, fruits, coconut, fish, eggs and unprocessed meat can form the basis of a balanced gluten-free diet. Traditional foods such as idli, dosa, appam and puttu may be suitable when prepared exclusively from uncontaminated rice, millet or other gluten-free ingredients. However, the ingredients used in each preparation must be checked. For example, some dosa or idli mixtures may contain wheat-based ingredients, and some commercial preparations may be contaminated during processing.
Legumes such as green gram, black gram, chickpeas, cowpeas, lentils and kidney beans are valuable sources of protein, fibre, iron, zinc and folate. Vegetables and fruits provide vitamins, minerals, dietary fibre and phytochemicals. Eggs, fish, poultry, meat and dairy products provide high-quality proteins and several essential micronutrients. Nuts and seeds contribute healthy fats, magnesium, zinc and other minerals.
Dietary diversity is particularly important because patients with untreated celiac disease may have developed multiple nutritional deficiencies. A balanced diet helps restore the nutritional reserves required for normal metabolism, immune function, muscle maintenance and intestinal epithelial regeneration. It also reduces the risk of developing new deficiencies after adopting a restrictive gluten-free diet.
One of the most challenging aspects of celiac disease management is avoiding gluten that is not immediately apparent in food. Gluten may be present in processed foods, sauces, seasoning mixtures, soups, bakery products, confectionery, ready-made meals and certain food additives.
Wheat flour is sometimes used as a thickening agent in gravies, sauces, soups and processed foods. Malt extract and malt flavouring derived from barley may contain gluten. Breadcrumbs, ordinary soy sauce, some marinades and certain processed meat products may also contain gluten. Ingredients and manufacturing processes differ between products, so label checking is essential.
Cross-contamination occurs when gluten-free food comes into contact with gluten-containing food during preparation, storage, transportation or serving. Even naturally gluten-free foods can become unsuitable if contaminated by wheat flour or other gluten-containing ingredients.
In domestic kitchens, separate utensils and preparation surfaces may be necessary, particularly where wheat flour is used regularly. Flour dust can contaminate food, utensils and kitchen surfaces. Shared toasters, sieves, chopping boards, wooden utensils, frying oil and cooking equipment can also transfer gluten residues. A clean preparation area, thoroughly washed utensils and separate storage containers help reduce this risk.
Restaurants, hotels, bakeries and institutional kitchens require particular attention. A dish described as rice-based or gluten-free may still be contaminated through shared cooking equipment, sauces, flour-coated surfaces or common frying oil. Patients should communicate their dietary requirements clearly and ask about ingredients and preparation procedures.
The practical objective is not to create unnecessary fear of every food or kitchen environment, but to establish reliable methods of preventing repeated gluten exposure.
A major challenge of long-term gluten-free dietary management is maintaining nutritional balance. Commercial gluten-free foods are not necessarily nutritionally equivalent to conventional wheat-based products. Some are made primarily from refined rice flour, corn starch, potato starch or tapioca starch and may contain relatively little fibre, protein, iron, folate, zinc and B vitamins.
Consequently, a diet based heavily on packaged gluten-free bread, biscuits, cakes and snacks may correct gluten exposure without adequately correcting nutritional deficiencies. It may also provide excessive refined carbohydrates, sugar, saturated fat or salt, depending on the product.
A nutritionally balanced gluten-free diet should include sufficient protein, complex carbohydrates, healthy fats, dietary fibre, vitamins and minerals. Protein is required for tissue repair, muscle maintenance, enzyme production and immune function. Adequate energy intake is necessary to restore body weight in patients who have experienced prolonged malabsorption. Fibre supports bowel function and contributes to a healthy intestinal microbial environment.
Patients who have been undernourished may initially require a gradual increase in food intake. Sudden dietary changes can sometimes produce bloating or altered bowel habits, particularly while intestinal function is recovering. Individual tolerance should guide the pace of dietary expansion.
A registered dietitian familiar with celiac disease can help assess nutritional adequacy, identify hidden gluten sources and design a sustainable gluten-free diet that reflects the individual’s age, health status, food preferences and cultural dietary practices.
Dietary fibre has an important role in maintaining intestinal health. It includes several types of carbohydrates that resist digestion in the upper gastrointestinal tract and are partly or substantially fermented by microorganisms in the colon.
Vegetables, fruits, legumes, nuts, seeds and suitable whole gluten-free grains provide different forms of dietary fibre. Fermentable fibres can be metabolised by intestinal bacteria to produce short-chain fatty acids, particularly acetate, propionate and butyrate.
Butyrate is an important energy source for colonic epithelial cells and participates in maintaining intestinal barrier function. Short-chain fatty acids can also influence intestinal pH, microbial ecology, epithelial metabolism and immune signalling. These mechanisms have generated interest in the relationship between dietary fibre, the gut microbiome and intestinal inflammation.
Celiac disease is associated with changes in the composition and function of the intestinal microbiota in some patients. These changes may be influenced by gluten exposure, intestinal inflammation, altered nutrient availability, antibiotics, dietary composition and other environmental factors. A gluten-free diet can also change the microbial composition because the elimination of wheat-based foods may reduce the intake of certain fibres and fermentable carbohydrates.
Adequate fibre intake is therefore desirable, but it should be increased gradually. Some patients experience bloating, abdominal discomfort or diarrhoea when they suddenly consume large quantities of legumes, raw vegetables or fermentable carbohydrates. The presence of persistent gastrointestinal symptoms does not necessarily indicate continued gluten exposure; other dietary intolerances and functional gastrointestinal disorders may coexist.
There is currently insufficient clinical evidence to recommend a particular fibre supplement or microbiome-directed diet as a treatment for the underlying celiac immune response. The main objective is to maintain a varied, nutritionally adequate gluten-free diet.
Secondary lactose intolerance is relatively common in active celiac disease. Lactase, the enzyme responsible for digesting lactose, is located on the brush border of small-intestinal epithelial cells. Because these cells are damaged during active celiac disease, lactase activity may decline.
Undigested lactose passes into the colon, where bacteria ferment it and produce gases and organic acids. This can cause bloating, abdominal pain, flatulence and diarrhoea. These symptoms may resemble those caused by gluten exposure.
Secondary lactose intolerance is often temporary. As the intestinal mucosa recovers after gluten withdrawal, lactase activity may improve and lactose tolerance may return. Therefore, permanent dairy exclusion is not necessary for every patient.
Individuals who develop symptoms after consuming milk may temporarily reduce lactose intake or use lactose-free milk and dairy products. Fermented dairy products such as some yoghurts may be better tolerated because bacterial fermentation reduces lactose content. Hard cheeses generally contain relatively little lactose. However, individual tolerance varies.
Dairy products are valuable sources of calcium, protein and, in fortified products, vitamin D. Excessive or unnecessary dairy restriction may increase the risk of inadequate calcium intake, particularly in patients who already have reduced bone mineral density. If dairy products must be excluded, alternative calcium-rich foods or appropriately fortified substitutes should be included.
Bone health is a major concern in celiac disease. Malabsorption of calcium and vitamin D, inadequate nutritional intake, inflammation and reduced body weight can contribute to osteopenia and osteoporosis. In some patients, secondary hyperparathyroidism develops because reduced calcium absorption stimulates increased parathyroid hormone secretion.
Dietary management should therefore provide adequate calcium, vitamin D, protein and other nutrients involved in bone metabolism. Calcium can be obtained from dairy products, calcium-fortified foods, certain fish eaten with their bones, and some vegetables. Vitamin D is obtained from dietary sources such as oily fish, eggs and fortified foods, but dietary intake alone may be insufficient in people with deficiency.
Weight-bearing physical activity and resistance exercise are important because mechanical loading stimulates bone formation and helps maintain muscle strength. Walking, stair climbing, resistance exercises and other suitable activities can support skeletal health. The exercise programme should be adapted to age, cardiovascular status, joint health and physical capacity.
Patients with substantial malabsorption, previous fragility fractures, prolonged untreated disease or other osteoporosis risk factors may require bone mineral density assessment. Supplementation with calcium and vitamin D should be based on dietary intake, laboratory findings and individual fracture risk rather than prescribed indiscriminately.
Physical activity contributes to general health and can be particularly beneficial for people recovering from celiac disease. Exercise supports cardiovascular function, muscle strength, insulin sensitivity, bone health, balance and psychological well-being.
During active disease, some patients experience severe fatigue, anaemia, muscle weakness, weight loss or dehydration. Such individuals may not initially tolerate strenuous exercise. Physical activity should be increased gradually as nutritional status and general health improve.
Walking is a practical starting point for many people. Resistance exercises help restore muscle mass and strength, especially in those who have lost weight or developed muscle wasting. Balance and flexibility exercises can also be valuable, particularly for older adults and individuals with reduced physical activity.
Regular exercise may improve metabolic health and help reduce the risk of cardiovascular disease, type 2 diabetes and age-related loss of muscle mass. However, exercise does not neutralise gluten exposure and cannot prevent the intestinal immune reaction if gluten continues to be consumed.
Exercise programmes should be individualised. Patients with severe anaemia, significant osteoporosis, recent fractures, cardiac disease or unexplained neurological symptoms should obtain medical advice before undertaking vigorous activity.
Celiac disease can produce different effects on body weight. Some patients present with low body weight, muscle wasting and malnutrition because of chronic malabsorption. Others have normal body weight or are overweight or obese at diagnosis. Therefore, low body weight should not be considered an essential feature of celiac disease.
After starting a gluten-free diet, intestinal absorption improves and body weight may increase. In previously undernourished patients, this is often a desirable consequence of nutritional recovery. However, some individuals gain excessive weight because their replacement diet contains large quantities of refined starches, sugar and fat.
A healthy gluten-free diet should therefore emphasise nutritional quality rather than simply eliminating gluten. Adequate protein, vegetables, fruits, legumes, naturally gluten-free whole grains and appropriate quantities of healthy fats can support normal body composition and metabolic health.
In individuals with overweight or obesity, weight management should follow the same general principles used for other populations, while maintaining strict gluten exclusion. Extreme calorie restriction and nutritionally unbalanced diets should be avoided, particularly during the early recovery period.
Diarrhoea is a common manifestation of active celiac disease and may produce dehydration and disturbances in electrolyte balance. Loss of water, sodium, potassium and bicarbonate can become clinically important in patients with severe or prolonged diarrhoea.
Adequate fluid intake is essential. Oral rehydration solution is useful when there are substantial fluid and electrolyte losses. It is preferable to very sugary beverages, which can sometimes aggravate diarrhoea through osmotic effects.
Once gluten is eliminated, diarrhoea generally improves, although the speed of recovery varies. Persistent diarrhoea despite a strict gluten-free diet should not automatically be attributed to celiac disease. Secondary lactose intolerance, irritable bowel syndrome, microscopic colitis, pancreatic insufficiency, small intestinal bacterial overgrowth, infections and other gastrointestinal disorders may need consideration.
Prolonged diarrhoea, reduced urine output, dizziness, severe weakness or signs of dehydration require medical assessment, particularly in older adults.
Alcohol does not contain gluten in every form, but its relationship with celiac disease requires attention. Distilled alcoholic beverages made from wheat, barley or rye are generally considered gluten-free after proper distillation because gluten proteins are not expected to pass into the distilled product. However, flavoured beverages, beer, malt beverages and products containing gluten-based additives may not be suitable. Beer made from barley or wheat should be avoided unless specifically produced and certified as gluten-free.
Alcohol consumption can also affect general gastrointestinal health, nutritional status and liver function. Excessive alcohol intake may interfere with nutrient absorption and increase the risk of liver disease. Therefore, avoiding excessive alcohol is advisable, especially in patients with nutritional deficiencies or associated liver abnormalities.
Smoking has no established therapeutic or protective role in celiac disease. It is harmful to cardiovascular and respiratory health and may adversely affect bone health. Smoking cessation is advisable for general health, irrespective of celiac disease.
Patients should also be cautious with non-prescription supplements, herbal preparations and traditional remedies. Some preparations may contain wheat-derived ingredients, gluten-containing excipients or unverified ingredients. The gluten-free status of medicines and supplements should be checked when there is a reasonable concern, particularly for products taken regularly.
Living with a lifelong restrictive diet can create psychological and social challenges. Patients may experience anxiety about accidental gluten exposure, frustration over food restrictions, difficulty eating outside the home and feelings of social isolation.
Chronic stress can influence gastrointestinal symptoms through interactions between the brain, autonomic nervous system, endocrine system and intestinal nervous system. Stress may alter intestinal motility, visceral sensitivity and symptom perception. It can therefore aggravate abdominal discomfort or bowel disturbances in some patients.
However, stress is not the established cause of celiac disease, and psychological stress does not replace the gluten-dependent immunological mechanism. Stress reduction should be viewed as a supportive measure for overall well-being rather than a treatment for the underlying disease.
Adequate sleep supports metabolic regulation, immune function, cognitive performance and psychological health. Regular sleep schedules, physical activity and relaxation practices may improve quality of life. Persistent fatigue despite dietary treatment should nevertheless prompt evaluation for anaemia, vitamin deficiencies, thyroid disease, sleep disorders, depression or continuing intestinal injury.
Psychological support may be particularly useful for individuals who experience substantial anxiety or difficulty adapting to lifelong dietary restrictions. Education and practical support from family members can make dietary management considerably easier.
The intestinal microbiome consists of bacteria, viruses, fungi and other microorganisms living in the gastrointestinal tract. These microorganisms participate in the digestion of complex carbohydrates, production of metabolites, maintenance of the intestinal barrier and regulation of mucosal immunity.
Several studies have identified differences in the intestinal microbiota of people with celiac disease compared with healthy individuals. However, these differences are variable and may reflect gluten exposure, intestinal inflammation, dietary changes, antibiotic use, geographical factors and other influences. It is not yet established that a particular microbial imbalance is the primary cause of celiac disease.
Probiotics are live microorganisms that may provide health benefits when administered in adequate quantities. Certain probiotic strains have been investigated for their possible effects on intestinal barrier function, inflammatory signalling, microbial metabolism and gastrointestinal symptoms.
Some experimental studies have also investigated whether particular bacteria can break down gluten peptides. Nevertheless, no probiotic preparation has been demonstrated to reliably prevent or reverse the gluten-specific immune response in patients with celiac disease. Probiotics cannot be used to make a gluten-containing diet safe.
A balanced diet containing naturally gluten-free fibre sources may support a diverse intestinal microbiome. Probiotic foods such as yoghurt may be included if they are gluten-free and tolerated. Their use should be regarded as supportive nutrition rather than a substitute for the established treatment.
Celiac disease and irritable bowel syndrome (IBS) can produce similar gastrointestinal symptoms, including abdominal pain, bloating, diarrhoea and altered bowel habits. They are, however, fundamentally different conditions.
Celiac disease is an immune-mediated disorder in which gluten exposure produces characteristic small-intestinal injury in susceptible individuals. IBS is a disorder of gut–brain interaction involving altered intestinal sensitivity, motility and communication between the nervous system and gastrointestinal tract. IBS does not produce the characteristic gluten-dependent villous atrophy of celiac disease.
Before diagnosing IBS in a patient with chronic gastrointestinal symptoms, celiac disease should be appropriately excluded. This is particularly important because starting a gluten-free diet before diagnostic testing can reduce the sensitivity of blood tests and intestinal biopsy.
Some patients with confirmed celiac disease continue to experience IBS-like symptoms even after adopting a gluten-free diet. Possible explanations include secondary lactose intolerance, altered intestinal microbiota, visceral hypersensitivity, incomplete mucosal healing or an independent coexistence of IBS.
A low-FODMAP diet may improve symptoms in selected patients with persistent IBS-like complaints. FODMAPs are fermentable carbohydrates found in foods such as certain fruits, vegetables, legumes, milk products and wheat-based foods. However, a low-FODMAP diet is not a treatment for celiac disease. It should only be considered after gluten exclusion has been established and other causes of persistent symptoms have been assessed. Long-term unnecessary restriction can reduce dietary diversity and create additional nutritional problems.
Older adults may have particular challenges because celiac disease can be diagnosed late in life and may coexist with osteoporosis, cardiovascular disease, diabetes, thyroid disorders, reduced muscle mass and other age-related conditions.
In this age group, the symptoms may be less typical. Anaemia, fatigue, osteoporosis, weight loss, peripheral neuropathy or unexplained nutritional deficiencies may be more prominent than diarrhoea. Therefore, dietary treatment should be accompanied by careful assessment of nutritional status and associated diseases.
Older patients should avoid excessive dietary restriction. A gluten-free diet that provides adequate protein, calcium, vitamin D, iron, zinc and other essential nutrients is especially important for maintaining muscle mass, bone strength and functional independence.
Regular walking, appropriate resistance exercise and balance training can help reduce muscle loss and fall risk. The exercise programme must be adjusted to the individual’s cardiovascular health, joint function and skeletal condition.
Medication review is also important because some medicines can cause diarrhoea, interfere with nutrient absorption or produce symptoms resembling active celiac disease. Persistent symptoms should be evaluated systematically rather than managed through progressively restricting the diet.
Celiac disease requires lifelong follow-up even when symptoms have completely disappeared. Clinical improvement is important, but it does not always prove that the intestinal mucosa has fully recovered.
Follow-up generally includes assessment of gastrointestinal and extraintestinal symptoms, body weight, dietary adherence and nutritional status. Blood tests may include complete blood count, ferritin, iron studies, folate, vitamin B12, liver enzymes and vitamin D, depending on the patient’s clinical circumstances.
Tissue transglutaminase IgA antibodies are commonly used to monitor the response to treatment in patients with normal IgA levels. Total IgA should be measured when interpreting IgA-based tests, because IgA deficiency can produce falsely negative results. In patients with IgA deficiency, appropriate IgG-based tests may be used.
Falling or normalised antibody levels generally support a favourable response to gluten withdrawal, but they do not guarantee complete mucosal healing. Persistently elevated antibodies may suggest continued gluten exposure, although test interpretation depends on the clinical context and the time elapsed since dietary treatment began.
Bone mineral density assessment may be appropriate in patients with substantial nutritional deficiencies, prolonged untreated disease, osteoporosis risk factors or previous fragility fractures. Repeat intestinal biopsy is not routinely necessary for every patient who improves clinically, but it may be considered in selected adults with persistent symptoms, abnormal laboratory findings or concern about incomplete mucosal recovery.
Persistent symptoms despite an apparently strict gluten-free diet require a systematic evaluation. The first step is to examine possible inadvertent gluten exposure. If this is excluded, clinicians may investigate lactose intolerance, IBS, microscopic colitis, pancreatic insufficiency, bacterial overgrowth, other autoimmune conditions and, rarely, refractory celiac disease.
Dietary management is particularly important during childhood because untreated celiac disease can interfere with normal growth, bone development and puberty. Children may present with chronic diarrhoea, abdominal distension, poor appetite, short stature, delayed puberty, anaemia or failure to gain weight.
A nutritionally adequate gluten-free diet generally allows catch-up growth and improvement in nutritional status. However, unnecessary dietary restrictions can be especially harmful during periods of rapid growth and development.
Parents and caregivers should be educated about gluten-containing ingredients, food labels, school meals, snacks and cross-contamination. Children should gradually learn to understand their dietary requirements so that they can manage them independently as they grow older.
Schools and social environments should provide reasonable dietary accommodations. The objective is to ensure safety without creating unnecessary social exclusion or anxiety around food.
Diet and lifestyle have a central role in the treatment and long-term management of celiac disease. The complete and lifelong elimination of gluten is the essential intervention because it removes the environmental trigger responsible for the abnormal immune response and allows the intestinal mucosa to recover. Naturally gluten-free foods such as rice, millets, legumes, vegetables, fruits, fish, eggs and unprocessed meats can provide the foundation for a balanced diet, particularly when selected according to local food habits and nutritional requirements.
However, successful management requires more than gluten avoidance. Prevention of cross-contamination, adequate dietary fibre, correction of vitamin and mineral deficiencies, maintenance of calcium and vitamin D status, appropriate physical activity, healthy body weight, adequate hydration and attention to sleep and psychological well-being all contribute to long-term health. The intestinal microbiome may also be influenced by dietary composition, although probiotics and other microbiome-directed interventions have not been established as treatments for the underlying disease.
An important principle is that symptom control and immunological control are not always identical. A patient may feel well while intestinal inflammation persists, and persistent gastrointestinal symptoms do not necessarily indicate continued gluten exposure. Regular clinical follow-up, dietary assessment and appropriate laboratory monitoring are therefore essential.
Ultimately, the most effective approach is a strict lifelong gluten-free diet combined with nutritionally balanced eating, appropriate physical activity and individualised medical monitoring. Lifestyle measures support recovery and general health, but none can substitute for the elimination of gluten.
Central scientific conclusion: In celiac disease, diet has a unique role because it removes the specific environmental antigen that initiates the disease process. Other lifestyle interventions support intestinal recovery, nutritional rehabilitation and general health, but they do not replace gluten exclusion.
Role of Hormones in Celiac Disease
Hormones have an important but complex relationship with celiac disease. Although celiac disease is fundamentally a gluten-dependent, immune-mediated disorder rather than a primary endocrine disease, its effects extend beyond the gastrointestinal tract and can influence several hormonal systems. The intestinal mucosa is responsible not only for nutrient absorption but also for the production and regulation of hormones involved in digestion, appetite, glucose metabolism, bone formation, mineral homeostasis and energy balance. Consequently, intestinal inflammation, villous atrophy and nutrient deficiencies can disturb endocrine functions and contribute to systemic manifestations.
Celiac disease develops in genetically susceptible individuals, particularly those carrying HLA-DQ2 or HLA-DQ8 molecules. Gluten-derived peptides undergo modification by tissue transglutaminase 2 (TG2), facilitating their presentation to gluten-specific CD4+ T lymphocytes. The resulting immune response involves inflammatory cytokines, B lymphocytes, autoantibodies and cytotoxic intraepithelial lymphocytes. This produces villous atrophy, crypt hyperplasia and impaired absorption of nutrients.
The relationship between hormones and celiac disease operates through several interconnected mechanisms. First, damage to the intestinal mucosa can interfere with the production and release of gastrointestinal hormones. Second, malabsorption of vitamins and minerals can disturb hormone synthesis, secretion and biological activity. Third, inflammatory cytokines can influence endocrine organs and hormonal signalling pathways. Fourth, celiac disease is associated with an increased prevalence of certain autoimmune endocrine disorders, particularly autoimmune thyroid disease and type 1 diabetes. Finally, hormones themselves can influence immune regulation, intestinal barrier function and inflammatory responses.
Understanding these interactions helps explain why celiac disease may present with growth disturbances, delayed puberty, reproductive abnormalities, osteoporosis, thyroid dysfunction, altered glucose metabolism and unexplained fatigue.
The gastrointestinal tract is an important endocrine organ. Specialised enteroendocrine cells distributed throughout the stomach and intestine produce hormones that regulate digestion, intestinal motility, appetite, pancreatic secretion, glucose metabolism and communication between the gut and brain.
The small-intestinal mucosa contains several types of enteroendocrine cells. These include I cells, which produce cholecystokinin; S cells, which produce secretin; K cells, which produce glucose-dependent insulinotropic polypeptide; and L cells, which produce glucagon-like peptides and peptide YY. Other enteroendocrine cells produce serotonin and additional regulatory substances.
Because celiac disease damages the small-intestinal epithelium, it can affect the structure, distribution and function of enteroendocrine cells. Changes in intestinal architecture, nutrient availability and inflammatory signalling may consequently alter the release of gastrointestinal hormones.
However, the precise hormonal changes vary between individuals, and not every patient with celiac disease develops clinically significant gastrointestinal endocrine abnormalities. Some changes are secondary to intestinal injury and improve after gluten withdrawal.
Cholecystokinin (CCK) is a peptide hormone secreted primarily by I cells in the duodenum and jejunum in response to the presence of fats and proteins in the intestinal lumen.
CCK stimulates pancreatic enzyme secretion, contracts the gallbladder, promotes relaxation of the sphincter of Oddi and contributes to the regulation of gastric emptying. These functions are essential for normal digestion, particularly the digestion and absorption of dietary fats.
In celiac disease, proximal small-intestinal injury may disturb the normal response of enteroendocrine cells to nutrients. Reduced nutrient absorption and altered mucosal structure can influence CCK secretion and the coordination of pancreatic and biliary digestive activity.
If fat digestion and absorption become impaired, deficiencies of fat-soluble vitamins A, D, E and K may develop. However, fat malabsorption in celiac disease is primarily related to mucosal injury and impaired absorptive function, rather than a proven universal deficiency of CCK.
The relationship between CCK and celiac disease is therefore mainly physiological and secondary to intestinal dysfunction.
Secretin is produced by S cells in the duodenum in response to acidic gastric contents entering the small intestine. Its principal function is to stimulate bicarbonate-rich fluid secretion from the pancreas and biliary ducts, helping neutralise gastric acid and establish a suitable pH for pancreatic enzyme activity.
In celiac disease, the duodenal mucosa is frequently affected by inflammation and villous atrophy. Such damage may influence the normal endocrine response to nutrients and acid exposure.
Disturbances in bicarbonate secretion could theoretically affect the digestive environment, but there is insufficient evidence that defective secretin production is a major independent mechanism of celiac disease. The principal digestive abnormalities arise from mucosal injury, reduced absorptive surface and associated nutritional disturbances.
Gastrin is a hormone produced primarily by G cells in the gastric antrum. It stimulates gastric acid secretion through its effects on parietal cells and enterochromaffin-like cells. Gastrin also participates in the regulation of gastric mucosal growth and gastrointestinal motility.
Celiac disease primarily affects the small intestine rather than the stomach. Nevertheless, some patients may have associated gastric abnormalities, including autoimmune gastritis, which can alter gastric acid secretion and interfere with iron and vitamin B12 absorption.
Gastrin concentrations may become elevated in conditions associated with reduced gastric acid secretion because the normal inhibitory feedback from gastric acidity is diminished. Therefore, an elevated gastrin concentration in a patient with celiac disease may reflect an associated gastric disorder rather than a direct consequence of celiac disease itself.
This distinction is clinically important because iron and vitamin B12 deficiencies can arise from both intestinal malabsorption and associated gastric disease.
GIP, now commonly called glucose-dependent insulinotropic polypeptide, is secreted by K cells located predominantly in the duodenum and proximal jejunum. It is one of the two major incretin hormones, the other being glucagon-like peptide-1 (GLP-1).
When carbohydrates and fats enter the small intestine, GIP is released into the circulation. It stimulates pancreatic beta cells to release insulin in a glucose-dependent manner. It also participates in lipid metabolism and influences the storage and utilisation of energy.
Since K cells are located in regions frequently affected by celiac disease, mucosal injury may influence the normal nutrient-dependent secretion of GIP. Altered nutrient absorption and changes in the delivery of carbohydrates and fats to the intestinal mucosa can also modify its release.
However, the relationship between GIP secretion and celiac disease has not been sufficiently characterised to establish a consistent hormonal abnormality. Any changes should be interpreted in the context of intestinal injury, dietary composition and associated metabolic conditions rather than regarded as a defining feature of celiac disease.
GLP-1 is produced mainly by enteroendocrine L cells located throughout the intestine, with substantial populations in the distal small intestine and colon. It is released after food intake and has important effects on glucose metabolism, appetite and gastrointestinal motility.
GLP-1 stimulates insulin secretion when blood glucose is elevated, suppresses inappropriate glucagon secretion, delays gastric emptying and promotes satiety through actions on the nervous system. It is therefore an important component of the physiological communication between the intestine and pancreas.
Celiac disease can influence this system through changes in intestinal structure, nutrient absorption, food composition and the distribution or activity of enteroendocrine cells. The gluten-free diet itself may also alter GLP-1 secretion because many commercial gluten-free products differ from conventional grain products in their carbohydrate composition, fibre content and glycaemic characteristics.
GLP-1 has also attracted interest because it can influence intestinal epithelial growth and repair in experimental systems. Nevertheless, its precise contribution to mucosal recovery in human celiac disease remains uncertain. There is no established evidence that manipulating GLP-1 signalling treats the underlying gluten-specific immune response.
Peptide YY is a gastrointestinal hormone secreted mainly by L cells in the ileum and colon. Its release increases after meals, particularly following the consumption of fats and proteins.
PYY contributes to appetite regulation by acting on the hypothalamus and other neural pathways. It also slows gastrointestinal motility and delays gastric emptying, helping regulate the movement of food through the digestive tract.
In celiac disease, intestinal inflammation, altered nutrient absorption and changes in dietary composition may influence PYY secretion. Patients who experience malabsorption, weight loss or reduced food intake may develop changes in appetite-regulating signals. Conversely, after successful treatment, improved nutrient absorption and changes in food intake may alter the hormonal regulation of appetite and body weight.
PYY is therefore relevant to the nutritional consequences of celiac disease, but there is insufficient evidence to regard abnormal PYY secretion as a primary mechanism of the disease.
Ghrelin is a peptide hormone produced mainly by specialised cells in the stomach. It is often described as a hunger hormone because its circulating concentration generally increases before meals and decreases after food consumption.
Ghrelin stimulates appetite through hypothalamic pathways and also influences growth hormone release. It participates in energy balance, gastrointestinal motility and metabolic regulation.
In untreated celiac disease, chronic intestinal inflammation, reduced nutrient absorption and weight loss can influence ghrelin secretion. Some studies have reported altered ghrelin concentrations in patients with active celiac disease, although findings are not entirely consistent. Differences in nutritional status, body composition, age, disease severity and treatment duration may explain some of the variation.
Following gluten withdrawal, nutritional recovery and changes in body weight may alter ghrelin levels. These changes may reflect the restoration of energy balance rather than a direct modification of the gluten-specific immune response.
Ghrelin is also being investigated for its possible effects on gastrointestinal motility and tissue repair. However, its therapeutic significance in celiac disease remains experimental.
Leptin is a hormone produced primarily by adipocytes, the cells responsible for storing fat. It communicates information about the body’s energy reserves to the hypothalamus and participates in the regulation of appetite, energy expenditure and reproductive function.
Leptin also has important immunological properties. Its receptor belongs to the cytokine receptor family, and leptin can influence the activity of T lymphocytes, monocytes, macrophages and other immune cells. In experimental systems, leptin can promote inflammatory immune responses and influence the balance between regulatory and effector T-cell populations.
The relationship between leptin and celiac disease is complicated by changes in body composition and nutritional status. Patients with active disease who are underweight or malnourished may have reduced leptin concentrations because adipose tissue reserves are diminished. After gluten withdrawal and nutritional recovery, leptin concentrations may increase as body fat is restored.
In patients who are overweight or obese, leptin concentrations may be higher because adipose tissue produces more leptin. Obesity can also be associated with leptin resistance, in which the normal appetite-regulating effects of leptin become less effective.
Although leptin can influence immune activity, there is insufficient evidence that it initiates celiac disease or determines its clinical course. Its role is better understood as part of the interaction between nutritional status, adipose tissue and immune regulation.
Insulin and glucagon are pancreatic hormones that maintain blood glucose within a physiologically appropriate range. Insulin is produced by pancreatic beta cells and promotes glucose uptake and storage, while glucagon is produced by alpha cells and stimulates hepatic glucose production during fasting.
Celiac disease does not ordinarily cause direct destruction of pancreatic beta cells. Nevertheless, an important association exists between celiac disease and type 1 diabetes mellitus.
Both conditions are autoimmune disorders associated with genetic susceptibility, particularly certain HLA haplotypes. Type 1 diabetes involves immune-mediated destruction of pancreatic beta cells, leading to insulin deficiency. Celiac disease involves a gluten-dependent immune reaction directed against intestinal tissues, with TG2 serving as a major autoantigen.
The coexistence of these conditions reflects shared genetic and immunological susceptibility rather than the direct effect of gluten on pancreatic insulin-producing cells. Individuals with type 1 diabetes have a higher prevalence of celiac disease than the general population, and screening for celiac disease is commonly recommended in the appropriate clinical context.
In patients who have both disorders, a gluten-free diet is necessary to control celiac disease, while insulin remains essential for the treatment of type 1 diabetes. Improved intestinal absorption after gluten withdrawal can sometimes alter nutritional intake and insulin requirements, particularly in children and patients who were previously malnourished. Blood glucose should therefore be monitored carefully during nutritional recovery.
It is also important to distinguish type 1 diabetes from type 2 diabetes. Type 2 diabetes is primarily associated with insulin resistance and impaired insulin secretion. It is not an established direct consequence of celiac disease, although both conditions can coexist.
Thyroid hormones, principally thyroxine (T4) and triiodothyronine (T3), regulate basal metabolic activity, energy expenditure, thermogenesis, cardiovascular function, growth, brain development and gastrointestinal motility.
The thyroid gland produces mainly T4, which is converted in peripheral tissues into the more biologically active T3 by selenium-dependent deiodinase enzymes. Thyroid hormone production is regulated by thyroid-stimulating hormone (TSH), secreted by the anterior pituitary gland.
Celiac disease has a recognised association with autoimmune thyroid disorders, particularly Hashimoto’s thyroiditis. Hashimoto’s thyroiditis involves an immune response against thyroid antigens, including thyroid peroxidase and thyroglobulin. Progressive destruction of thyroid tissue may reduce thyroid hormone production and cause hypothyroidism.
The increased coexistence of celiac disease and autoimmune thyroid disease is thought to reflect shared genetic susceptibility and immune-regulatory mechanisms. Certain HLA and non-HLA genetic variants can contribute to susceptibility to more than one autoimmune disorder.
Hypothyroidism can produce fatigue, weight gain, constipation, dry skin, hair loss, cold intolerance and cognitive slowing. These manifestations may overlap with symptoms of untreated celiac disease, making clinical assessment important.
Hyperthyroidism can also occur in patients with celiac disease, particularly through associated autoimmune Graves’ disease. Graves’ disease involves antibodies that stimulate the TSH receptor, producing excessive thyroid hormone secretion. Its manifestations include weight loss, palpitations, tremor, heat intolerance and increased bowel movements.
The presence of thyroid dysfunction should not be assumed to result from gluten-induced intestinal injury. It represents a distinct endocrine disorder that may coexist with celiac disease because of shared autoimmune susceptibility.
There is also a practical nutritional interaction. Untreated celiac disease can interfere with the absorption of oral levothyroxine, the standard treatment for hypothyroidism. After gluten withdrawal and intestinal recovery, levothyroxine absorption may improve, sometimes requiring reassessment of the dose. Patients should not change thyroid medication independently; dose adjustments should be guided by TSH and clinical evaluation.
Parathyroid hormone (PTH) is secreted by the parathyroid glands in response to reduced blood calcium concentrations. Its main function is to maintain calcium homeostasis by acting on bone and kidneys and indirectly influencing intestinal calcium absorption through vitamin D metabolism.
In celiac disease, intestinal damage may reduce the absorption of calcium and vitamin D. Reduced calcium availability can stimulate PTH secretion, producing secondary hyperparathyroidism.
PTH increases renal calcium reabsorption, promotes phosphate excretion and stimulates the production of active vitamin D, or calcitriol, in the kidneys. It also increases bone turnover by influencing the activity of osteoblast-lineage cells, which regulate osteoclast formation.
When calcium and vitamin D deficiencies persist, the increased PTH response can contribute to the mobilisation of calcium from bone. This may produce reduced bone mineral density, osteopenia and osteoporosis.
Secondary hyperparathyroidism is therefore an important endocrine mechanism linking intestinal malabsorption to skeletal complications in celiac disease. It is different from primary hyperparathyroidism, in which the parathyroid glands themselves produce excessive PTH, often because of a parathyroid adenoma.
Correction of calcium and vitamin D deficiencies, together with a strict gluten-free diet, can help restore normal mineral metabolism. PTH concentrations may gradually return towards normal as calcium absorption improves.
Vitamin D occupies a special position because it is technically a vitamin obtained from food or produced in the skin through sunlight exposure, but its active form functions as a steroid-like hormone.
Vitamin D is converted in the liver into 25-hydroxyvitamin D and subsequently in the kidneys and certain other tissues into its active form, 1,25-dihydroxyvitamin D, or calcitriol. Calcitriol binds to the vitamin D receptor, which regulates the expression of numerous genes involved in calcium absorption, phosphate metabolism, bone physiology and immune function.
In celiac disease, fat malabsorption can reduce vitamin D absorption. The resulting deficiency may impair calcium absorption and contribute to secondary hyperparathyroidism, osteomalacia and osteoporosis.
Vitamin D also influences immune regulation. It can affect dendritic-cell maturation, T-cell differentiation, regulatory T-cell activity and inflammatory cytokine production. These effects have generated considerable interest in its possible relationship with autoimmune diseases.
However, although vitamin D deficiency is clinically important in celiac disease, there is insufficient evidence that supplementation independently suppresses the gluten-specific immune reaction. Its established role is the correction of deficiency, maintenance of bone health and support of normal physiological and immune functions.
Calcitonin is a hormone produced by the parafollicular C cells of the thyroid gland. It can inhibit osteoclast activity and reduce the release of calcium from bone, although its role in maintaining normal calcium concentrations in adult humans is relatively limited compared with that of PTH and vitamin D.
Celiac disease may influence the balance of bone metabolism through calcium and vitamin D malabsorption, secondary hyperparathyroidism and changes in bone turnover. Calcitonin participates in the wider physiological system that regulates bone resorption, but there is no established evidence that abnormal calcitonin secretion is a characteristic feature of celiac disease.
The major endocrine mechanism underlying celiac-associated bone disease is generally the interaction between calcium deficiency, vitamin D deficiency and secondary hyperparathyroidism rather than a primary calcitonin abnormality.
Growth hormone (GH) is secreted by the anterior pituitary gland and stimulates growth, protein synthesis and metabolic regulation. Many of its growth-promoting effects are mediated through insulin-like growth factor 1 (IGF-1), which is produced mainly by the liver in response to GH.
IGF-1 promotes the proliferation and differentiation of cells in bone, cartilage and other tissues. It is particularly important for normal childhood growth and skeletal development.
Untreated celiac disease can impair the GH–IGF-1 axis indirectly through malnutrition, chronic inflammation and reduced availability of essential nutrients. In children, these disturbances may result in reduced growth velocity, short stature and delayed skeletal maturation.
Importantly, low IGF-1 in a child with untreated celiac disease does not necessarily indicate primary growth hormone deficiency. Chronic nutritional insufficiency and inflammation can reduce IGF-1 production or alter its biological activity even when pituitary growth hormone secretion is adequate.
Following gluten withdrawal and nutritional recovery, growth velocity may improve, and catch-up growth can occur. Early diagnosis is particularly important because prolonged growth impairment may compromise final adult height.
Adults with celiac disease may also experience changes in body composition and bone metabolism related to malnutrition, although the classic growth-related consequences are most evident in children.
Celiac disease can affect reproductive health, particularly when the disease remains undiagnosed or is associated with substantial malnutrition. The reproductive system is sensitive to energy availability, body composition, chronic inflammation and nutritional status.
In females, the hypothalamus regulates reproductive function through the secretion of gonadotropin-releasing hormone (GnRH). GnRH stimulates the anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH), which regulate ovarian function and the production of oestrogen and progesterone.
Severe malnutrition and chronic systemic illness can disturb this hypothalamic–pituitary–ovarian axis. Reduced GnRH pulsatility may lead to impaired gonadotropin secretion, menstrual irregularities, delayed menarche or secondary amenorrhoea.
Oestrogen is important not only for reproductive function but also for bone maintenance. Reduced oestrogen availability can increase bone resorption and aggravate the skeletal consequences of calcium and vitamin D deficiency.
In males, testosterone is regulated by the hypothalamic–pituitary–gonadal axis. Severe nutritional deficiency and chronic illness may interfere with normal reproductive hormone regulation and contribute to reduced testosterone concentrations, impaired libido or reproductive disturbances in some patients.
Some studies have reported associations between celiac disease and reproductive difficulties, including delayed puberty, menstrual abnormalities and certain adverse pregnancy outcomes. However, findings vary, and not every individual with celiac disease experiences reproductive impairment. Many people with well-managed celiac disease have normal reproductive function and healthy pregnancies.
A strict gluten-free diet and correction of nutritional deficiencies may improve reproductive health when the abnormalities are related to active disease and malnutrition. Persistent reproductive problems require appropriate gynaecological or endocrinological evaluation rather than being attributed automatically to celiac disease.
Prolactin is secreted by lactotroph cells in the anterior pituitary gland. Its principal physiological function is the stimulation and maintenance of milk production after childbirth. It also influences reproductive regulation and has immunomodulatory effects.
Prolactin secretion is mainly inhibited by dopamine released from the hypothalamus. Increased prolactin can suppress GnRH secretion and interfere with normal reproductive hormone function.
Celiac disease is not a recognised primary cause of hyperprolactinaemia. However, reproductive abnormalities in patients with celiac disease may require assessment of prolactin when clinically indicated, particularly when menstrual disturbance, infertility or reduced libido is present.
Prolactin also interacts with immune cells and can influence certain inflammatory responses. Nevertheless, there is insufficient clinical evidence to establish prolactin as a major regulator or therapeutic target in celiac disease.
Cortisol is a steroid hormone produced by the adrenal cortex. It is regulated by the hypothalamic–pituitary–adrenal (HPA) axis, in which hypothalamic corticotropin-releasing hormone stimulates pituitary secretion of adrenocorticotropic hormone, which in turn stimulates cortisol production.
Cortisol regulates glucose metabolism, protein and fat metabolism, vascular function and the body’s response to physiological stress. It also has important anti-inflammatory and immunomodulatory effects.
Chronic illness, nutritional stress, pain, sleep disturbances and psychological stress can influence HPA-axis activity. Therefore, some patients with active celiac disease may experience changes in stress-related hormonal regulation. However, these changes are not sufficiently specific or consistent to be regarded as a defining endocrine feature of the disease.
Celiac disease is also associated with autoimmune conditions that may affect the adrenal glands, although autoimmune Addison’s disease is much less common than autoimmune thyroid disease. In Addison’s disease, destruction of the adrenal cortex causes inadequate production of cortisol and often aldosterone.
Unexplained weight loss, low blood pressure, persistent vomiting, salt craving, skin pigmentation and severe weakness may suggest adrenal insufficiency and require prompt medical assessment. These manifestations should not be attributed to ordinary celiac-related malabsorption without investigation.
Adiponectin is a hormone produced predominantly by adipose tissue. It influences insulin sensitivity, fatty-acid oxidation, glucose metabolism and inflammatory regulation.
Unlike leptin, circulating adiponectin concentrations are often inversely associated with body fat mass. Adiponectin has anti-inflammatory and insulin-sensitising effects in several experimental and clinical contexts.
In celiac disease, changes in body weight and nutritional status may influence adiponectin concentrations. Patients with malnutrition and reduced adipose tissue may show different adiponectin patterns from individuals who are overweight or metabolically unhealthy.
Other adipose-derived signalling molecules, including resistin, also participate in metabolic and inflammatory pathways. Their precise contribution to celiac disease remains under investigation, and there is no established role for measuring these hormones in routine diagnosis or monitoring.
One of the most interesting aspects of celiac disease is the interaction between the immune system and endocrine signalling. Hormones are not simply regulators of metabolism and reproduction; several also influence immune-cell development, cytokine production, epithelial integrity and inflammatory responses.
Vitamin D acts through its nuclear receptor to influence immune-cell differentiation and inflammatory signalling. Leptin can promote certain pro-inflammatory immune responses. Ghrelin has been investigated for possible anti-inflammatory and tissue-protective effects. Oestrogens can influence both innate and adaptive immune responses, while glucocorticoids regulate inflammation through intracellular glucocorticoid receptors.
These interactions help explain why nutritional status, reproductive physiology, metabolic health and intestinal immunity can influence one another.
Nevertheless, it is important not to confuse general immunomodulatory properties with established disease causation. Celiac disease is initiated by the interaction of gluten-derived peptides, HLA susceptibility molecules and gluten-specific immune responses. Hormones may influence the surrounding physiological environment, but no single hormonal imbalance has been demonstrated to be the primary cause of celiac disease.
A strict gluten-free diet can gradually restore intestinal architecture and improve nutrient absorption. As the intestinal mucosa recovers, several hormonal disturbances associated with malnutrition and intestinal dysfunction may also improve.
In children, improved nutrient absorption can restore the normal GH–IGF-1 growth pathway, resulting in increased growth velocity and catch-up growth. In individuals with calcium and vitamin D deficiency, correction of malabsorption can reduce secondary hyperparathyroidism and improve bone metabolism.
In patients with reproductive disturbances associated with severe malnutrition, restoration of adequate energy intake and nutritional status may improve hypothalamic–pituitary–gonadal function. Menstrual regularity and reproductive hormone balance may recover in some individuals.
Changes in gastrointestinal hormones may also occur as nutrient absorption and enteroendocrine function improve. Appetite-regulating hormones such as ghrelin, leptin and PYY may change with restoration of body weight and normal energy balance.
However, the effects of a gluten-free diet on endocrine function are not identical in all patients. Associated autoimmune thyroid disease, type 1 diabetes and other endocrine disorders may persist even after the intestinal mucosa has recovered. These conditions require their own long-term treatment.
Hormonal investigations should be selected according to clinical manifestations rather than performed indiscriminately in every patient.
In children with short stature, delayed puberty or impaired growth, evaluation may include growth charts, growth velocity, thyroid function, IGF-1 and other investigations guided by clinical findings. A low IGF-1 concentration should be interpreted in relation to nutritional status and inflammation before diagnosing growth hormone deficiency.
In patients with suspected thyroid disease, serum TSH and free T4 are the principal initial investigations. Thyroid peroxidase antibodies and thyroglobulin antibodies may help identify autoimmune thyroiditis when appropriate.
In patients with bone disease, serum calcium, phosphate, 25-hydroxyvitamin D, alkaline phosphatase and PTH may be assessed. These measurements help identify vitamin D deficiency, secondary hyperparathyroidism and disturbances in mineral metabolism.
For reproductive abnormalities, the appropriate evaluation depends on the clinical presentation and may include LH, FSH, oestradiol, progesterone, testosterone, prolactin and thyroid function tests. These results must be interpreted in relation to age, menstrual status, nutritional condition and other physiological factors.
In patients with diabetes, blood glucose and HbA1c are important for metabolic monitoring. Individuals with type 1 diabetes and celiac disease may require adjustment of insulin doses as intestinal absorption and dietary intake change.
The evaluation of suspected adrenal insufficiency requires appropriate cortisol and ACTH testing under medical supervision. Such investigations are indicated when symptoms suggest adrenal disease, not as routine screening for every patient with celiac disease.
A scientifically important distinction must be maintained between hormonal disturbances caused indirectly by intestinal injury and endocrine disorders that coexist with celiac disease.
Hormones participate in several important aspects of celiac disease, although the disease itself is not primarily caused by hormonal dysfunction. Intestinal mucosal damage can influence the production and release of gastrointestinal hormones such as cholecystokinin, secretin, GIP, GLP-1 and peptide YY. Nutritional deficiencies and chronic inflammation can affect hormonal regulation of growth, bone metabolism, reproduction and energy balance. Ghrelin, leptin and adiponectin connect nutritional status with metabolic and immune regulation.
The most clinically significant endocrine relationships are the association of celiac disease with autoimmune thyroid disorders and type 1 diabetes, the development of secondary hyperparathyroidism due to calcium and vitamin D malabsorption, and impaired GH–IGF-1 activity in children with growth retardation. Reproductive disturbances may also occur in patients with prolonged untreated disease and substantial nutritional deficiency.
A strict gluten-free diet can restore intestinal absorption and improve many secondary hormonal disturbances. However, associated autoimmune endocrine disorders may persist and require independent treatment. Therefore, the management of celiac disease should include attention not only to intestinal inflammation and nutritional deficiencies but also to growth, bone metabolism, thyroid function, glucose regulation and reproductive health when clinically indicated.
The central scientific interpretation is that celiac disease creates an interaction between intestinal immunity, nutritional physiology and endocrine regulation. Hormones influence metabolism, growth, reproduction and immune responses, while gluten-induced intestinal injury can disturb the nutritional and physiological conditions necessary for their normal functioning. This interaction helps explain why celiac disease can produce manifestations far beyond the gastrointestinal tract.
Important Biological Ligands Involved in Celiac Disease
Biological ligands have a central role in the molecular pathogenesis of celiac disease because the disorder develops through a series of specific molecular recognition and binding interactions between dietary antigens, enzymes, antigen-presenting molecules, antibodies, receptors and intracellular signalling proteins. These interactions determine how gluten-derived peptides are processed, recognised by the immune system and ultimately converted into an inflammatory response that damages the small-intestinal mucosa. In molecular biology, a ligand is a molecule or molecular group that binds selectively to another molecule, usually a protein, through structural, chemical and electrostatic compatibility. Ligands include proteins, peptides, amino acids, hormones, neurotransmitters, antibodies, carbohydrates, lipids and other small molecules. Their biological effects depend not simply on their presence but on their ability to bind appropriate molecular targets and influence the activity of those targets.
Celiac disease provides an especially informative example of ligand–receptor biology. Gluten-derived peptides act as dietary antigenic ligands. Tissue transglutaminase 2 modifies selected peptides and also serves as an autoantigen. HLA-DQ2 and HLA-DQ8 molecules bind deamidated gluten peptides and present them to T lymphocytes. T-cell receptors recognise these peptide–HLA complexes, while B-cell receptors recognise antigens such as TG2. Cytokines and their receptors subsequently regulate inflammatory activity and epithelial destruction. The disease is therefore not produced by one isolated molecular interaction. It emerges from a coordinated network of ligand binding, antigen recognition, immune-cell activation and tissue injury.
The most important initiating ligands in celiac disease are peptides derived from gluten proteins. Gluten is a complex mixture of storage proteins found in wheat, barley and rye. Its principal immunologically relevant components include gliadins and glutenins in wheat, hordeins in barley and secalins in rye. These proteins contain relatively high proportions of glutamine and proline. Proline-rich sequences are resistant to complete digestion by ordinary human gastrointestinal proteases. Consequently, partially digested peptides can survive passage through the stomach and small intestine and interact with the intestinal mucosal immune system.
Among the best-studied gluten peptides is the 33-amino-acid alpha-gliadin peptide, commonly called the 33-mer. It contains multiple overlapping T-cell epitopes capable of stimulating celiac-associated immune responses after appropriate processing. Other immunogenic peptides are also involved, and the 33-mer is not the only pathogenic gluten-derived sequence. These peptides function as antigenic ligands because they bind to particular molecular targets in the immune system. Their biological significance depends on their amino-acid sequence, three-dimensional conformation, susceptibility to enzymatic modification and affinity for antigen-presenting molecules.
An important point is that gluten peptides are not intrinsically pathogenic in everyone. Their ability to initiate celiac disease depends on genetic susceptibility, particularly the presence of HLA-DQ2 or HLA-DQ8, together with the development of an inappropriate immune response.
Tissue transglutaminase 2, or TG2, occupies a particularly important position in the molecular interactions of celiac disease. It is an enzyme that catalyses protein deamidation and transamidation. It is also the principal autoantigen recognised by the characteristic anti-TG2 antibodies found in patients with celiac disease.
TG2 modifies selected glutamine residues in gluten peptides through a reaction called deamidation. During this reaction, glutamine is converted into glutamate, introducing a negative charge into the peptide. This modification changes the peptide’s molecular properties and increases its binding affinity for HLA-DQ2 and HLA-DQ8 molecules. The modified peptide can consequently be presented more effectively to gluten-specific CD4+ T lymphocytes.
TG2 therefore has two important molecular roles. First, it enzymatically modifies gluten-derived ligands, making many of them more immunogenic. Second, TG2 itself becomes an immune target, leading to the production of anti-TG2 antibodies. The interaction between TG2, gluten peptides and B lymphocytes also helps explain the development of autoimmunity. B cells that recognise TG2 can internalise TG2-associated material containing gluten peptides. They can then present gluten-derived peptides to gluten-specific T cells and receive T-cell help for antibody production. This is an example of linked recognition.
Anti-TG2 antibodies are important diagnostic biomarkers. Nevertheless, the precise contribution of these antibodies to direct villous destruction remains incompletely understood. TG2 is a normal human enzyme involved in tissue repair, extracellular matrix organisation and other cellular functions. Its involvement in celiac disease arises from its interaction with gluten peptides in a genetically susceptible immune environment.
HLA-DQ2 and HLA-DQ8 are specialised antigen-presenting molecules belonging to the major histocompatibility complex class II family. They are not enzymes or antibodies. Their function is to bind peptide antigens and display them on the surface of antigen-presenting cells for recognition by CD4+ T lymphocytes.
HLA-DQ2 is commonly associated with the genetic variants HLA-DQ2.5 and HLA-DQ2.2, while HLA-DQ8 is associated with a distinct combination of HLA-DQA1 and HLA-DQB1 alleles. Their importance in celiac disease arises from their peptide-binding properties. Deamidated gluten peptides contain negatively charged glutamate residues at positions that can interact favourably with the binding grooves of HLA-DQ2 or HLA-DQ8 molecules.
The interaction can be understood as a form of molecular complementarity. The peptide-binding groove provides a specific molecular environment, and the modified gluten peptide contains chemical groups that can form favourable interactions within it. The resulting peptide–HLA complex becomes a molecular ligand for the T-cell receptor. This is the crucial transition from antigen processing to antigen-specific adaptive immune activation.
Most people with celiac disease carry HLA-DQ2 or HLA-DQ8, but many individuals carrying these molecules never develop the disease. Their presence confers genetic susceptibility rather than guaranteeing disease development.
The T-cell receptor is a specialised membrane protein expressed on T lymphocytes. It recognises antigenic peptides only when they are presented in association with appropriate major histocompatibility complex molecules. In celiac disease, the relevant ligand is not free gluten peptide alone. It is the molecular complex formed by a deamidated gluten peptide bound to HLA-DQ2 or HLA-DQ8. The T-cell receptor recognises this combined molecular structure.
When the T-cell receptor binds the peptide–HLA complex, additional co-receptor and intracellular signalling interactions activate the T lymphocyte. CD4 acts as a co-receptor that stabilises interaction with the class II HLA molecule. Intracellular signalling proteins then initiate the transcriptional and metabolic changes required for T-cell activation.
Activated gluten-specific CD4+ T cells produce inflammatory cytokines, particularly interferon-gamma, and other mediators that promote intestinal inflammation. They also provide help to B lymphocytes, contributing to the production of anti-TG2 antibodies. This interaction illustrates an important principle of molecular immunology: the biological specificity of an immune response depends on the complementary recognition of a molecular complex rather than on the binding of an isolated antigen alone.
The B-cell receptor is a membrane-bound immunoglobulin expressed on the surface of B lymphocytes. It recognises specific molecular structures, known as epitopes, on antigens. In celiac disease, B cells that recognise TG2 can bind the enzyme through their B-cell receptors. When TG2 is associated with gluten-derived material, these B cells can internalise the complex and process its protein components.
The B cells subsequently present gluten-derived peptides through HLA-DQ2 or HLA-DQ8 molecules. Gluten-specific helper T cells recognise these peptides and provide the signals needed for B-cell activation, proliferation and differentiation into antibody-producing plasma cells. This process helps explain the production of anti-TG2 antibodies despite the fact that the disease is initiated by a dietary antigen. The B cell recognises TG2, while the helper T cell recognises a gluten peptide presented by the B cell. The two immune-cell populations cooperate through linked recognition.
Anti-TG2 antibodies are important biological products of this process and are widely used in the diagnosis of celiac disease. Their presence indicates an immune response associated with the disease, although their precise contribution to direct villous destruction remains incompletely understood.
Anti-TG2 antibodies are immunoglobulins directed against tissue transglutaminase 2. They are among the most important serological markers of celiac disease. The principal diagnostic antibody is IgA anti-TG2. IgG anti-TG2 may also be relevant in selected circumstances, particularly when total IgA deficiency is present, although IgG-based tests must be interpreted within the appropriate diagnostic context.
These antibodies bind to antigenic regions on TG2. Their binding can form immune complexes and may influence certain TG2-related biological processes. However, the extent to which anti-TG2 antibodies directly cause intestinal injury remains an active area of research. The most firmly established mechanism of mucosal injury is the cellular immune response involving gluten-specific T cells, inflammatory cytokines and cytotoxic intraepithelial lymphocytes. Therefore, anti-TG2 antibodies should not be considered the sole or principal agents responsible for villous atrophy.
From the ligand perspective, anti-TG2 antibodies are molecular recognition products that bind a self-protein. Their formation demonstrates how a dietary antigen can lead to an autoimmune response against a human enzyme.
Interleukin-15 (IL-15) is a cytokine with a particularly important role in celiac disease. It is produced by several cell types, including intestinal epithelial cells and antigen-presenting cells. It regulates the survival, proliferation and functional activity of natural killer cells and selected T-cell populations.
IL-15 is especially important in the activation of intraepithelial lymphocytes in the intestinal mucosa. In active celiac disease, increased IL-15 signalling can promote cytotoxic characteristics in these lymphocytes. IL-15 binds to a receptor complex consisting of IL-15 receptor alpha, the IL-2/15 receptor beta chain (CD122) and the common gamma chain (CD132). This receptor interaction activates intracellular signalling pathways, including JAK–STAT pathways.
Activated intraepithelial lymphocytes can express cytotoxic molecules and recognise stressed intestinal epithelial cells. This contributes to epithelial-cell destruction and villous atrophy. IL-15 is therefore a major cytokine ligand connecting the inflammatory environment to the cellular destruction of the intestinal epithelium.
Interferon-gamma (IFN-γ) is produced principally by activated T lymphocytes and natural killer cells. It is one of the important inflammatory mediators in celiac disease. IFN-γ binds to its receptor, which consists of IFN-γ receptor 1 and IFN-γ receptor 2 subunits. Receptor activation stimulates JAK1 and JAK2 kinases, followed by activation of STAT1. The resulting signalling pathway changes the expression of genes involved in antigen presentation, immune-cell activation and inflammatory responses.
In the intestinal mucosa, IFN-γ contributes to inflammation and can influence epithelial-cell function and barrier integrity. It also increases the expression of certain antigen-presentation molecules and inflammatory mediators. The importance of IFN-γ is not that it specifically causes celiac disease, but that it amplifies the inflammatory response once gluten-specific immune activation has occurred.
Tumour necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine produced by activated macrophages, T lymphocytes and other immune cells. It binds to two principal receptors, TNFR1 and TNFR2, which activate different intracellular signalling pathways. TNFR1 can initiate inflammatory signalling and, under particular conditions, programmed cell death. TNFR2 is involved in immune regulation, cellular survival and tissue responses.
In celiac disease, TNF-α contributes to the inflammatory environment and can influence epithelial-cell function, immune-cell recruitment and tissue remodelling. Its activity may interact with other cytokines, including IFN-γ and IL-15. TNF-α is not a disease-specific ligand, and its presence is not sufficient to establish celiac disease. It is part of the broader inflammatory network involved in intestinal injury.
Interleukin-21 (IL-21) is a cytokine produced mainly by specialised CD4+ T-cell populations, including follicular helper T cells. It binds to the IL-21 receptor, which signals through the common gamma chain and activates JAK–STAT pathways.
IL-21 promotes B-cell differentiation, antibody production and the development of certain effector T-cell populations. It therefore provides an important link between T-cell activation and humoral immune responses. In celiac disease, IL-21 is relevant to the interaction between gluten-specific T cells and B lymphocytes. It can contribute to B-cell activation and the development of antibody responses, including the production of antibodies against TG2.
Its role is part of the adaptive immune network and is not limited to celiac disease. IL-21 also participates in immune responses to infections and in other autoimmune conditions.
Interleukin-2 (IL-2) is a cytokine produced primarily by activated T lymphocytes. It binds to the IL-2 receptor, which can contain three subunits: CD25, CD122 and CD132. IL-2 is essential for T-cell proliferation, survival and differentiation. It is also particularly important for the maintenance and function of regulatory T cells, which help prevent inappropriate immune responses against self-antigens.
In celiac disease, IL-2 signalling is relevant because gluten-specific T-cell activation occurs in an environment where immune regulation is insufficient to prevent the pathological response. Regulatory T cells are present, but their ability to control the gluten-specific inflammatory response is inadequate. IL-2 therefore has a dual significance: it can support inflammatory T-cell expansion, but it is also essential for maintaining immune tolerance through regulatory T-cell function. Its biological effect depends on the responding cell population and the context of receptor signalling.
The interaction between natural killer group 2 member D (NKG2D) and its ligands is an important component of epithelial injury in celiac disease. NKG2D is an activating receptor expressed on natural killer cells and certain cytotoxic T lymphocytes, including subsets of intraepithelial lymphocytes.
Its ligands include MICA and MICB, which are cell-surface proteins belonging to the MHC class I-related family. These proteins are often expressed at higher levels by cells experiencing stress, inflammation or cellular damage. In celiac disease, intestinal epithelial cells can increase the expression of MICA and related stress ligands under the influence of inflammatory signalling, particularly IL-15.
When NKG2D binds to MICA or MICB, it can activate cytotoxic responses in immune cells. This interaction promotes the recognition and destruction of stressed epithelial cells. The IL-15–NKG2D–MICA/MICB pathway is therefore an important molecular mechanism linking epithelial stress to cytotoxic lymphocyte activity and villous injury.
T-cell activation generally requires more than the recognition of an antigenic peptide by the T-cell receptor. A second co-stimulatory signal is normally required. CD28 is a receptor expressed on T lymphocytes. Its principal ligands are CD80 (B7-1) and CD86 (B7-2), expressed on antigen-presenting cells.
The interaction between CD28 and CD80/CD86 strengthens T-cell activation and promotes cytokine production, proliferation and survival. Another important interaction involves CTLA-4, an inhibitory receptor that competes with CD28 for CD80 and CD86. CTLA-4 helps regulate immune responses and prevents excessive T-cell activation. These interactions are relevant to the general regulation of T-cell responses in celiac disease. However, they are not unique to the disease and should be understood as part of the wider immune-regulatory network.
Transforming growth factor-beta (TGF-β) is a multifunctional cytokine involved in immune regulation, cellular differentiation, extracellular matrix formation and tissue repair. TGF-β binds to its receptor complex, consisting of TGF-β receptor type I and type II. This activates intracellular SMAD signalling pathways that regulate gene expression.
TGF-β is important for the development and maintenance of regulatory T cells, which suppress excessive immune responses and help maintain tolerance to harmless antigens. It also participates in epithelial repair and extracellular matrix remodelling. In celiac disease, its activity is relevant to the balance between inflammatory damage and tissue recovery. However, TGF-β can have different effects depending on the inflammatory environment. In some circumstances, it supports immune tolerance; in others, in combination with inflammatory cytokines, it may participate in the development of particular effector T-cell populations.
In addition to dietary antigens and immune cytokines, several structural molecules participate in intestinal tissue integrity and repair. Collagen, laminin and fibronectin are extracellular matrix proteins that interact with integrin receptors on epithelial and other cells. These interactions regulate cell attachment, migration, survival and tissue organisation.
Integrins are transmembrane receptor proteins that bind extracellular matrix ligands and transmit signals to the intracellular cytoskeleton. They are important for maintaining epithelial architecture and facilitating tissue repair. In celiac disease, villous injury and inflammation alter the extracellular matrix environment. The interactions between integrins and their ligands participate in the restoration of tissue architecture after gluten withdrawal. These structural ligand–receptor interactions are not the initiating cause of celiac disease, but they are important for maintaining the integrity and recovery of the intestinal mucosa.
The intestinal immune system continuously interacts with microorganisms and their molecular components. Certain microbial molecules act as ligands for pattern-recognition receptors, particularly Toll-like receptors (TLRs). One important example is lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria. LPS binds to the TLR4 receptor complex, with the assistance of proteins such as CD14 and MD-2. This interaction activates intracellular signalling pathways, including NF-κB, and can stimulate the production of inflammatory cytokines.
Other microbial molecules, including bacterial lipoproteins and nucleic acids, can activate different Toll-like receptors. These interactions help the intestinal immune system recognise microbial structures and coordinate innate immune responses. The intestinal microbiome may be altered in celiac disease, and microbial components may influence epithelial barrier function and immune regulation. However, there is no established evidence that a particular microbial ligand is necessary or sufficient to initiate celiac disease. Gluten remains the principal recognised environmental antigen.
Damaged or stressed cells can release endogenous molecules that activate innate immune receptors. These molecules are called damage-associated molecular patterns (DAMPs). Examples include extracellular ATP, HMGB1 and certain heat-shock proteins. These molecules can interact with receptors such as purinergic receptors, Toll-like receptors and other innate immune signalling proteins.
In celiac disease, intestinal epithelial injury and inflammation may generate signals associated with cellular stress and damage. These signals can potentially amplify local inflammatory responses and influence the activity of immune cells. DAMPs should be distinguished from gluten-derived antigenic peptides. Gluten peptides are the specific dietary antigens recognised through the HLA-dependent adaptive immune response, whereas DAMPs are endogenous signals associated with tissue stress or injury. Their contribution to celiac disease is part of the broader biology of inflammation rather than a defining diagnostic feature.
Several hormones and metabolic molecules interact with receptors expressed in intestinal epithelial cells and immune cells. These interactions may influence intestinal motility, epithelial repair, nutrient metabolism and immune regulation. Vitamin D’s active metabolite, calcitriol, binds to the vitamin D receptor (VDR), a nuclear receptor that regulates gene transcription. This interaction influences calcium absorption, epithelial biology and immune-cell differentiation.
Retinoic acid, derived from vitamin A, binds to retinoic acid receptors (RARs) and retinoid X receptors (RXRs). It influences mucosal immune tolerance, regulatory T-cell development and the migration of lymphocytes to intestinal tissues. Short-chain fatty acids, particularly butyrate, bind to certain G-protein-coupled receptors and also influence intracellular enzyme activity, including histone deacetylases. These mechanisms can affect regulatory T-cell differentiation, epithelial metabolism and intestinal barrier function. These molecules are biologically relevant to the intestinal environment in celiac disease, but none has been established as a substitute for gluten exclusion.
The important ligand–receptor interactions in celiac disease can be understood according to their biological functions. Deamidated gluten peptides bind HLA-DQ2 or HLA-DQ8 and initiate antigen presentation. The resulting gluten–HLA complexes are recognised by T-cell receptors, leading to activation of gluten-specific CD4+ T cells. TG2 is recognised by B-cell receptors and anti-TG2 antibodies, providing the molecular basis for the autoimmune antibody response.
Cytokines such as IL-15, IFN-γ, TNF-α, IL-21 and IL-2 bind to their respective receptors and regulate inflammatory activity, lymphocyte proliferation and antibody production. MICA and MICB bind to NKG2D, enabling cytotoxic lymphocytes to recognise stressed epithelial cells. CD80 and CD86 interact with CD28 and CTLA-4 to regulate T-cell activation. TGF-β binds to its receptors and influences immune tolerance and tissue repair.
Microbial LPS interacts with the TLR4 complex and contributes to innate immune signalling, while endogenous molecules such as extracellular ATP and HMGB1 can act as damage-associated signals. Calcitriol binds to the vitamin D receptor, retinoic acid binds to RAR and RXR receptors, and butyrate interacts with G-protein-coupled receptors and intracellular targets. Collagen, laminin and fibronectin interact with integrins and support epithelial attachment and tissue repair. These different molecular interactions form an interconnected network rather than a single linear pathway.
The sequence begins with the ingestion of gluten proteins and their partial digestion by gastrointestinal enzymes. Proline-rich gluten peptides survive digestion and reach the intestinal mucosa, where tissue transglutaminase 2 modifies selected glutamine residues through deamidation. The resulting peptides acquire greater affinity for HLA-DQ2 or HLA-DQ8 molecules and are presented to gluten-specific CD4+ T lymphocytes. T-cell receptors recognise the gluten–HLA complexes and activate the adaptive immune response.
Activated T cells produce inflammatory cytokines and provide help to B lymphocytes. TG2-specific B cells can internalise TG2-associated material, present gluten peptides and receive T-cell help, leading to the production of anti-TG2 antibodies. Meanwhile, IL-15 promotes the cytotoxic activity of intraepithelial lymphocytes. Inflammatory signalling increases the expression of stress-associated molecules such as MICA and MICB on intestinal epithelial cells. Their interaction with NKG2D on cytotoxic lymphocytes contributes to epithelial-cell destruction.
The combined effects of inflammatory cytokines, cytotoxic lymphocytes and tissue-remodelling processes produce villous atrophy and crypt hyperplasia. The absorptive capacity of the small intestine is consequently reduced, leading to malabsorption and the nutritional manifestations of celiac disease. Although this sequence provides the principal established immunological framework, the molecular interactions overlap in time and involve additional signalling pathways.
Understanding ligand–receptor interactions has important implications for developing treatments beyond dietary gluten exclusion. Several approaches are under investigation, although none should currently be considered a replacement for a strict gluten-free diet.
One strategy is to prevent gluten peptides from binding to HLA-DQ2 or HLA-DQ8. If the interaction between the antigenic peptide and the HLA-binding groove could be blocked safely, activation of gluten-specific T cells might be reduced. This approach is being investigated through peptide-based and other molecular strategies.
A second strategy is to inhibit TG2 activity or prevent its interaction with gluten peptides. Since TG2-mediated deamidation increases the immunogenicity of many gluten peptides, selective inhibition could theoretically reduce their ability to activate T cells. However, TG2 also has important normal physiological functions, so any inhibitor would need to be sufficiently selective and safe.
A third strategy involves interfering with IL-15 signalling. Since IL-15 promotes cytotoxic intraepithelial lymphocyte activity, blocking this pathway might reduce epithelial injury. This is a particularly interesting therapeutic concept because it targets an important mechanism of tissue destruction. Other approaches include modifying inflammatory cytokine signalling, regulating T-cell activation, inducing antigen-specific immune tolerance and enzymatically degrading gluten peptides before they reach the intestinal mucosa.
The difficulty is that celiac disease involves multiple interacting molecular pathways. Blocking one ligand–receptor interaction may reduce a component of the immune response without eliminating all the mechanisms responsible for intestinal injury.
From a molecular perspective, celiac disease demonstrates how the biological effect of a substance depends on its structural compatibility with specific binding partners. Gluten-derived peptides become immunologically significant because their amino-acid sequences permit modification by TG2 and favourable binding to HLA-DQ2 or HLA-DQ8. The resulting peptide–HLA complexes are recognised by specific T-cell receptors. This sequence of molecular recognition events produces an antigen-specific immune response.
The disease also demonstrates the distinction between an external antigen and an endogenous autoantigen. Gluten peptides initiate the adaptive immune response, whereas TG2 becomes a target of the autoimmune antibody response. Cytokines subsequently act as signalling ligands, and stress-associated molecules participate in epithelial injury.
Thus, several different classes of biological ligands operate within the same pathological system: dietary peptides, self-proteins, cytokines, antibodies, cell-surface stress molecules, microbial components and metabolic signalling molecules. It would nevertheless be scientifically inaccurate to describe every molecule in this network as a ligand in the same functional sense. Some are enzymes, some are receptors, some are antigen-presenting proteins and others are signalling molecules. Their relationships must be defined according to the specific molecular interaction involved..
Celiac disease is a particularly important example of a disease in which molecular ligand recognition connects dietary exposure with genetic susceptibility, autoimmunity and tissue destruction. The most important initiating ligands are gluten-derived peptides, particularly those modified by TG2. Their interaction with HLA-DQ2 or HLA-DQ8 creates antigenic complexes recognised by gluten-specific T-cell receptors. TG2 itself becomes an autoantigen recognised by B-cell receptors and anti-TG2 antibodies.
Cytokines such as IL-15, IFN-γ, TNF-α, IL-21 and IL-2 regulate the inflammatory response. The interaction between NKG2D and MICA/MICB is particularly important in the recognition and destruction of stressed intestinal epithelial cells. Additional ligand systems involving co-stimulatory molecules, microbial components, vitamin D, retinoic acid and extracellular matrix proteins influence immune regulation and intestinal tissue maintenance.
The central molecular pathway can be summarised as follows: gluten peptide undergoes TG2-mediated deamidation, binds HLA-DQ2 or HLA-DQ8, and is recognised by the T-cell receptor. This activates cytokine signalling and cytotoxic immune responses, leading to epithelial injury and villous atrophy. This sequence provides the most important molecular framework for understanding celiac disease. It also identifies potential targets for future therapeutic research, particularly the interactions involving TG2, HLA-DQ2/DQ8, IL-15 and cytotoxic lymphocyte receptors.
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