Coeliac disease is caused by an abnormal immune response to gluten in a genetically susceptible person. Gluten is found primarily in wheat, barley and rye, and one of its constituent proteins, gliadin, contains peptides that can provoke the immune response characteristic of coeliac disease. In affected individuals, exposure to gluten activates immune mechanisms that produce inflammation and damage to the small-intestinal lining.
The immune system therefore mistakenly treats components associated with gluten as a threat and attacks tissues in the intestine. The resulting inflammation damages the villi, the microscopic projections responsible for increasing the intestinal surface available for nutrient absorption. The immediate trigger is gluten exposure, but gluten alone does not explain why only some people develop the disease. A combination of genetic susceptibility and environmental or biological factors determines who develops the autoimmune condition.
Genetics provide the principal underlying susceptibility. Coeliac disease is strongly associated with specific variants of the HLA-DQ region of the immune system, particularly HLA-DQ2 and HLA-DQ8-related variants. These molecules help immune cells recognise protein fragments, and particular variants are capable of presenting gluten-derived peptides in ways that promote the autoimmune response in susceptible people. However, possessing a susceptibility variant does not mean that a person will necessarily develop coeliac disease.
These variants are common in the population, whereas coeliac disease is considerably less common. This distinction is important because genetic predisposition should not be interpreted as genetic destiny. Family history nevertheless matters: first-degree relatives of someone with coeliac disease have a substantially higher risk than the general population and are therefore among the groups for whom testing is recommended.
Gluten initiates a complex chain of biological events rather than simply irritating the intestine mechanically. Gluten-derived peptides can survive normal gastrointestinal digestion and reach the small-intestinal mucosa. In susceptible people, the enzyme tissue transglutaminase modifies particular gluten peptides, increasing their ability to interact with susceptible HLA molecules. Gluten-specific T cells can then become activated and release inflammatory signals. B cells can produce characteristic antibodies, including antibodies directed against tissue transglutaminase and endomysial components.
The resulting immune activity damages intestinal epithelial cells and disrupts the normal architecture of the mucosa. The villi become shortened or flattened and the crypts can become enlarged, reducing absorptive efficiency. This immunological sequence distinguishes coeliac disease from ordinary food intolerance, where the principal problem is not autoimmune destruction of intestinal tissue.
Environmental factors appear to influence whether genetically susceptible people actually develop coeliac disease. NHS information identifies early-life gastrointestinal infection, including certain viral infections, as a possible factor associated with increased risk. Research has also examined the timing and circumstances of gluten introduction, infant feeding practices, changes in the gut microbiome and other influences on immune development. These factors are not equivalent to established single causes, and no simple environmental event explains most cases.
The current understanding is better represented by a multifactorial model in which genetic susceptibility establishes the potential for disease, gluten provides the necessary dietary trigger, and additional environmental or immunological factors may influence whether and when clinical disease emerges. This explains why people with similar genetic backgrounds can have different outcomes despite consuming gluten.
Certain medical conditions are associated with increased risk of coeliac disease. These include type 1 diabetes, autoimmune thyroid disease, Down's syndrome and Turner syndrome. The relationship does not necessarily mean that each condition directly causes coeliac disease. Instead, they may share genetic, immunological or developmental factors that increase susceptibility to autoimmune disease generally. A person with one of these conditions is therefore more likely to be investigated for coeliac disease when compatible symptoms or other indications occur. A first-degree family history is another important risk factor. NHS guidance recommends testing first-degree relatives of people with coeliac disease because their probability of developing the condition is considerably higher than that of the general population.
The mechanism of intestinal damage explains many of the downstream effects of the disease. Inflammation and villous atrophy reduce the effective absorptive surface of the small intestine, impairing uptake of nutrients. Iron deficiency can result in anaemia, while inadequate absorption of folate or vitamin B12 can produce other forms of anaemia. Calcium and vitamin D disturbances can contribute to impaired bone health. Severe or prolonged malabsorption can contribute to weight loss and malnutrition.
Damage to the intestinal lining can also reduce lactase activity, so people with newly diagnosed coeliac disease can develop secondary lactose intolerance and experience temporary difficulty digesting dairy products. As the intestinal mucosa heals after gluten removal, lactase activity can improve and dairy tolerance may return.
Coeliac disease is not caused by eating ordinary amounts of gluten in a person who lacks the relevant susceptibility, and it is not simply a consequence of eating an unhealthy diet. Nor is it caused by an allergy to gluten. It is possible for coeliac disease to develop in someone who has eaten gluten for many years, meaning that the absence of childhood symptoms does not exclude later diagnosis.
Conversely, many people carry susceptible HLA variants without ever developing clinically recognised disease. The condition can therefore emerge through an interaction between inherited immune characteristics, gluten exposure and additional biological or environmental factors. This multifactorial model also explains why the precise reason one susceptible individual develops coeliac disease while another does not remains incompletely understood.
The practical implication of the causal mechanism is that removing gluten removes the essential dietary stimulus responsible for continued intestinal injury. Treatment is therefore directed at complete and sustained gluten exclusion rather than merely reducing symptoms with medication. Before diagnosis, however, removing gluten can interfere with antibody testing and intestinal assessment. NHS guidance explicitly recommends continuing to eat gluten during diagnostic testing and not starting a gluten-free diet until the diagnosis has been confirmed by the appropriate clinician.
Once coeliac disease is established, lifelong gluten avoidance is required even if symptoms are mild or absent because the immune response and intestinal damage can continue without obvious immediate symptoms. The cause is therefore best understood as an interaction between gluten exposure and autoimmune susceptibility, not as a simple reaction to a particular food ingredient in isolation.
