Objective: Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.
Design: Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.
Results: Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.
Conclusions: These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.
Significance of this study:
What is already known on this subject?
Some individuals experience a range of symptoms in response to the ingestion of wheat and related cereals, yet lack the characteristic serological or histological markers of coeliac disease.
Accurate figures for the population prevalence of this sensitivity are not available, although estimates that put the number at similar to or greater than for coeliac disease are often cited.
Despite the increasing interest from the medical community and the general public, the aetiology and mechanism of the associated symptoms are largely unknown and no biomarkers have been identified.
What are the new findings?
Reported sensitivity to wheat in the absence of coeliac disease is associated with significantly increased levels of soluble CD14 and lipopolysaccharide-binding protein, as well as antibody reactivity to microbial antigens, indicating systemic immune activation.
Affected individuals have significantly elevated levels of fatty acid-binding protein 2 that correlates with the markers of systemic immune activation, suggesting compromised intestinal epithelial barrier integrity.
How might it impact on clinical practice in the foreseeable future?
The results demonstrate the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of coeliac disease.
The data offer a platform for additional research directed at assessing the use of the examined markers for identifying affected individuals and/or monitoring the response to treatment, investigating the underlying mechanism and molecular triggers responsible for the breach of the epithelial barrier, and evaluating novel treatment strategies in affected individuals.
Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease, by Melanie Uhde, Mary Ajamian, Giacomo Caio,
Roberto De Giorgio, Alyssa Indart, Peter H Green, Elizabeth C Verna, Umberto Volta,
Armin Alaedini in Gut [Published Online 25 July 2016]