Pathogenesis of gluten/wheat sensitivity

Although the exact pathogenesis of gluten/wheat sensitivity has not yet been fully clarified, current data point to a central role for the innate immune system. Intestinal biopsies from affected individuals have revealed increased expression of toll-like receptor 2 (TLR2, which plays a role in the recognition of gluten components and the triggering of inflammatory immune responses) and reduced expression of the Treg marker FOXP3 (a transcription factor that is crucial for the development and function of regulatory T cells and plays a central role in maintaining immune tolerance) have been found.

Inflammatory changes in the small and large intestine have been observed in affected individuals. Although no villous changes such as those seen in coeliac disease occur, many affected individuals show a slightly increased number of intraepithelial lymphocytes (IELs). An increased number of mast cells in the duodenum has also been found, which correlates with more severe symptoms such as abdominal pain and bloating.

Studies show elevated serum levels of soluble CD14, LPS-binding protein and antibodies against microbial products (e.g. LPS, flagellin). These markers correlate with elevated FABP2, an indication of intestinal damage. Evidence of intestinal dysbiosis has also been found in affected individuals.

Recent studies provide strong evidence that expectations have a significant influence on symptom perception in gluten/wheat sensitivity. Participants who believed they were consuming gluten reported significantly stronger symptoms, regardless of whether they actually received gluten or not. Conversely, individuals who consumed gluten without expecting to do so reported significantly milder symptoms.

The current study situation does not provide sufficient evidence to identify specific wheat components such as gluten, FODMAPs or ATIs as the sole triggers of gluten/wheat sensitivity. The results are inconsistent and limited by methodological weaknesses. In addition, the nocebo effect appears to play a central role in symptom perception. Future studies should use standardised protocols, well-defined patient cohorts and appropriate control groups to better understand the pathogenesis. The search for valid biomarkers remains crucial to overcome diagnostic uncertainty and develop targeted therapeutic approaches.