Functional consequences of intestinal microbiota altered by ingestion of gluten and wheat alpha-amylase-trypsin inhibitors

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The activity of inflammatory bowel disease (IBD) is modulated by food constituents and the intestinal microbiota. However, major nutritional and microbial factors remain to be characterized. We have identified the family of nutritional alpha-amylase-trypsin inhibitors (ATIs), proteins of grain maturation and pest resistance in wheat, as strong activators of innate immune responses in antigen presenting myeloid cells via the toll like receptor 4 (TLR4) signalling complex. ATIs are therefore the long sought for cause of non-celiac (non-allergy) wheat sensitivity, which is characterized by worsening of pre-existent inflammatory disease with wheat consumption. ATIs resist intestinal degradation and trigger innate immune activation after oral ingestion in vivo. We also found that mice exposed to a diet that is devoid of ATIs are less susceptible to experimental colitis compared to mice exposed to a diet containing wheat or traces of pure ATIs. Mice ingesting ATIs exhibit enhanced activation of intestinal myeloid cells, which appear to promote expansion of inflammatory T cells in the gut. Moreover, ATIs induce intestinal dysbiosis. We plan to explore the contribution of nutritional ATIs to intestinal inflammation and the mechanisms by which they induce intestinal dysbiosis in different models of IBD, using variant feeding patterns of ATIs and ATIs/gluten in relation to colitis induction. A special focus will be the direct and indirect effects of luminal ATIs on the pro- vs- anti-inflammatory activities of the intestinal microbiota in connection with disease severity. We will also explore how far the IBD promoting activities involve migration and/or activation of myeloid cells to the mesenteric lymph nodes where major T cell activation may occur. These studies are intended to generate data for a (separate) clinical pilot trial to assess the benefit of a wheat and thus ATI free diet on the course of IBD.