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

炎症性肠病（IBD）的活动是由食物成分和肠道微生物群调节的。然而，主要的营养和微生物因素仍有待研究。我们已经确定了营养α -淀粉酶-胰蛋白酶抑制剂（ATIs）家族，小麦籽粒成熟和抗虫蛋白，作为抗原递呈髓细胞先天免疫反应的强激活剂，通过toll样受体4 （TLR4）信号复合物。因此，长期以来人们一直在寻找非乳糜泻（非过敏）小麦敏感性的原因，其特征是食用小麦会使原有的炎症性疾病恶化。体内口服后抗肠道降解并触发先天免疫激活。我们还发现，与饮食中含有小麦或微量纯ATIs的小鼠相比，暴露于缺乏ATIs的饮食中的小鼠对实验性结肠炎的易感程度较低。摄入ATIs的小鼠表现出增强的肠髓细胞激活，这似乎促进了肠道炎症T细胞的扩张。此外，ATIs还会引起肠道生态失调。我们计划在不同的IBD模型中，利用不同的ATIs喂养模式和ATIs/麸质与结肠炎诱导的关系，探索营养性ATIs对肠道炎症的贡献及其诱导肠道生态失调的机制。一个特别的重点将是肠道ATIs对肠道微生物群与疾病严重程度相关的抗炎活性的直接和间接影响。我们还将探讨IBD促进活动涉及骨髓细胞迁移和/或激活到肠系膜淋巴结的程度，在肠系膜淋巴结可能发生主要的T细胞激活。这些研究旨在为一项（单独的）临床试验提供数据，以评估小麦和无ATI饮食对IBD病程的益处。

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.