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

炎症性肠病(IBD)的活动受食物成分和肠道微生物区系的调节。然而，主要的营养和微生物因素仍有待确定。我们已经鉴定了营养α-淀粉酶-胰蛋白酶抑制因子(ATIS)家族，它们是小麦籽粒成熟和抗虫害的蛋白质，是通过Toll样受体4(TLR4)信号复合体呈递抗原的髓系细胞中天然免疫反应的强烈激活因子。因此，ATI是长期寻找的非乳糜泻(非过敏性)小麦过敏的原因，其特征是随着小麦消费，先前存在的炎症性疾病恶化。ATIS在体内口服后可抵抗肠道降解，并触发先天免疫激活。我们还发现，与接触含有小麦或微量纯Atis的饮食的小鼠相比，暴露于不含Atis的饮食的小鼠较不容易患实验性结肠炎。摄入ATIS的小鼠表现出肠道髓系细胞的增强激活，这似乎促进了肠道中炎性T细胞的扩张。此外，ATIS还可引起肠道生态失调。我们计划在不同的IBD模型中，利用不同的饲喂方式和不同的ATIS/面筋与结肠炎的诱导相关，来探讨营养性ATI对肠道炎症的贡献以及它们诱导肠道菌群失调的机制。一个特别的焦点将是鲁米那阿替斯对肠道微生物群的促炎和抗炎活动的直接和间接影响，与疾病的严重程度有关。我们还将探索在多大程度上促进IBD的活动涉及髓系细胞迁移和/或激活到可能发生主要T细胞激活的肠系膜淋巴结。这些研究的目的是为一项(单独的)临床试点试验提供数据，以评估小麦和无ATI饮食在IBD病程中的益处。

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.