Role of dietary fiber-microbiota Interactions in the development and function of small intestinal T cells

摘要 克罗恩病和溃疡性结肠炎统称为炎症性肠病(IBD) 肠道免疫反应异常导致慢性炎症的疾病。IBD 据估计，有150万美国人、220万欧洲人和数百人受到影响 在世界其他地方有数千人。虽然IBD的发病机制尚未完全阐明，但 被认为是多因素的，由遗传学、微生物组和 环境。与增加IBD风险相关的主要环境因素之一 是一个人所消耗的饮食。因此，利用营养来治疗疾病的能力 是对IBD进展进行深入干预的独特机会。面临的主要挑战 实施饮食疗法对IBD的具体作用机制缺乏了解 解释饮食干预对IBD严重程度或进展的影响的途径。 IBD的流行病学研究表明，膳食纤维是最稳定的常量营养素 与IBD风险的变化有关。纤维影响消化过程的几个方面。 值得注意的是，它也是微生物组中几个细菌物种的主要能源，以及 纤维消耗的差异强烈影响微生物组的组成和代谢 行为。然而，很少有研究系统地讨论纤维消费的作用 在微生物群的波动中，导致肠道免疫反应的特定变化。 这个项目的总体目标是发现相关的膳食纤维-微生物-免疫细胞 预防、诱导或改变肠道炎症进程的相互作用。我们将分析 缺氧引起的微生物区系组成和肠道细胞种群的变化 使用可发酵纤维摄入的模型，在该模型中，小鼠被喂以含有以下物质的复合饮食 可发酵和不可发酵纤维或缺乏可发酵纤维的半纯化成分饮食。 此外，我们将选择代表不同纤维类型的纯化纤维，并将它们补充到 非发酵饮食，以确定其摄入量调节肠道反应的人 健康状态和发炎期间。最后，为了评估饮食缺乏的影响 可发酵纤维对免疫系统的影响在人类微生物区系的背景下，我们将定植细菌 用健康的人类供体粪便样本释放小鼠，并给它们喂食混合纤维、非 可发酵纤维或非发酵纤维日粮中添加特定纤维以识别 特定纤维补充剂对人体免疫反应的调节作用 微生物区系，以及参与这种相互作用的细菌成员。

Summary Crohn’s disease and Ulcerative colitis collectively referred as inflammatory bowel disease (IBD) are diseases in which an aberrant intestinal immune response leads to chronic inflammation. IBD affects an estimated 1.5 million Americans, 2.2 million people in Europe and hundreds of thousands in the rest of the world. The pathogenesis of IBD, while not completely elucidated, is thought to be multifactorial and caused by the interplay of genetics, the microbiome and the environment. One of the major environmental factors associated with increasing the risk for IBD is the diet that an individual consumes. Therefore, the ability to harness nutrition to treat disease is a unique opportunity for profound intervention in IBD progression. The major challenge for implementing dietary therapy for IBD is the lack of understanding of detailed mechanistic pathways to explain the impact of dietary interventions on IBD severity or progression. Epidemiological studies of IBD have shown dietary fiber as the most consistent macronutrient associated with changing risk of IBD. Fiber affects several aspects of the digestive process. Notably, it is also a main energy source for several bacterial species of the microbiome, and differences in fiber consumption strongly affect the microbiome composition and metabolic behavior. However, very few studies have systematically addressed the role of fiber consumption in fluctuations of the microbiome that lead to specific changes in the intestinal immune response. The overall goal of this project is to discover relevant dietary fiber-microbe-immune cell interactions that prevent, induce or alter the course of gut inflammation. We will analyze the changes in microbiota composition and intestinal cell populations caused by the lack of fermentable fiber intake using a model in which mice are fed a complex diet that contains fermentable and non-fermentable fiber or semi-purified ingredients diet lacking fermentable fiber. Moreover, we will select purified fibers representing different fiber types and supplement them in the non-fermentable diet to identify those whose consumption modulate intestinal responses in a healthy state and during inflammation. Finally, to assess the impact of consuming a diet lacking fermentable fiber on the immune system in the context of human microbiota, we will colonize germ free mice with healthy human donor fecal samples and feed them either a mixed fiber, a non- fermentable fiber or a non-fermentable fiber diet supplemented with specific fibers to identify specific fiber supplementations that result in the modulation of immune responses by human microbiota, as well as the bacterial members mediating this interaction.