Dietary fiber and soy protein-based microbiome metabolites for IBD prevention

总结 炎症性肠病（IBD）的确切病因仍不清楚。尽管识别>100 人类遗传多态性被认为在IBD中起作用，遗传易感性通常解释了 只有一小部分的疾病风险。环境因素的重要贡献-包括饮食和肠道 微生物群已经成为其他疾病驱动因素的突出嫌疑人。然而，功能 这些潜在因素之间的相互关系仍然未知。使用一个gnotobiotic小鼠模型，在 这些动物被合成的人类肠道微生物群定殖， 代谢特征的细菌，我们已经开始阐明机械相互作用 在膳食纤维、肠道微生物群和结肠粘液屏障之间， 抵抗肠道细菌的入侵在膳食纤维缺乏期间，肠道微生物群诉诸宿主- 分泌粘液糖蛋白作为营养源，导致粘液层侵蚀。膳食纤维 剥夺，连同纤维剥夺，粘液侵蚀微生物群，促进更大的上皮访问， 致死性结肠炎的粘膜病原体，啮齿类柠檬酸杆菌。更令人吃惊的是，当同样的合成 白细胞介素10（IL-10）是一种细胞因子， 与人类IBD有关，动物在缺乏免疫抑制剂的情况下发生致命的自发性炎症。 明显的病原体，但只能吃低纤维食物因此，我们的工作揭示了功能性相互联系 饮食、肠道微生物群、粘膜屏障功能和自发性IBD发展之间的关系。我们的中央 假设在纤维和粘液降解细菌之间存在动态平衡，使得在低浓度下， 纤维条件下，粘液层被越来越多地侵蚀，导致可以被 通过预防性或治疗性纤维消耗或其他细菌代谢物来改善， 炎症拟议的工作将通过首先测量各自的 粘蛋白降解细菌的贡献及其对侵蚀粘膜屏障的功能， 引发炎症我们已经确定，除了几个纯纤维，我们的纤维 缺乏饮食可以减少疾病，并偶然发现，包含大豆（但不是牛奶）蛋白质也 通过促进支链脂肪酸异丁酸酯的产生而部分减少疾病。异丁酸是 我们的假设是，大豆蛋白提供了一种基于肽的氨基酸来源， 酸到结肠进行细菌代谢。因为异丁酸是一种研究很少的代谢物，我们将 研究其微生物来源和抑制宿主炎症的作用机制。我们预计 我们的研究结果将提供对遗传和环境触发因素的功能性洞察， 共同促成IBD。因此，我们的发现将为未来的人类研究提供途径， 建立在易于处理的模型中收集的饮食-微生物群相互作用的功能知识的基础上。

Summary The precise etiology of inflammatory bowel disease (IBD) remains unknown. Despite identification of >100 human genetic polymorphisms that are thought to play a role in IBD, genetic predisposition typically explains only a fraction of disease risk. Important contributions for environmental factors—including diet and the gut microbiota—have become prominent suspects as additional disease drivers. However, the functional interconnections between these potential contributors remain unknown. Using a gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced and metabolically characterized commensal bacteria, we have begun to elucidate the mechanistic interactions between dietary fiber, the gut microbiota and the colonic mucus barrier, which serves as a primary defense against encroachment by intestinal bacteria. During dietary fiber deficiency, the gut microbiota resorts to host- secreted mucus glycoproteins as a nutrient source, leading to erosion of the mucus layer. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium. More strikingly, when this same synthetic microbiota is assembled in mice deficient in interleukin 10 (IL-10), a cytokine for which loss of function defects have been associated with human IBD, animals develop lethal spontaneous inflammation in the absence of an overt pathogen, but only on a low fiber diet. Our work has therefore revealed functional interconnections between diet, the gut microbiota, mucosal barrier function and spontaneous IBD development. Our central hypothesis is that there is a dynamic balance between fiber- and mucus-degrading bacteria, such that in low fiber conditions the mucus layer is increasingly eroded resulting in temporal disease progression that can be ameliorated by preventative or therapeutic fiber consumption or other bacterial metabolites that counterbalance inflammation. The proposed work will extend the findings outlined above by first measuring the respective contributions of mucin-degrading bacteria and their functions towards eroding the mucosal barrier and precipitating inflammation. We have already established that addition of several pure fibers to our fiber deficient diet reduces disease and have fortuitously discovered that inclusion of soy (but not milk) protein also reduces disease in part by promoting production of the branched chain fatty acid isobutyrate. Isobutyrate is produced from L-valine and our hypothesis is that soy protein delivers a peptide-based source of this amino acid to the colon for bacterial metabolism. Because isobutyrate is a poorly studied metabolite, we will investigate its microbial source(s) and mechanism of action in dampening host inflammation. We anticipate that our findings will provide functional insight into the constellation of genetic and environmental triggers that conspire to precipitate IBD. As such, our findings will provide paths to future research in humans, which are built on a foundation of functional knowledge of diet-microbiota interactions gathered in a tractable model.