Low dietary fiber and gut microbiota-induced mucus layer erosion as IBD triggers

摘要 被统称为炎症性肠病(IBD)的多种疾病的确切病因仍然存在 未知。尽管发现了被认为起作用的&gt；100个人类基因多态，但 IBD遗传易感性的一个无法解释的方面是，它通常只解释了疾病风险的一小部分。这个 因此，修饰因素的存在被用来解释弱渗透性疾病的发展。 环境因素--包括饮食和肠道微生物密集群落(微生物区系)--一直是 杰出的嫌疑犯。然而，这些潜在贡献者之间的功能互连仍然存在 未知。使用灵知生菌小鼠模型，在该模型中，动物被人工合成的人类肠道定居 由完全测序和代谢特征的共生细菌组成的微生物区系，我们已经开始 为了阐明膳食纤维、肠道微生物区系和结肠粘液之间的机制相互作用 屏障，是抵御肠道细菌入侵的主要防御手段。在膳食纤维过程中 缺乏时，肠道微生物群求助于宿主分泌的粘液糖蛋白作为营养来源，导致 粘液层的侵蚀。缺乏膳食纤维，以及缺乏纤维、侵蚀粘液的微生物群， 通过粘膜病原体轮状柠檬酸杆菌促进更大的上皮性通路和致死性结肠炎。更多 引人注目的是，当同样的合成微生物群在白介素10(IL-10)缺乏的小鼠身上组装时，一个 与人类IBD相关的功能缺陷丧失的细胞因子，动物会发展为致命的 在没有轮齿乳杆菌的情况下发生自发性炎症，但仅在低纤维饮食中发生。因此，我们的工作 揭示了饮食、肠道微生物区系、粘膜屏障功能和自发性之间的功能联系 IBD的发展。我们的中心假设是纤维和粘液之间存在动态平衡 降解菌，在低纤维条件下，粘液层被越来越多地侵蚀，导致 涉及宿主或微生物变化的暂时性疾病进展，这可以通过以下方式得到改善 预防性或治疗性纤维消费。拟议的工作将通过以下方式扩展上述调查结果 首先测定粘液降解菌各自对侵蚀的贡献和作用 粘膜屏障和促炎作用。接下来，我们将衡量不同类型的影响 膳食纤维及其剂量和消费时间表，这是治疗或预防所需的 发炎。最后，我们将对微生物、免疫学和粘膜进行时间进程实验。 屏障读数，以确定该模型中的疾病进展--这发生在几个 几周-是由肠道微生物和宿主之间的动态平衡变化驱动的。我们预计我们的 这些发现将提供对遗传和环境触发因素星座的详细功能洞察 合谋引发IBD症状。因此，它们将为未来的人类研究提供途径，这是 建立在纤维-微生物区系相互作用的功能知识的基础上，收集在一个易于处理的模型中。

Summary The precise etiologies of the multiple disorders collectively known as inflammatory bowel disease (IBD) remain unknown. Despite identification of >100 human genetic polymorphisms that are thought to play a role, an unexplained facet of genetic predisposition to IBD is that it typically explains only a fraction of disease risk. The existence of modifying factors has thus been invoked to explain the weakly penetrant disease development. Environmental factors—including diet and the dense community of gut microbes (microbiota)—have been prominent suspects. 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 C. rodentium, but only on a low fiber diet. Our work has therefore revealed functional interconnections between diet, 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 a temporal disease progression involving host or microbial changes and that this can be ameliorated by preventative or therapeutic fiber consumption. 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. Following this, we will measure the impact of different types of dietary fibers, along with their dosing and consumption schedules, that are required to treat or prevent inflammation. Finally, we will perform time course experiments with microbial, immunological and mucosal barrier readouts to determine how disease progression in this model—which occurs over the course of several weeks—is driven by changes in the homeostasis between gut microbes and the host. We anticipate that our findings will provide detailed functional insight into the constellation of genetic and environmental triggers that conspire to precipitate IBD symptoms. As such, they will provide paths to future research in humans, which are built on a foundation of functional knowledge of fiber-microbiota interactions gathered in a tractable model.