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

总结 统称为炎症性肠病（IBD）的多种疾病的确切病因仍然存在 未知尽管鉴定出>100种被认为起作用的人类遗传多态性， IBD遗传易感性的一个无法解释的方面是，它通常只能解释一小部分疾病风险。的 因此，修饰因子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（微生物群）的密集社区-已经被 重要嫌疑人然而，这些潜在贡献者之间的功能性相互联系仍然存在， 未知使用一个gnotobiotic小鼠模型，其中动物与合成的人类肠道殖民 微生物群组成的完全测序和代谢特征的肠道细菌，我们已经开始 阐明膳食纤维、肠道微生物群和结肠粘液之间的相互作用机制 屏障，其作为抵抗肠道细菌侵入的主要防御。在膳食纤维 缺乏时，肠道微生物群依靠宿主分泌的粘液糖蛋白作为营养源，导致 粘液层的侵蚀。膳食纤维缺乏，加上纤维缺乏，粘液侵蚀微生物群， 促进粘膜病原体啮齿类柠檬酸杆菌对上皮的更大接触和致死性结肠炎。更 令人惊讶的是，当同样的合成微生物群在缺乏白细胞介素10（IL-10）的小鼠中组装时， 细胞因子的功能丧失缺陷与人IBD相关，动物发展为致死性 在缺乏C的情况下自发性炎症。啮齿类动物，但只有低纤维饮食。因此，我们的工作 揭示了饮食，肠道微生物群，粘膜屏障功能和自发性 IBD发展。我们的核心假设是纤维和粘液之间存在着动态平衡- 降解细菌，使得在低纤维条件下，粘液层被越来越多地侵蚀， 涉及宿主或微生物变化的暂时性疾病进展，并且这可以通过以下方式改善： 预防性或治疗性纤维消耗。拟议的工作将扩大上述调查结果， 首先测量粘蛋白降解细菌各自的贡献和它们对侵蚀的功能， 粘膜屏障和沉淀性炎症。接下来，我们将衡量不同类型的影响 膳食纤维，沿着他们的剂量和消费时间表，需要治疗或预防 炎症最后，我们将进行时间过程实验与微生物，免疫和粘膜 屏障读数，以确定该模型中的疾病进展-这发生在几个 是由肠道微生物和宿主之间的内稳态变化驱动的。我们预计， 研究结果将提供详细的功能洞察星座的遗传和环境触发器， 共同促成IBD症状。因此，它们将为未来的人类研究提供途径， 建立在纤维微生物群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.