Microbiota-derived metabolites and the regulation of host immunity and inflammation

项目总结 土壤传播的蠕虫感染估计在全球感染了20亿人，仍然是 大多数被忽视的传染病群体是一个重大的公共卫生和经济挑战。受感染的 个人可能患有营养不良、生长迟缓、认知功能受损、贫血和严重 慢性炎症所致的免疫病理学。对蠕虫寄生虫的免疫力依赖于2型 炎症反应，以辅助性T细胞2型(Th2)细胞、第2组固有淋巴样细胞活化为特征 (ILC2)、嗜酸性粒细胞、交替激活的巨噬细胞以及B细胞产生IgE和Ig G。这些保护性的 2型反应受遗传和环境因素的影响，包括饮食和微生物区系 代谢物。因此，迫切需要进一步的研究来了解这些变化的机制基础。 影响2型免疫反应的因素改善治疗和预防变态反应性疾病的策略 肠道蠕虫感染。微生物群是各种代谢物的来源，这些代谢物可以在 吸收部位(肠道)，以及远端部位，如通过血流的大脑。因为不同的饮食 包括膳食纤维在内的成分会影响微生物区系的组成和代谢产物的类型 由于微生物群的产生，饮食对免疫细胞的许多影响都可以通过微生物群来调节。然而， 膳食纤维对微生物源代谢物的影响及其对2型的调节作用 在过敏反应或蠕虫感染的情况下，免疫力和炎症情况仍然很差 已定义。我们利用非靶向比较代谢组学分析对小鼠进行的新的初步研究 研究发现，高纤维饮食会显著改变微生物区系的组成， 微生物区系衍生代谢物水平的变化。这种新陈代谢重新编程与 以第二组天然激活为特征的促炎性2型免疫反应的发展 淋巴细胞(ILC2s)、嗜酸性粒细胞聚集和加速寄生虫排出的小鼠模型 蠕虫感染。根据这些初步数据，我们假设高纤维饮食诱导的调节 微生物区系代谢产物促进ILC2诱导的2型炎症和对蠕虫寄生虫的免疫 感染。基于这些初步数据，目标1中概述的研究将测试哪些微生物区系源自 代谢产物激活ILC2s，引发嗜酸性粒细胞增多症和2型炎症，以促进抗寄生虫免疫。 在目标2中，我们将使用化学和遗传方法来测试微生物区系内的胆汁酸如何代谢 途径调节膳食纤维诱导的2型炎症和对感染的免疫。成功后 完成我们提出的目标，我们期望对生物学有一个全新的理解。 纤维饮食、微生物衍生代谢产物和ILC2s在调节2型炎症和抗蠕虫中的作用 豁免权。

PROJECT SUMMARY Soil-transmitted helminth infections are estimated to infected two billion people worldwide, remaining one of the most neglected groups of infectious diseases and a significant public health and economic challenge. Infected individuals can suffer from malnutrition, growth retardation, impaired cognitive function, anemia and severe immunopathology as a result of chronic inflammation. Immunity to helminth parasites is dependent on type 2 inflammatory responses, characterized by activation of T helper type 2 (Th2) cells, group 2 innate lymphoid cells (ILC2), eosinophils, alternatively-activated macrophages, and B cell production of IgE and IgG. These protective type 2 responses are influenced by genetic and environmental factors, including diet and microbiota-derived metabolites. Therefore, further studies are urgently needed to understand the mechanistic basis of how these factors influence type 2 immune responses to improve strategies to treat and prevent allergic diseases and intestinal helminth infections. The microbiota is the source of various metabolites which can exert their effects at the site of absorption (intestine), as well at distant sites such as brain via bloodstream. Since various dietary components, including dietary fiber, influence the composition of the microbiota and the types of metabolites the microbiota produces, many of the effects of diet on immune cells can be mediated via the microbiota. However, the influence of dietary fiber on microbiota-derived metabolites and their roles in regulating type 2 immunity and inflammation in the context of allergic responses or helminth infection remain poorly defined. Our new preliminary studies in mice employing untargeted comparative metabolomic analyses identified that a high fiber diet drives a significant shift in the composition of the microbiota and remarkable changes in the levels of microbiota-derived metabolites. This metabolic reprogramming was associated with the development of a proinflammatory type 2 immune response, characterized by activation of group 2 innate lymphoid cells (ILC2s), accumulation of eosinophils, and accelerated parasite expulsion in a murine model of helminth infection. Based on these preliminary data, we hypothesize that high fiber diet-induced modulation of microbiota-derived metabolites promotes ILC2-induced type 2 inflammation and immunity to helminth parasite infection. Based on these preliminary data, studies outlined in Aim 1 will test which microbiota-derived metabolites activate ILC2s and trigger eosinophilia and type 2 inflammation to promote anti-parasite immunity. In Aim 2, we will employ chemical and genetic approaches to test how the microbiota-intrinsic bile acid metabolic pathway regulates dietary fiber-induced type 2 inflammation and immunity to infection. Upon successful completion of our proposed aims, we expect to contribute to a fundamentally new understanding of the biology of fiber diet, microbiota-derived metabolites, and ILC2s in regulating type 2 inflammation and anti-helminth immunity.