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

项目摘要 土壤传播的蠕虫感染估计在全世界感染了20亿人， 最被忽视的传染病群体和重大的公共卫生和经济挑战。感染 个体可能患有营养不良、生长迟缓、认知功能受损、贫血和严重的 免疫病理学作为慢性炎症的结果。对蠕虫寄生虫的免疫力取决于2型 炎症反应，特征为2型辅助性T细胞（Th 2细胞）、2组先天性淋巴样细胞活化 ILC 2、嗜酸性粒细胞、交替激活的巨噬细胞和B细胞产生IgE和IgG。这些保护 2型反应受遗传和环境因素的影响，包括饮食和微生物来源的 代谢物。因此，迫切需要进一步的研究来了解这些机制的基础， 影响2型免疫应答的因素，以改善治疗和预防过敏性疾病的策略， 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），以及通过血流到达远端部位（如脑）。由于各种饮食 成分，包括膳食纤维，影响微生物群的组成和代谢物的类型， 虽然饮食对免疫细胞的影响是由微生物群产生的，但饮食对免疫细胞的许多影响可以通过微生物群介导。然而，在这方面， 膳食纤维对微生物代谢产物的影响及其在调节2型糖尿病中的作用 在过敏反应或蠕虫感染的情况下，免疫和炎症仍然很差， 定义了我们采用非靶向比较代谢组学分析在小鼠中进行的新的初步研究 发现高纤维饮食会导致微生物群组成的显著变化， 微生物衍生代谢物水平的变化。这种代谢重编程与 发展促炎性2型免疫应答，其特征在于第2组先天免疫应答的激活。 淋巴样细胞（ILC 2），嗜酸性粒细胞的积累，并加速寄生虫排出的小鼠模型， 蠕虫感染基于这些初步的数据，我们假设高纤维饮食诱导的 微生物群衍生的代谢产物促进ILC 2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种微生物来源的 代谢物激活ILC 2并触发嗜酸性粒细胞增多和2型炎症以促进抗寄生虫免疫。 在目标2中，我们将采用化学和遗传学方法来测试微生物-内在胆汁酸代谢 途径调节膳食纤维诱导的2型炎症和对感染的免疫力。一旦成功 完成我们提出的目标，我们希望有助于从根本上了解生物学 纤维饮食，微生物衍生的代谢产物和ILC 2在调节2型炎症和抗蠕虫中的作用 免疫力

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.