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

微生物群衍生的代谢物以及宿主免疫和炎症的调节

基本信息

批准号：
10512805
负责人：
David Artis
金额：
$ 80.57万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-14 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512805
关键词：
Acids Address Adoptive Cell Transfers Allergic Disease Anemia Antiinflammatory Effect B-Lymphocytes Bacteria Bile Acids Biological Biology Blood Circulation Brain Cells Cholic Acids Chronic Communicable Diseases Data Deoxycholic Acid Development Diet Dietary Component Dietary Fiber Distant Economic Burden Environmental Risk Factor Eosinophilia Fermentation Fiber Gene Expression Gene Expression Profiling Genes Genetic Genetic Engineering Germ-Free Growth Helminths IgE Immune Immune response Immunity Immunoglobulin G Immunologics Impaired cognition In Vitro Individual Indoles Infection Infectious Agent Inflammation Inflammatory Inflammatory Response Intestines Inulin Lymphoid Cell Malnutrition Mammalian Cell Mediating Metabolic Metabolic Pathway Mus Parasites Parasitic infection Pathway interactions Persons Phenols Physiological Production Public Health Regulation Role Site Soil Source Stromal Cells Testing Th2 Cells Therapeutic Tissues Volatile Fatty Acids absorption allergic response base bile acid metabolism cell type chemical genetics cognitive function comparative cytokine dehydroxylation eosinophil genetic approach health economics helminth infection immunopathology immunoregulation improved in vivo infection rate macrophage member mesenchymal stromal cell metabolomics microbial microbiota microbiota metabolites mouse model mutant neglect novel overexpression prevent receptor response tool transcriptional reprogramming transcriptomics

项目摘要

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.

项目概要据估计，土源性蠕虫感染已感染全球 20 亿人，仍然是全球最常见的蠕虫感染之一。最被忽视的传染病群体以及重大的公共卫生和经济挑战。已感染个人可能会遭受营养不良、生长迟缓、认知功能受损、贫血和严重的免疫病理学是慢性炎症的结果。对蠕虫寄生虫的免疫力取决于 2 型炎症反应，其特征是 2 型辅助 T (Th2) 细胞（第 2 组先天淋巴细胞）的激活 (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 IgG。这些保护性的 2 型反应受到遗传和环境因素的影响，包括饮食和微生物群代谢物。因此，迫切需要进一步的研究来了解这些现象的机制基础。影响 2 型免疫反应的因素可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，这些代谢物可以在以下方面发挥作用：吸收部位（肠），以及通过血液吸收的远处部位，例如大脑。由于各种饮食包括膳食纤维在内的成分会影响微生物群的组成和代谢物的类型由于微生物群产生，饮食对免疫细胞的许多影响可以通过微生物群介导。然而，膳食纤维对微生物群衍生代谢物的影响及其在调节 2 型中的作用过敏反应或蠕虫感染情况下的免疫力和炎症仍然很差定义的。我们采用非靶向比较代谢组学分析对小鼠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发生显着变化，并且显着微生物群衍生的代谢物水平的变化。这种代谢重编程与促炎 2 型免疫反应的发展，其特征是激活第 2 组先天免疫反应小鼠模型中淋巴样细胞（ILC2）、嗜酸性粒细胞积聚和加速寄生虫排出蠕虫感染。基于这些初步数据，我们假设高纤维饮食诱导的调节微生物群衍生的代谢物促进 ILC2 诱导的 2 型炎症和对蠕虫寄生虫的免疫力感染。根据这些初步数据，目标 1 中概述的研究将测试哪些微生物群衍生代谢物激活 ILC2 并引发嗜酸性粒细胞增多和 2 型炎症，从而促进抗寄生虫免疫。在目标 2 中，我们将采用化学和遗传学方法来测试微生物群内在胆汁酸代谢的情况途径调节膳食纤维引起的 2 型炎症和感染免疫力。成功后完成我们提出的目标，我们期望为对生物学的全新理解做出贡献纤维饮食、微生物群衍生代谢物和 ILC2 在调节 2 型炎症和抗蠕虫中的作用免疫。