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

• 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
• 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

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.

项目总结