Bacterial metabolites controlling Th17 cells

控制 Th17 细胞的细菌代谢物

• 批准号: 9571441
• 负责人: Jun R. Huh
• 金额: $ 46.01万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9571441
• 关键词: Bacterial; metabolites; controlling; Th17; cells

ABSTRACT Bile acids are cholesterol-derived, natural surfactants, produced in the liver. They are critical to lipid digestion, antibacterial defense, and cholesterol synthesis, as well as other aspects of human biology. Importantly, bile acid dysregulation has been linked to intestinal bowel disease. Intestinal inflammation is modulated through a fine balance between the intestinal microbiota and the mucosal immune system. Imbalance can activate immune signaling pathways, leading to uncontrolled, pathological immune responses. Gut-residing bacteria in both the small and large intestines are exposed to a significant amount of bile acids and are known to convert host- derived bile acids into more hydrophobic, and thus, more bioavailable derivatives. We hypothesize that bacteria-produced secondary bile acids directly regulate the differentiation and/or function of key immune cells under inflammatory conditions, providing a communications link between commensal bacteria and mucosal immunity. We propose 1) to dissect the mechanisms of bile acid-mediated immune modulation and identify bile acid immune cell targets, 2) to identify bacteria and their enzymes that generate immune-modulatory bile acids and 3) to identify the novel metabolites of bile acids that regulate mucosal inflammation in vivo, at physiological concentrations. Elucidation of these mechanisms will not only provide novel therapeutic options for inflammatory diseases, but also open exciting avenues to study unique regulatory interactions between gut-residing microorganisms, small molecule metabolites and host immune cells.

摘要