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.

抽象的 胆汁酸是胆固醇衍生的天然表面活性剂，在肝脏中产生。他们对 脂质消化，抗菌防御和胆固醇合成以及其他方面 人类生物学。重要的是，胆汁酸失调与肠道疾病有关。 肠炎通过肠道菌群之间的良好平衡来调节 和粘膜免疫系统。失衡可以激活免疫信号通路，领先 不受控制的病理免疫反应。小型和小细菌 大肠暴露于大量的胆汁酸中，已知可以转化宿主 - 将胆汁酸推导为更疏水，从而使更多的生物利用衍生物。 我们假设细菌产生的二级胆汁酸直接调节分化 和/或关键免疫细胞在炎症条件下的功能，提供通信 共生细菌与粘膜免疫之间的联系。我们建议1）剖析 胆汁酸介导的免疫调节机制并鉴定胆汁酸免疫细胞 目标，2）鉴定产生免疫调节胆酸的细菌及其酶 3）确定调节体内粘膜炎症的新型胆汁酸代谢产物， 在生理浓度下。阐明这些机制不仅可以提供新颖的 炎症性疾病的治疗选择，但也开放了令人兴奋的途径来研究独特的 肠道微生物，小分子代谢产物和 宿主免疫细胞。