Bacterial metabolites controlling Th17 cells

摘要 胆汁酸是胆固醇衍生的天然表面活性剂，在肝脏中产生。它们对于 脂质消化，抗菌防御，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。 肠道炎症通过肠道微生物群之间的良好平衡来调节 和粘膜免疫系统。不平衡可以激活免疫信号通路， 不受控制的病理性免疫反应肠道内的细菌， 大肠暴露于大量的胆汁酸中，并且已知将宿主转化为胆汁酸。 将胆汁酸衍生为更疏水的衍生物，从而得到更生物可利用的衍生物。 我们假设细菌产生的次级胆汁酸直接调节分化 和/或功能的关键免疫细胞在炎症条件下，提供了一个通信 肠道细菌和粘膜免疫之间的联系。我们建议1）解剖 胆汁酸免疫调节机制及胆汁酸免疫细胞的鉴定 目标，2）鉴定产生免疫调节胆汁酸的细菌及其酶 和3）鉴定调节体内粘膜炎症的胆汁酸的新代谢物， 在生理浓度。阐明这些机制不仅将提供新的 炎症性疾病的治疗选择，而且还开辟了令人兴奋的途径，研究独特的 肠道微生物、小分子代谢物和 宿主免疫细胞

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.