Human gut bacteria produce bile acid metabolites that alter Th17 response

The gut microbiota profoundly influences the host immune system while the latter contains its bacterial inhabitants. Bacteria-derived small molecules such as bile acids are one of the mechanisms by which the gut microbiota affect the host at a molecular level. We and others recently reported that bile acid metabolites modulate distinct subsets of T helper cells in the adaptive immune system. However, how the gut microbiota regulates the level of immune-modulatory bile acid metabolites and its relevance in human diseases remain unknown. Here, through a human stool screen, we identify a subset of gut bacteria that make a Th17-modulatory bile acid, 3-oxolithocholic acid (3-oxoLCA). By revealing 3-oxoLCA producing isolates and their biosynthetic pathways, for the first time, we further discover a downstream bile acid isomer, isolithocholic acid (isoLCA) as a potent TH17 inhibitor, a far more abundant secondary bile acid whose level could exceed 200 uM in some humans. 3-oxoLCA and/ or isoLCA produced from human isolates that retrieved from our screen inhibited the differentiation of Th17 cells. Both 3-oxoLCA and isoLCA are attenuated in patients with Crohns disease. Our study exemplifies how the gut microbiota alters abundances of the immune modulatory small molecules, which are closely associated with severity of gut-associated inflammatory diseases.肠道菌群可显著影响宿主免疫系统，而宿主免疫系统本身亦容纳了肠道菌群的细菌定植体。细菌衍生的小分子物质（如胆汁酸）便是肠道菌群在分子层面调控宿主的重要途径之一。我们及其他研究团队近期已证实，胆汁酸代谢物可调控适应性免疫系统中不同亚群的辅助性T细胞（T helper cells）。然而，肠道菌群如何调控免疫调节性胆汁酸代谢物的水平，以及其与人类疾病的关联，目前仍未明确。本研究通过人类粪便筛选实验，鉴定出一类可合成调控Th17细胞的胆汁酸——3-氧代石胆酸（3-oxolithocholic acid, 3-oxoLCA）的肠道细菌亚群。在明确可合成3-oxoLCA的菌株及其生物合成途径的基础上，我们首次进一步发现了一种下游胆汁酸异构体——异石胆酸（isolithocholic acid, isoLCA），其可作为强效的Th17细胞抑制剂；该次级胆汁酸丰度极高，在部分人群体内其水平可超过200 μM。从本研究筛选得到的人类菌株所合成的3-oxoLCA和/或isoLCA，可抑制Th17细胞的分化。克罗恩病（Crohn's disease）患者体内的3-oxoLCA与isoLCA水平均显著降低。本研究阐明了肠道菌群如何调控免疫调节性小分子物质的丰度，而这类物质与肠道相关炎症性疾病的严重程度密切相关。