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.

肠道微生物群（gut microbiota）可对宿主免疫系统产生深远影响，而宿主本身亦定植有这些细菌。细菌衍生的小分子（如胆汁酸）便是肠道微生物群在分子层面调控宿主的机制之一。本团队与其他研究团队近期已证实，胆汁酸代谢产物可调控适应性免疫系统中不同亚群的辅助性T细胞。然而，肠道微生物群如何调控免疫调控性胆汁酸代谢产物的水平，以及该过程与人类疾病的关联，目前仍不明晰。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）。通过解析合成3-氧代石胆酸的菌株及其生物合成途径，本研究首次发现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；作为一种丰度远高于其他次级胆汁酸的物质，部分人群体内其水平可超过200 μM。从本研究筛选获得的人类菌株合成的3-氧代石胆酸与/或异石胆酸，可抑制Th17细胞的分化。克罗恩病（Crohn's disease）患者体内的3-氧代石胆酸与异石胆酸水平均有所降低。本研究阐释了肠道微生物群如何改变免疫调控性小分子的丰度，而这类小分子与肠道相关炎症性疾病的严重程度密切相关。