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.