Human gut bacteria produce T(H)17-modulating bile acid metabolites

초록

The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (T(H)17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits T(H)17 cell differentiation(1). Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed T(H)17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-gamma t, a key T H 17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3 alpha-hydroxysteroid dehydrogenase genes that are required for their biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of T(H)17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit T(H)17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.

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