Human gut bacteria produce ΤΗ17-modulating bile acid metabolites

• Autor: Paik, Donggi ; Yao, Lina ; Zhang, Yancong ; Bae, Sena ; D’Agostino, Gabriel D. ; Zhang, Minghao ; Kim, Eunha ; Franzosa, Eric A. ; Avila-Pacheco, Julian ; Bisanz, Jordan E. ; Rakowski, Christopher K. ; Vlamakis, Hera ; Xavier, Ramnik J. ; Turnbaugh, Peter J. ; Longman, Randy S. ; Krout, Michael R. ; Clish, Clary B. ; Rastinejad, Fraydoon ; Huttenhower, Curtis ; Huh, Jun R. ; Devlin, A. Sloan
• Assuntos: 3α-Hydroxysteroid dehydrogenase ; Acids ; Bacteria ; Bile ; Bile acids ; Biosynthesis ; Cell differentiation ; Dehydrogenases ; Differentiation (biology) ; Enzymes ; Gene expression ; Helper cells ; Homeostasis ; Hydroxysteroids ; Immune system ; Immunomodulation ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Inflammatory diseases ; Interleukins ; Intestine ; Lymphocytes ; Lymphocytes T ; Metabolites ; Microbiota ; Receptors ; Retinoic acid
• É parte de: Nature (London), 2022-03, Vol.603 (7903), p.907-912
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• Descrição: The microbiota modulatesgut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. 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 asthe abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-yt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3a-hydroxysteroid dehydrogenase genesthat are required fortheir biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of TH17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.
  
• Editor: London: Nature Publishing Group
  
• Idioma: Inglês