TY - JOUR
T1 - Human gut bacteria produce ΤΗ17-modulating bile acid metabolites
AU - Paik, Donggi
AU - Yao, Lina
AU - Zhang, Yancong
AU - Bae, Sena
AU - D’Agostino, Gabriel D.
AU - Zhang, Minghao
AU - Kim, Eunha
AU - Franzosa, Eric A.
AU - Avila-Pacheco, Julian
AU - Bisanz, Jordan E.
AU - Rakowski, Christopher K.
AU - Vlamakis, Hera
AU - Xavier, Ramnik J.
AU - Turnbaugh, Peter J.
AU - Longman, Randy S.
AU - Krout, Michael R.
AU - Clish, Clary B.
AU - Rastinejad, Fraydoon
AU - Huttenhower, Curtis
AU - Huh, Jun R.
AU - Devlin, A. Sloan
N1 - Funding Information:
We thank the members of the Devlin, Huh and Clardy laboratories (Harvard Medical School (HMS)) for discussions; the staff at the HMS ICCB-Longwood Screening Facility, BPF Genomics Core Facility at Harvard Medical School for their expertise and instrument support; N. Lee, J. Vasquez, C. Powell, B. Russell and M. Henke for technical support and advice; M. Trombly and S. Blacklow for reading the manuscript; L. E. Comstock for the pLGB30 plasmid (Addgene plasmid 126620); and L. García-Bayona for her technical support. We are grateful to the human patients who participated in the human stool screen, PRISM and HMP2 studies. We acknowledge NIH grant P30DK034854 and the use of the Harvard Digestive Disease Center’s core services, resources, technology and expertise. This work was supported by National Institutes of Health grants R01 DK110559 (to J.R.H. and A.S.D.), R01AR074500 (P.J.T.), U54DE023798 (C.H.), R24DK110499 (C.H.), T32GM095450 and MIRA R35 GM128618 (A.S.D.), a Harvard Medical School Dean’s Innovation Grant in the Basic and Social Sciences (A.S.D. and J.R.H.), a John and Virginia Kaneb Fellowship (A.S.D.), a Harvard Medical School Christopher Walsh Fellowship (L.Y.) and a Wellington Postdoctoral Fellowship (L.Y.). J.E.B. was the recipient of a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship and is supported by the National Institute of Allergy and Infectious Diseases (K99AI147165). P.J.T. is a Chan Zuckerberg Biohub investigator. The computations in this paper were run in part on the FASRC Cannon cluster supported by the FAS Division of Science Research Computing Group at Harvard University. The images in Figs. 2 c, 4a, d , Extended Data Figs. 1b, c , 3i, l were created using BioRender.
Funding Information:
We thank the members of the Devlin, Huh and Clardy laboratories (Harvard Medical School (HMS)) for discussions; the staff at the HMS ICCB-Longwood Screening Facility, BPF Genomics Core Facility at Harvard Medical School for their expertise and instrument support; N. Lee, J. Vasquez, C. Powell, B. Russell and M. Henke for technical support and advice; M. Trombly and S. Blacklow for reading the manuscript; L. E. Comstock for the pLGB30 plasmid (Addgene plasmid 126620); and L. García-Bayona for her technical support. We are grateful to the human patients who participated in the human stool screen, PRISM and HMP2 studies. We acknowledge NIH grant P30DK034854 and the use of the Harvard Digestive Disease Center’s core services, resources, technology and expertise. This work was supported by National Institutes of Health grants R01 DK110559 (to J.R.H. and A.S.D.), R01AR074500 (P.J.T.), U54DE023798 (C.H.), R24DK110499 (C.H.), T32GM095450 and MIRA R35 GM128618 (A.S.D.), a Harvard Medical School Dean’s Innovation Grant in the Basic and Social Sciences (A.S.D. and J.R.H.), a John and Virginia Kaneb Fellowship (A.S.D.), a Harvard Medical School Christopher Walsh Fellowship (L.Y.) and a Wellington Postdoctoral Fellowship (L.Y.). J.E.B. was the recipient of a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship and is supported by the National Institute of Allergy and Infectious Diseases (K99AI147165). P.J.T. is a Chan Zuckerberg Biohub investigator. The computations in this paper were run in part on the FASRC Cannon cluster supported by the FAS Division of Science Research Computing Group at Harvard University. The images in Figs. c, , Extended Data Figs. , were created using BioRender.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/3/31
Y1 - 2022/3/31
N2 - The microbiota modulates gut 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 as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-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 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.
AB - The microbiota modulates gut 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 as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-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 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.
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U2 - 10.1038/s41586-022-04480-z
DO - 10.1038/s41586-022-04480-z
M3 - Article
C2 - 35296854
AN - SCOPUS:85126387713
SN - 0028-0836
VL - 603
SP - 907
EP - 912
JO - Nature
JF - Nature
IS - 7903
ER -
