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A biosynthetic pathway for a prominent class of microbiota-derived bile acids

Nature Chemical Biology volume 11, pages 685–690 (2015)Cite this article

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Abstract

The gut bile acid pool is millimolar in concentration, varies widely in composition among individuals and is linked to metabolic disease and cancer. Although these molecules are derived almost exclusively from the microbiota, remarkably little is known about which bacterial species and genes are responsible for their biosynthesis. Here we report a biosynthetic pathway for the second most abundant class in the gut, 3β-hydroxy(iso)-bile acids, whose levels exceed 300 μM in some humans and are absent in others. We show, for the first time, that iso–bile acids are produced by Ruminococcus gnavus, a far more abundant commensal than previously known producers, and that the iso–bile acid pathway detoxifies deoxycholic acid and thus favors the growth of the keystone genus Bacteroides. By revealing the biosynthetic genes for an abundant class of bile acids, our work sets the stage for predicting and rationally altering the composition of the bile acid pool.

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Figure 1: Chemical transformations of bile acids by gut bacteria.
Figure 2: Elucidation of the biosynthetic pathway for isoDCA formation in E. lenta and R. gnavus.
Figure 3: IsoDCA is less bacteriostatic than DCA.

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Acknowledgements

We are grateful to P. Turnbaugh (UCSF) for helpful discussions, to A. Hofmann (UCSD) for helpful discussions and for providing an initial sample of isoDCA and to T. Iida (Nihon University) for providing us with an authentic sample of 12-epi-isoDCA. We thank P.O. de Montellano for use of his GC-MS, Y. Varma for background research and experimentation on bile acids, P. Cimermancic for help with the phylogenetic analysis and members of the Fischbach group for helpful discussions. This research was supported by an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (M.A.F.), a Glenn Award for Research in Biological Mechanisms of Aging (M.A.F.), a Medical Research Program grant from the W.M. Keck Foundation (M.A.F.), a Fellowship for Science and Engineering from the David and Lucile Packard Foundation (M.A.F.) and US National Institutes of Health grants OD007290 and GM081879 (M.A.F.).

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA

    A Sloan Devlin & Michael A Fischbach

  2. California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California, USA

    A Sloan Devlin & Michael A Fischbach

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  1. A Sloan Devlin
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A.S.D. and M.A.F. conceived the project, designed the experiments and wrote the manuscript. A.S.D. performed the experiments.

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Correspondence to Michael A Fischbach.

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M.A.F. is on the scientific advisory board of NGM Biopharmaceuticals.

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Devlin, A., Fischbach, M. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat Chem Biol 11, 685–690 (2015). https://doi.org/10.1038/nchembio.1864

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