Letter | Published:

A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites

Nature volume 551, pages 648652 (30 November 2017) | Download Citation

Abstract

The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream1,2, where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.

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Acknowledgements

We thank A. I. Scott for technical assistance and S. Yoshida (Kyoto University) for critical review of the manuscript. This work was funded by a grant from the National Institutes of Health NIDDK (R01-DK101674) to J.L.S. and M.A.F., an NIH Director’s New Innovator Award (DP2-OD006515) to J.L.S., and Early Independence Award (DP5-OD023056) to M.H.S., FDA Grant BAA-12-00118 to G.P.N., NIH Awards U19AI057229, U19AI100627, R33CA183654, R33CA0183692, R01GM10983601, R01CA184968, R01CA19665701, R21CA183660, R01NS08953301, 5UH2AR067676 and R01HL120724 to G.P.N., Department of Defence Grants OC110674 and W81XWH-14-1-0 180 to G.P.N., Gates Foundation Grant OPP1113682 to G.P.N., DP1 DK113598 to M.A.F., R01 DK110174 to M.A.F., HHMI-Simons Faculty Scholars Award to M.A.F., Byers Award in Basic Science to M.A.F., a Fellowship for Science and Engineering from the David and Lucile Packard Foundation to M.A.F. and a BASF research grant to M.A.F, and two Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Awards to M.A.F. and J.L.S. A.J.H. was supported by an NIH postdoctoral NRSA (T32-AI007328). W.V.T. and B.D.M. were each supported by a National Science Foundation Graduate Research Fellowship Grant No. DGE-114747.

Author information

Author notes

    • Matthew H. Spitzer
    •  & Michael A. Fischbach

    Present addresses: Department of Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, California 94143, USA (M.H.S.); Department of Bioengineering and ChEM-H, Stanford University, Stanford, California 94305, USA (M.A.F.).

Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Dylan Dodd
    • , Matthew H. Spitzer
    • , Anthony Le
    •  & Tina M. Cowan
  2. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Dylan Dodd
    • , Matthew H. Spitzer
    • , William Van Treuren
    • , Bryan D. Merrill
    • , Andrew J. Hryckowian
    • , Steven K. Higginbottom
    • , Garry P. Nolan
    •  & Justin L. Sonnenburg
  3. California Institute for Quantitative Bioscience and Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco 94143, California, USA.

    • Michael A. Fischbach

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Contributions

D.D., M.A.F. and J.L.S. conceived the study. D.D. generated the mutant bacteria. D.D., A.J.H. and W.V.T. performed the anaerobic growth curve experiments. A.L. and T.M.C. supervised generation of the LC–MS/MS assay. D.D. performed the metabolite incubations and LC–MS/MS experiments. B.D.M. assembled genomes from publicly available raw sequence data. D.D. and B.D.M. analysed genomic data. D.D. and S.K.H. performed gnotobiotic experiments. M.H.S. performed mass cytometry experiments and analysed data. G.P.N. supervised mass cytometry experiments and analysis. D.D., M.A.F. and J.L.S. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael A. Fischbach or Justin L. Sonnenburg.

Reviewer Information Nature thanks M. Blaut, M. Redinbo, G. Siuzdak and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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https://doi.org/10.1038/nature24661

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