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Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid

Author

Listed:
  • Kali M. Pruss

    (Stanford University School of Medicine)

  • Haoqing Chen

    (Department of Pathology Stanford University School of Medicine)

  • Yuanyuan Liu

    (Department of Pathology Stanford University School of Medicine)

  • William Treuren

    (Stanford University School of Medicine)

  • Steven K. Higginbottom

    (Stanford University School of Medicine)

  • John B. Jarman

    (Department of Pathology Stanford University School of Medicine)

  • Curt R. Fischer

    (ChEM-H, Stanford University
    Octant Bio)

  • Justin Mak

    (Stanford Healthcare)

  • Beverly Wong

    (Stanford Healthcare)

  • Tina M. Cowan

    (Department of Pathology Stanford University School of Medicine)

  • Michael A. Fischbach

    (Stanford University School of Medicine
    ChEM-H, Stanford University
    Stanford University
    Chan Zuckerberg Biohub)

  • Justin L. Sonnenburg

    (Stanford University School of Medicine
    Chan Zuckerberg Biohub
    Center for Human Microbiome Studies)

  • Dylan Dodd

    (Stanford University School of Medicine
    Department of Pathology Stanford University School of Medicine)

Abstract

The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD−/− mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites.

Suggested Citation

  • Kali M. Pruss & Haoqing Chen & Yuanyuan Liu & William Treuren & Steven K. Higginbottom & John B. Jarman & Curt R. Fischer & Justin Mak & Beverly Wong & Tina M. Cowan & Michael A. Fischbach & Justin L., 2023. "Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36138-3
    DOI: 10.1038/s41467-023-36138-3
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    References listed on IDEAS

    as
    1. Shuo Han & Will Treuren & Curt R. Fischer & Bryan D. Merrill & Brian C. DeFelice & Juan M. Sanchez & Steven K. Higginbottom & Leah Guthrie & Lalla A. Fall & Dylan Dodd & Michael A. Fischbach & Justin , 2021. "A metabolomics pipeline for the mechanistic interrogation of the gut microbiome," Nature, Nature, vol. 595(7867), pages 415-420, July.
    2. Dylan Dodd & Matthew H. Spitzer & William Van Treuren & Bryan D. Merrill & Andrew J. Hryckowian & Steven K. Higginbottom & Anthony Le & Tina M. Cowan & Garry P. Nolan & Michael A. Fischbach & Justin L, 2017. "A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites," Nature, Nature, vol. 551(7682), pages 648-652, November.
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    1. Bennett W. Fox & Maximilian J. Helf & Russell N. Burkhardt & Alexander B. Artyukhin & Brian J. Curtis & Diana Fajardo Palomino & Allen F. Schroeder & Amaresh Chaturbedi & Arnaud Tauffenberger & Cheste, 2024. "Evolutionarily related host and microbial pathways regulate fat desaturation in C. elegans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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