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Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Author

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  • Zeneng Wang

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Elizabeth Klipfell

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Brian J. Bennett

    (BH-307 Center for the Health Sciences, University of California, Los Angeles, California 90095, USA)

  • Robert Koeth

    (Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Bruce S. Levison

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Brandon DuGar

    (Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Ariel E. Feldstein

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Earl B. Britt

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Xiaoming Fu

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Yoon-Mi Chung

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Yuping Wu

    (Cleveland State University, Cleveland, Ohio 44115, USA)

  • Phil Schauer

    (Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Jonathan D. Smith

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Hooman Allayee

    (Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA)

  • W. H. Wilson Tang

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Joseph A. DiDonato

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA)

  • Aldons J. Lusis

    (BH-307 Center for the Health Sciences, University of California, Los Angeles, California 90095, USA)

  • Stanley L. Hazen

    (Cleveland Clinic, Cleveland, Ohio 44195, USA
    Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cleveland Clinic, Cleveland, Ohio 44195, USA)

Abstract

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

Suggested Citation

  • Zeneng Wang & Elizabeth Klipfell & Brian J. Bennett & Robert Koeth & Bruce S. Levison & Brandon DuGar & Ariel E. Feldstein & Earl B. Britt & Xiaoming Fu & Yoon-Mi Chung & Yuping Wu & Phil Schauer & Jo, 2011. "Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease," Nature, Nature, vol. 472(7341), pages 57-63, April.
    • Handle: RePEc:nat:nature:v:472:y:2011:i:7341:d:10.1038_nature09922
    DOI: 10.1038/nature09922
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    Cited by:

    1. Zahraa Al Bander & Marloes Dekker Nitert & Aya Mousa & Negar Naderpoor, 2020. "The Gut Microbiota and Inflammation: An Overview," IJERPH, MDPI, vol. 17(20), pages 1-21, October.
    2. Chiu-Huang Kuo & Chin-Hung Liu & Ji-Hung Wang & Bang-Gee Hsu, 2022. "Serum Trimethylamine N-Oxide Levels Correlate with Metabolic Syndrome in Coronary Artery Disease Patients," IJERPH, MDPI, vol. 19(14), pages 1-9, July.
    3. Ruth Nussinov & Jason A Papin, 2017. "How can computation advance microbiome research?," PLOS Computational Biology, Public Library of Science, vol. 13(9), pages 1-3, September.
    4. Nicole Farmer & Cristhian A. Gutierrez-Huerta & Briana S. Turner & Valerie M. Mitchell & Billy S. Collins & Yvonne Baumer & Gwenyth R. Wallen & Tiffany M. Powell-Wiley, 2021. "Neighborhood Environment Associates with Trimethylamine-N-Oxide (TMAO) as a Cardiovascular Risk Marker," IJERPH, MDPI, vol. 18(8), pages 1-15, April.

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