Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

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, Jonathan D. Smith, Hooman Allayee, W. H. Wilson Tang, Joseph A. DiDonato, Aldons J. Lusis and Stanley L. Hazen ()
Additional contact information
Zeneng Wang: Cleveland Clinic, Cleveland, Ohio 44195, USA
Elizabeth Klipfell: 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
Brandon DuGar: Cleveland Clinic, Cleveland, Ohio 44195, USA
Ariel E. Feldstein: Cleveland Clinic, Cleveland, Ohio 44195, USA
Earl B. Britt: Cleveland Clinic, Cleveland, Ohio 44195, USA
Xiaoming Fu: Cleveland Clinic, Cleveland, Ohio 44195, USA
Yoon-Mi Chung: 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
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
Joseph A. DiDonato: 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

Nature, 2011, vol. 472, issue 7341, 57-63

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09922

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