Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

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Abstract

Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely 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 up-regulation 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 (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

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Most cited references 62

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 4 March 2011

Publication date (Print): 7 April 2011

Publication date PMC-release: 7 October 2011

Volume: 472

Issue: 7341

Pages: 57-63

Affiliations

[1 ]Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195

[2 ]Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195

[3 ]Department of Medicine/Division of Cardiology, BH-307 Center for the Health Sciences, University of California, Los Angeles, CA 90095

[4 ]Department of Mathematics, Cleveland State University, Cleveland, OH 44115

[5 ]Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland, OH 44195

[6 ]Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195

[7 ]Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089

Author notes

[8 ]To whom correspondence should be addressed: Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, OH 44195 Tel: 216-445-9763, Fax: 216-636-0392, hazens@ 123456ccf.org

Article

Manuscript ID: nihpa271797

DOI: 10.1038/nature09922

PMC ID: 3086762

PubMed ID: 21475195

SO-VID: 9c0a22e0-1a34-4b91-8b61-811d25ab31c8

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