Journal
NATURE
Volume 472, Issue 7341, Pages 57-U82Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09922
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Funding
- National Institutes of Health [R01 HL103866, P01 HL098055, P01HL087018-020001, P01 HL28481, P01 HL30568, T32-DK07789]
- Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA [1UL1RR024989]
- Abbott Diagnostics
- [P01 HL076491-055328]
- [R01 HL103931]
- [R01 DK080732]
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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.
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