Document Type
Article
Publication Date
4-7-2011
Publication Title
Nature
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.
Repository Citation
Wang, Zeneng; Klipfell, Elizabeth; Bennett, Brian J.; Koeth, Robert; Levison, Bruce S.; DuGar, Brandon; Feldstein, Ariel E.; Britt, Earl B.; Fu, Xiaoming; Chung, Yoo Mi; Wu, Yuping; Schauer, Phil; Smith, Jonathan D.; Allayee, Hooman; Tang, W.H. Wilson; DiDonato, Joseph A.; Lusis, Aldons J.; and Hazen, Stanley L., "Gut Flora Metabolism of Phosphatidylcholine Promotes Cardiovascular Disease" (2011). Mathematics and Statistics Faculty Publications. 196.
https://engagedscholarship.csuohio.edu/scimath_facpub/196
DOI
10.1038/nature09922
Version
Postprint
Volume
472
Issue
7341
Comments
This research was supported by National Institutes of Health grants R01 HL103866, P01 HL098055, P01HL087018-020001, P01 HL28481 and P01 HL30568. B.J.B. was supported by NIH training grant T32-DK07789. The clinical study GeneBank was supported in part by P01 HL076491-055328, R01 HL103931 and the Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA (1UL1RR024989). Some of the laboratory studies (haemaglobin A1C, fasting glucose) in GeneBank were supported by R01 DK080732 and Abbott Diagnostics provided supplies for performance of some of the fasting lipid profile, glucose, creatinine, troponin I and hsCRP measured in GeneBank.