title: Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
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.
authors.affiliation: Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Klipfell
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.forename: Robert
authors.initials: R
authors.lastname: Koeth
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.forename: Brandon
authors.initials: B
authors.lastname: Dugar
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.forename: Earl B
authors.initials: EB
authors.lastname: Britt
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.forename: Yoon-Mi
authors.initials: YM
authors.lastname: Chung
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: Phil
authors.initials: P
authors.lastname: Schauer
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D001622:Betaine / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000378:metabolism* / Q000382:microbiology*; D008076:Cholesterol, HDL / Q000097:blood; D002794:Choline / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism* / Q000382:microbiology*; D005786:Gene Expression Regulation; D005856:Germ-Free Life; D006801:Humans; D008099:Liver / Q000201:enzymology; D008264:Macrophages / Q000378:metabolism; D055432:Metabolomics; D008744:Methylamines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D051116:Receptors, Scavenger / Q000378:metabolism; D018570:Risk Assessment
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D004041:Dietary Fats; D008744:Methylamines; D010713:Phosphatidylcholines; D051116:Receptors, Scavenger; D001622:Betaine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C005855:trimethyloxamine; D002794:Choline