title: Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
abstract: BACKGROUND
  Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.
  
  
  METHODS
  We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography.
  
  
  RESULTS
  Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.
  
  
  CONCLUSIONS
  The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.).
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland 44195, USA.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeth
authors.forename: Earl B
authors.initials: EB
authors.lastname: Britt
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001622:Betaine / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood*; D002794:Choline / Q000008:administration & dosage / Q000097:blood; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D053208:Kaplan-Meier Estimate; D008297:Male; D054892:Metagenome / Q000187:drug effects / Q000502:physiology*; D008744:Methylamines / Q000097:blood* / Q000652:urine; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000378:metabolism*; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D000900:Anti-Bacterial Agents; D008744:Methylamines; D010713:Phosphatidylcholines; D001622:Betaine; C005855:trimethyloxamine; D002794:Choline