(15-06-14) Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

W.H. Wilson Tang, M.D., Zeneng Wang, Ph.D., Bruce S. Levison, Ph.D., Robert A. Koeth, B.S., Earl B. Britt, M.D.,
Xiaoming Fu, M.S., Yuping Wu, Ph.D., and Stanley L. Hazen, M.D., Ph.D.



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.)

Source: n engl j med 368;17 nejm.org april 25, 2013

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