There is a growing awareness in many fields of medicine that intestinal microbial organisms, collectively termed microbiota, play a crucial role in the global metabolism of their host. Recent animal studies have demonstrated mechanistic links 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). The relevance of this connection in humans is unknown but was investigated in two linked studies.
In the first, 40 healthy volunteers were recruited and levels of plasma and urinary TMAO were measured after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. In the second study, 4007 adults who were undergoing elective coronary angiography were recruited and followed for three years with a comparison made between baseline fasting plasma TMAO levels and incident major adverse cardiovascular events (death, myocardial infarction, or stroke). The results demonstrated a highly significant correlation between TMAO levels and the risk of a primary outcome event and also that circulating TMAO was modifiable by antibiotic therapy. In the healthy volunteer study, time-dependent increases in levels of both TMAO 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. In the coronary disease cohort study, increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (HR for highest vs. lowest TMAO quartile, 2.54; 95% CI, 1.96 to 3.28; P<0.001). In addition, an elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001).
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.
- Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84.