A new meta-analysis based on multiple cohort studies found that elevated concentrations of trimethylamine N-oxide (TMAO)—a gut microbiota-derived metabolite of choline, L-carnitine or betaine—were associated with increased risks of major adverse cardiovascular events (MACE) and all-cause mortality .
Choline, L-carnitine and betaine are metabolized by intestinal bacteria to form trimethylamine, which is then oxidized to TMAO by the enzyme flavin monooxygenase 3 in the liver. Because there is an increasing number of studies investigating the association of circulating levels of TMAO and MACE (e.g, myocardial infarction, stroke, and heart failure), researchers from the Department of Epidemiology at Tulane University (New Orleans, LA) decided to systematically evaluate data from these studies.
They identified 19 cohort studies from the literature for the meta-analysis. These studies, mostly conducted in Europe and the United States, totaled nearly 20,000 participants, with duration ranging from 1 to 8 years. Compared with participants with low TMAO levels, those with high levels were associated with a 62% increased risk for the development of MACE and a 63% increased risk for all-cause mortality, and there appeared to be a dose-dependent relationship. The observed association was independent of conventional CVD risk factors such as kidney dysfunction, diabetes, and obesity.
Although the observed association is statistically quite significant, several points are worth pondering before one can evaluate its clinical relevance. First, TMAO was measured only once in these studies. As the gut microbiota is a highly dynamic environment that can be affected by many environmental factors, one measurement may not represent the long-term levels of TMAO produced by the gut microbiota. Second, intakes of food or supplement containing choline, L-carnitine and betaine were not assessed in these studies. Thus, the investigators were unable to take into account the impact of diet on TMAO levels, gut microbiota health status, and the outcomes of interest. Third, the study cohorts included patients with pre-existing cardiovascular conditions. Therefore, the observed association may not be applicable to low-risk populations. Fourth, each study utilized a different definition of elevated TMAO levels. Clinically, there hasn’t been a reference range for TMAO. Further, most of the study participants were Caucasians. The finding may not be applicable to other race and ethnic groups.
Nevertheless, the research question is valid, as some mechanism studies have demonstrated the role of TMAO in the pathogenesis of atherosclerosis . Further studies are needed to help researchers understand the causality of the observed association.
The study results were published in The Journal of American Heart Association (June 2017).
 Heianza, Y., et al., Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta-Analysis of Prospective Studies. J Am Heart Assoc, 2017. 6(7): p. e004947.
 Velasquez, M.T., et al., Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel), 2016. 8(11): 326.