Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies

Abstract

Circulating trimethylamine N‐oxide (TMAO), a canonical metabolite from gut flora, has been related to the risk of cardiovascular disorders. However, the association between circulating TMAO and the risk of cardiovascular events has not been quantitatively evaluated. We performed a systematic review and meta‐analysis of all available cohort studies regarding the association between baseline circulating TMAO and subsequent cardiovascular events. Embase and PubMed databases were searched for relevant cohort studies. The overall hazard ratios for the developing of cardiovascular events (CVEs) and mortality were extracted. Heterogeneity among the included studies was evaluated with Cochran's Q Test and I 2 statistics. A random‐effect model or a fixed‐effect model was applied depending on the heterogeneity. Subgroup analysis and meta‐regression were used to evaluate the source of heterogeneity. Among the 11 eligible studies, three reported both CVE and mortality outcome, one reported only CVEs and the other seven provided mortality data only. Higher circulating TMAO was associated with a 23% higher risk of CVEs (HR = 1.23, 95% CI: 1.07–1.42, I 2 = 31.4%) and a 55% higher risk of all‐cause mortality (HR = 1.55, 95% CI: 1.19–2.02, I 2 = 80.8%). Notably, the latter association may be blunted by potential publication bias, although sensitivity analysis by omitting one study at a time did not significantly change the results. Further subgroup analysis and meta‐regression did not support that the location of the study, follow‐up duration, publication year, population characteristics or the samples of TMAO affect the results significantly. Higher circulating TMAO may independently predict the risk of subsequent cardiovascular events and mortality.

Circulating gut microbiota metabolite trimethylamine N‐oxide and oral contraceptive use in polycystic ovary syndrome

“…It has been suggested that TMAO could serve as a novel and independent biomarker in humans for development of atherosclerosis and prediction of cardiovascular morbidity and mortality. 10,[13][14][15] In line with the results of previous studies in other high-risk populations such as gestational diabetes and type 2 diabetes, 11,12 the results of the current study provide evidence that TMAO and its precursors are increased in PCOS. These alterations might contribute to increased cardiometabolic risk of PCOS in addition to other proposed mechanisms including hyperandrogenism, anovulation, obesity, insulin resistance, dyslipidemia and subclinical inflammation.…”

“…2 Recent animal and human data in PCOS showed alterations in composition of gut microbiota in PCOS, partly associated with androgen excess. [13][14][15] Even though limited studies have reported dysbiosis in PCOS, to the best of our knowledge, no data are available on gut microbiota-derived metabolites and impact of any treatment on those in the syndrome. 8,9 Trimethylamine N-oxide (TMAO) is the most well-known gut microbiota-related cardiometabolic risk factor which is highly related to atherosclerotic cardiovascular disease, type 2 diabetes and gestational diabetes mellitus.…”

“…Elevated circulating concentrations of both TMAO and its precursors are associated with increased risk of adverse cardiovascular events, independently of traditional risk factors. [13][14][15] Even though limited studies have reported dysbiosis in PCOS, to the best of our knowledge, no data are available on gut microbiota-derived metabolites and impact of any treatment on those in the syndrome. The primary aim of this study was to determine whether microbiota-related cardiometabolic risk markers are altered in PCOS.…”

“…It has been suggested that TMAO could serve as a novel and independent biomarker in humans for development of atherosclerosis and prediction of cardiovascular morbidity and mortality 10,[13][14][15]. It has been suggested that TMAO could serve as a novel and independent biomarker in humans for development of atherosclerosis and prediction of cardiovascular morbidity and mortality 10,[13][14][15].…”

Gut microbiota‐derived metabolite trimethylamine N‐oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose‐response meta‐ analysis

“…Obesity is one of the most important predictors of CVD and T 2 DM, and from an etiologic point of view, it is important to elucidate whether the associations between TMAO and CVD or other NCDs are established via an independent association between TMAO and obesity as a prognostic cardio‐metabolic risk factor. While no summarized evidence regarding the associations between obesity and TMAO is available, there are several meta‐analyses regarding the association between increased TMAO levels and risk of CVD mortality and T 2 DM . It should also be noted that no study is available to summarize the association between TMAO and obesity measurements.…”