Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies

Background Gut microbial metabolites have been implicated as novel risk factors for cardiovascular events and premature death. The strength and consistency of associations between blood concentrations of the gut microbial metabolites, trimethylamine‐N‐oxide ( TMAO ) and its precursors, with major adverse cardiovascular events ( MACE ) or death have not been comprehensively assessed. We quantified associations of blood concentrations of TMAO and its precursors with risks of MACE and mortality. Methods and Results PubMed and Embase databases were searched up, and a total of 19 prospective studies from 16 publications (n=19 256, including 3315 incident cases) with quantitative estimates of the associations of TMAO with the development of MACE or death were included in our main analysis. Multivariate‐adjusted relative risks ( RR s) were used when these were available. Elevated concentrations of TMAO were associated with a pooled RR of 1.62 (95% CI, 1.45, 1.80; P heterogeneity =0.2; I 2 =23.5%) for MACE compared with low TMAO levels, and 1 study of black participants influenced the heterogeneity of the association. After excluding the data of blacks, the RR s were not different according to body mass index, prevalence of diabetes mellitus, history of cardiovascular diseases, and kidney dysfunction. Furthermore, elevated TMAO concentrations were associated with a pooled RR of 1.63 (1.36, 1.95) for all‐cause mortality. Individuals with elevated concentrations of TMAO precursors ( l ‐carnitine, choline, or betaine) had an approximately 1.3 to 1.4 times higher risk for MACE compared to those with low concentrations. Conclusions Elevated concentrations of TMAO and its precursors were associated with increased risks of MACE and all‐cause mortality independently of traditional risk factors.