Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?

Abstract

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which—at least in part—could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.

Effect of three oral pathogens on the TMA-TMAO metabolic pathway

“…3.2 Pg and Fn modulates the diversity and structure of gut microbiota TMAO originates from TMA and its precursors in the gut (Canyelles et al, 2023). Therefore, a comprehensive analysis was conducted to assess the diversity and composition of the gut microbiome.…”

Potential Impact of a Pregnant Woman’s Microbiota on the Development of Fetal Heart Defects: A Review of the Literature

“…However, recent studies suggest that elevated levels of TMAO in the blood can affect our health. High levels of TMAO are associated with an increased risk of certain diseases with a particular focus on cardiovascular disease including atherosclerosis and kidney disease [ 52 ]. TMAO is also produced by our body through the metabolism of dietary compounds such as choline, betaine, and carnitine.…”

Gut microbiota’s causative relationship with peripheral artery disease: a Mendelian randomization study

“…TMAO is a metabolite of the gut microbiota correlated with atherosclerosis and has been confirmed as a high-risk factor for cardiovascular diseases ( Zhao and Wang, 2020 ; Thomas and Fernandez, 2021 ; Anto and Blesso, 2022 ). Animal studies have revealed that supplementing diets with choline or TMAO can exacerbate atherosclerotic plaque lesions ( Canyelles et al, 2023 ). Elevated levels of TMAO can inhibit reverse cholesterol transport and bile acid metabolism, amplifying vascular inflammation and cellular apoptosis, leading to atherosclerosis ( Chen et al, 2023 ).…”