Trimethylamine N-oxide pathway (TMAO pathway)

The Trimethylamine N-oxide (TMAO) pathway is a multi-step metabolic axis that links dietary intake, gut microbial activity, and host hepatic metabolism [1, 11]. The process begins with the microbial conversion of dietary nutrients such as choline, L-carnitine, and phosphatidylcholine into trimethylamine (TMA) via specific gut microbiota enzymes, primarily choline TMA-lyase (CutC/D) and carnitine monooxygenase (CntA/B) [8, 14]. TMA is subsequently absorbed into the portal circulation and oxidized in the liver by flavin-containing monooxygenase 3 (FMO3) to form TMAO [13, 16]. Elevated systemic levels of TMAO are strongly associated with an increased risk of major adverse cardiovascular events, including atherosclerosis, myocardial infarction, and stroke, as well as chronic kidney disease and metabolic disorders [1, 14]. TMAO exerts its pathological effects by promoting vascular inflammation through NF-κB and NLRP3 inflammasome activation, enhancing platelet hyperreactivity, and impairing reverse cholesterol transport [11, 14]. Therapeutic strategies targeting this pathway include the development of non-lethal microbial TMA lyase inhibitors (e.g., DMB, IMC) and host FMO3 inhibitors, as well as dietary modifications and probiotic interventions to reduce circulating TMAO levels [3, 9, 17].

Other names

TMA/FMO3/TMAO pathwayGut-microbiota-liver axisTMAO metabolic axisGut-heart axis

Inhibition of microbial choline TMA-lyase (CutC/D) and carnitine monooxygenase (CntA/B), inhibition of hepatic flavin-containing monooxygenase 3 (FMO3), and modulation of gut microbiota composition to reduce trimethylamine production.