Role of Gut Microbiota-Derived Metabolites (TMAO) in Atherosclerosis Pathogenesis

Background: A growing body of evidence highlights the gut microbiota as a critical modulator of cardiovascular health, with particular emphasis on its role in the development and progression of atherosclerosis. Among the most studied microbial metabolites is trimethylamine-N-oxide (TMAO), a compound produced via hepatic oxidation of trimethylamine (TMA), itself generated by gut microbial metabolism of dietary choline, carnitine, and phosphatidylcholine. Elevated plasma TMAO levels have been consistently associated with increased risk of major adverse cardiovascular events, yet the precise mechanisms linking TMAO to atherogenesis continue to be elucidated. Methods and Results: This review synthesizes current translational and experimental evidence on the role of TMAO in the pathogenesis of atherosclerosis. Mechanistic studies demonstrate that TMAO promotes endothelial dysfunction, enhances foam cell formation via upregulation of scavenger receptors (CD36, SR-A1), and modulates reverse cholesterol transport. TMAO has also been shown to activate inflammatory pathways, particularly the NLRP3 inflammasome and NF-κB signaling, contributing to vascular inflammation and plaque instability. Animal models reveal accelerated atherosclerotic lesion development with dietary supplementation of TMAO or its precursors, while microbial suppression or inhibition of TMA formation attenuates disease progression. Emerging therapeutic approaches—such as dietary modification, targeted microbial enzyme inhibitors (e.g., CutC), and probiotic interventions—are being explored to mitigate TMAO-associated cardiovascular risk. Conclusion: TMAO serves as a mechanistic and prognostic link between gut microbial metabolism and atherosclerotic cardiovascular disease. Integrating microbiota-derived biomarkers like TMAO into cardiovascular risk assessment may enhance precision prevention strategies. Future research should focus on developing clinically viable TMAO-lowering interventions and further elucidating host–microbiome–vascular interactions in atherosclerosis.