Gut Microbiota-Derived Metabolites and Cardiovascular Disease: Focus on Trimethylamine- <i>N</i> -oxide

Cardiovascular disease remains the leading cause of global morbidity and mortality, with growing evidence highlighting the role of gut microbiota-derived metabolites in its pathogenesis. Among these, trimethylamine-<i>N</i>-oxide (TMAO) has emerged as a key pro-atherogenic metabolite and an independent cardiovascular risk factor. This review synthesizes current knowledge of TMAO's role in atherosclerotic plaque formation, focusing on its effects on inflammatory activation, immune dysregulation, lipid metabolism disruption, endothelial dysfunction, and platelet-mediated thrombosis. Specifically, we describe how TMAO activates inflammasome signaling, alters macrophage polarization to promote foam cell formation, impairs reverse cholesterol transport, compromises endothelial integrity, and enhances thrombotic potential through platelet hyperreactivity. Additionally, we evaluate emerging therapeutic strategies aimed at reducing TMAO, including dietary interventions and modulation of gut microbiota, and pharmacological inhibition of microbial TMA lyases and hepatic flavin-containing monooxygenases (FMO_S). Our review highlights TMAO's dual utility as both a diagnostic biomarker and therapeutic target while underscoring the potential of microbiota-directed strategies for cardiovascular risk reduction. By integrating recent scientific advances, this review aims to provide a framework to improving clinical management and prevention strategies related to TMAO, offering a new perspective for cardiovascular health management.