The gut microbiota and cardiovascular disease: Exploring the role of microbial dysbiosis and metabolites in pathogenesis and therapeutics

The gut microbiota, a dynamic ecosystem of microorganisms inhabiting the human body, plays a pivotal role in modulating host physiology and immune function, with intense implications for the cardiovascular system. Cardiovascular diseases (CVDs) stand out as the leading cause of mortality worldwide. Gut microbiome dysbiosis is implicated in diverse CVDs, such as hypertension, atherosclerosis, coronary artery disease, heart failure, and myocardial infarction, through mechanisms mediated by microbial-derived metabolites. Key compounds include trimethylamine N-oxide (TMAO) (linked to plaque instability), short-chain fatty acids (SCFAs) (which regulate blood pressure and endothelial function), phenylacetylglutamine (PAGln) (a promoter of thrombotic pathways), and bile acids (influencing lipid metabolism). These metabolites serve as both biomarkers of CVD risk and therapeutic targets. Emerging strategies to modulate the gut microbiota, such as precision probiotics, dietary interventions (e.g., fiber-rich or polyphenol-heavy diets), and pharmacologic inhibitors of microbial enzymes (e.g., TMA lyase blockers), highlight the potential for microbiome-directed therapies. However, challenges remain in elucidating causal microbial pathways, standardizing interventions across diverse populations, and translating preclinical findings into clinical practice. In this mechanistic and translational review, we synthesize current evidence on the bidirectional relationship between gut microbial dysbiosis and CVDs. We explore how modifiable factors, including diet, pharmacotherapy, and early-life microbial colonization, reshape gut communities, driving systemic inflammation, metabolic dysfunction, and vascular pathology. Future research must prioritize longitudinal human studies, multi-omics integration, and randomized trials to harness the gut microbiota's full potential in CVD prevention and personalized treatment.