Microbiome, Microbial Metabolites, and Atherosclerosis: Current Evidence, Gaps, and Future Directions

Atherosclerotic cardiovascular disease (ASCVD) represents a significant global health challenge. Although there are classic risk factor models predicting ASCVD, they are incomplete. In this regard, alternate models are being researched and human microbiome as a key factor is gaining traction. Recognized as a dynamic endocrine-like system, the gut microbiota profoundly influences atherosclerosis through complex host–microbe interactions and a vast array of bioactive metabolites. This review synthesized evidence linking specific microbial community signatures and metabolites to ASCVD. Methodological overview including study design spectrum, multiomics technologies and model systems are reviewed. Various microbial community signatures, namely, gut, oral, nasopharyngeal and vascular wall, and the role of microbial metabolites implicated in atherogenesis are explored. Furthermore, the mechanistic factors like endothelial dysfunction, immune modulation, lipid metabolism, and thrombotic factors related to microbiomes are reviewed. The field is now proceeding toward microbiome-based biomarkers for risk stratification and innovative therapeutic interventions, including precision nutrition, probiotics, and small-molecule inhibitors targeting microbial enzymes. Despite significant progress, critical knowledge gaps persist, notably establishing definitive causality in humans and the scarcity of large-scale, long-term randomized clinical trials. Future research should utilize high-resolution multiomics and artificial intelligence modeling technologies to guide toward precision cardiovascular medicine.