Microbial metabolite-driven mechanisms linking the gut microbiome to atherosclerosis: multi-omic and translational...

Atherosclerotic cardiovascular disease remains the leading cause of mortality worldwide, and a substantial residual risk persists despite optimal management of traditional risk factors. Increasing evidence implicates the gut microbiome as a mechanistic contributor to atherogenesis, not merely through taxonomic shifts but via the production of bioactive microbial metabolites that link diet, microbial metabolism, and host vascular biology. These metabolites have emerged as central effectors of the gut-artery axis, influencing intestinal barrier integrity, systemic immunity, lipid handling, and thrombosis. Among the best-characterized pathways, trimethylamine N-oxide and phenylacetylglutamine have been robustly linked to macrophage lipid accumulation, platelet hyperreactivity, and adverse cardiovascular outcomes. More recently, imidazole propionate, a histidine-derived microbial metabolite, has emerged as a candidate mediator of vascular inflammation and plaque development through imidazoline-1 receptor-dependent activation of mTORC1 signaling, supported by mechanistic and experimental evidence. Advances in metagenomics, metabolomics, and proteomics now enable systems-level interrogation of microbiome-host interactions, facilitating causal inference through integrative metabolite-protein and pathway-level analyses. These approaches have revealed reproducible molecular networks associated with subclinical and clinical atherosclerosis, providing a framework for biomarker discovery and therapeutic targeting. People with HIV represent a particularly informative human model, in which persistent gut barrier disruption and dysbiosis sustain immune activation and confer excess cardiovascular risk, with distinct microbial and metabolite signatures linked to vascular inflammation and plaque progression. This review synthesizes current evidence linking gut microbial function to atherosclerosis, with a specific focus on metabolite-driven mechanisms, multi-omic integration, and translational relevance. We highlight emerging biomarkers and therapeutic strategies targeting microbial metabolic pathways and discuss methodological challenges that must be addressed to advance the gut-artery axis toward precision cardiovascular medicine.