The Immune-Metabolic Axis in Atherosclerosis: Decoding the Influence of Gut Microbiota and Microbiota-Derived Metabolites

Cardiovascular disease (CVD) continues to be the leading non-communicable disease and the main cause of death worldwide, with atherosclerosis being the primary underlying condition factor. Emerging evidence highlights the crucial role of the host microbiota in regulating immune responses and metabolic pathways involved in atherogenesis. Gut and oral microbiota imbalance has been associated with atherosclerosis development, marked by a decrease in anti-inflammatory, butyrate-producing taxa such as Faecalibacterium prausnitzii, Roseburia intestinalis, and Blautia, along with an increase in pro-inflammatory bacteria like Enterobacteriaceae, Streptococcus spp., and Chlamydia pneumoniae. The detection of oral microbes within vascular and atherosclerotic lesions further connects oral health with cardiovascular outcomes. Microbial metabolites, such as trimethylamine-N-oxide (TMAO) and microbial-associated molecular patterns, have been shown to increase the risk of coronary heart disease. Conversely, certain gut bacteria, notably Akkermansia muciniphila, Bacteroides dorei, and Bacteroides vulgatus, exhibit protective effects by reducing atherosclerotic lesions and systemic inflammation. Additionally, gut microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs) and bile acid derivatives, regulate immune homeostasis and lipid metabolism via GPR41 and GPR43 receptors. Although microbial signatures associated with atherosclerosis remain debated, growing evidence supports the microbiota and its metabolites as integral to the immune-metabolic axis influencing CVD. Understanding these dual roles may guide the development of microbiome-targeted interventions, including dietary modifications, prebiotics, probiotics, and receptor agonists, to prevent and manage atherosclerosis.