Gut Microbiota - Derived Metabolites in Atherosclerosis: Pathways, Biomarkers, and Targets

This review aims to analyze the critical role of gut microbiota-derived metabolites in the pathogenesis of atherosclerosis, a chronic inflammatory disease driven by lipid accumulation and immune dysregulation, and a leading cause of cardiovascular mor-bidity and mortality. Gut dysbiosis, marked by reduced microbial diversity and over-growth of pro-inflammatory bacteria, compromises intestinal barrier integrity, allow-ing translocation of lipopolysaccharides (LPS) and peptidoglycans, which activate TLR/NF-κB pathways and promote systemic inflammation. Trimethylamine N-oxide (TMAO), derived from dietary choline and L-carnitine, exacerbates endothelial dys-function, foam cell formation, and thrombosis, while secondary bile acids, such as de-oxycholic and lithocholic acid, modulate inflammation via FXR/TGR5 signaling, with effects varying by concentration. In contrast, short-chain fatty acids (SCFAs), particu-larly butyrate, exert anti-atherogenic effects by enhancing gut barrier function, reduc-ing inflammation, and improving lipid and glucose metabolism through GPCR and HDAC pathways. Therapeutic strategies, including dietary interventions (fiber-rich Mediterranean diets), probiotics (Lactobacillus, Bifidobacterium), prebiotics, fecal mi-crobiota transplantation (FMT), and small-molecule inhibitors ( DMB, IMC), target these metabolites to mitigate atherosclerosis. This review highlights gut microbio-ta-derived metabolites as pivotal biomarkers and therapeutic targets, emphasizing the potential of personalized microbiome-based interventions for atherosclerosis preven-tion and management.