Effects of diet-modulated gut microbiota and microbial metabolites in atherosclerosis

Diet is a key regulatory factor for the gut microbiota, profoundly influencing its composition and metabolic activities, and is of great significance to the occurrence and development of atherosclerosis. Dysregulation of the gut microbiota can alter the production of key microbial metabolites. These metabolites play a crucial role in regulating host lipid metabolism, inflammatory responses, and endothelial integrity, and these factors are closely related to the pathogenesis of atherosclerotic plaques. In this review, we identify several key findings. Short-chain fatty acids, particularly butyrate and propionate, exert anti-atherosclerotic effects by promoting regulatory T cell differentiation, inhibiting histone deacetylases, and improving endothelial function. Bile acids modulate atherosclerosis via farnesoid X receptor and TGR5 signaling, with microbiota-mediated secondary bile acid composition playing a critical but species-dependent role. Tryptophan metabolites derived from both host and microbial metabolism exhibit dual roles in vascular inflammation, with indole-3-propionic acid and indole-3-carboxaldehyde showing consistent atheroprotective effects in preclinical models. Trimethylamine N-oxide is consistently associated with increased cardiovascular risk in observational studies, yet causal evidence in humans remains inconclusive. A high-fiber and plant-based diet can promote the growth of beneficial microbiota and the production of short-chain fatty acids, while a Western and high-protein diet can increase proteolytic bacteria and raise the level of trimethylamine N-oxide. In addition, food and medicine homologous compounds (including saponins, flavonoids, polysaccharides, and alkaloids) can regulate the composition of the gut microbiota and the activity of microbial enzymes, which represents a promising but unvalidated therapeutic strategy. This review consolidates the evidence regarding the intricate interplay between dietary habits, gut microbiota, and metabolite dynamics, highlighting their collective influence on atherosclerotic cardiovascular disease.