Seven microbiota-derived metabolites — TMAO, LPS, SCFAs, bile acids, phenylacetylglutamine (PAGln), indolepropionic acid (IPA), and hydrogen sulfide (H₂S) — emerge as mechanistic intermediaries between dietary patterns and cardiovascular outcomes. Western and animal-protein-heavy diets drive proteolytic fermentation, dysbiosis, and elevated TMAO and PAGln, both linked to atherosclerosis, platelet activation, endothelial dysfunction, and thrombosis. Plant-based and Mediterranean patterns shift fermentation toward saccharolytic pathways, boosting SCFA production and protecting intestinal barrier integrity, thereby reducing metabolic endotoxemia driven by LPS translocation.
This review arrives at a moment when the gut-cardiovascular axis is transitioning from mechanistic curiosity to clinical target. TMAO has accumulated the strongest human evidence — prospective cohort data consistently associate higher plasma TMAO with major adverse cardiac events — but the PAGln signal is newer and less replicated, warranting caution. Critically, TMAO's cardiovascular impact is modulated by renal clearance, dietary choline source, and individual microbial composition, complicating universal risk thresholds. The bile acid arm, operating through FXR and TGR5 receptor signaling, adds further context-dependence that resists simple dietary prescription. As a narrative review rather than meta-analysis, causal hierarchies cannot be established here. The practical implication for adults remains durable: maximizing dietary fiber, polyphenols, and plant protein while limiting red and processed meat represents the most evidence-consistent strategy to favorably shift the entire metabolite portfolio simultaneously.
