Nutritional Modulation of the Gut Microbiome-Metabolite Axis in Cardiovascular Disease: From Dietary Patterns to Cardiovascular Risk.

purpose of reviewCardiovascular disease (CVD) remains the leading cause of mortality worldwide, and dietary modification represents one of the most important modifiable strategies for its prevention and management. Increasing evidence indicates that the cardiovascular effects of diet extend beyond direct effects of nutrients and are partly mediated by interactions between dietary substrates, the gut microbiota, and host metabolism. This review critically evaluates the role of diet-microbiota interactions in CVD pathogenesis and provides an integrated, metabolite-centered perspective on how major dietary patterns influence gut microbial metabolism and cardiovascular health. Particular attention is given to trimethylamine N-oxide (TMAO), lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), bile acids (BAs), phenylacetylglutamine (PAGln), indolepropionic acid (IPA), and hydrogen sulfide (H₂S). RECENT

findingsDietary patterns substantially influence microbial composition, substrate availability, intestinal barrier integrity, and the production or transformation of microbiota-associated metabolites. Western-style, animal-based, and high-fat dietary patterns, may promote proteolytic and sulfidogenic fermentation, dysbiosis, impaired intestinal barrier function, and increased production or availability of potentially harmful metabolites. TMAO and PAGln have been associated with atherosclerosis, endothelial dysfunction, platelet activation, thrombosis, and other cardiometabolic outcomes, although their associations with cardiovascular risk may depend on dietary source, renal function, host metabolism, and individual microbial characteristics. LPS provides an important link between intestinal permeability, metabolic endotoxemia, inflammation, and vascular dysfunction. In contrast, fiber-rich and plant-based dietary patterns promote saccharolytic fermentation and SCFA production, support microbial diversity and intestinal barrier integrity, and may reduce endotoxemia and the production of potentially adverse microbial metabolites. Mediterranean dietary patterns, characterized by high consumption of plant foods, whole grains, fiber, olive oil, polyphenols, and fish together with lower intake of red and processed meat and refined sugars, appear to favor a more beneficial microbial and metabolic profile. BAs have more complex and context-dependent effects through microbial transformation and host signaling pathways, particularly FXR and TGR5. Emerging evidence also suggests potentially important cardiovascular roles for IPA and H₂S; however, their dietary regulation and clinical relevance remain less well established. The gut microbiota represents an important metabolic interface linking dietary patterns with cardiovascular physiology and disease. The available evidence suggests that dietary patterns rich in plant foods, fiber, unsaturated fats, polyphenols, and other bioactive components may support beneficial microbial functions and metabolite profiles, whereas Western-style dietary patterns may favor microbial pathways associated with endotoxemia, inflammation, thrombosis, and atherogenesis. However, individual metabolites should not be interpreted in isolation because their cardiovascular effects may vary according to dietary source, microbial phenotype, host metabolism, renal function, and overall dietary context. Emerging evidence supports a biomarker-guided and individualized approach to nutritional modulation of the gut microbiota, including strategies targeting microbial metabolite production. Nevertheless, the clinical efficacy of microbiota-targeted interventions remains to be established. Future longitudinal and randomized interventional studies integrating dietary assessment, microbiome composition, metabolomics, host metabolic characteristics, and cardiovascular outcomes are needed to clarify causality and determine whether personalized nutrition and microbiota-targeted strategies can improve CVD prevention and reduce residual cardiovascular risk.