Comparative insights into the gut-heart axis: cross-species and cross-population perspectives

Gut microbiota research has rapidly expanded our understanding of host-microbe interactions in cardiovascular diseases, yet translation of these insights remains challenged by species-specific differences and substantial population heterogeneity. In this review, we synthesize current evidence across rodents, swine, non-human primates, and multi-ethnic human cohorts to delineate conserved versus context-dependent features of the gut-heart axis. Rodent models remain indispensable for mechanistic discovery, enabling causal testing through germ-free, antibiotic-treated, and humanized microbiota platforms, whereas large-animal models better replicate human cardiac anatomy, physiology, and microbial ecology. Human studies provide essential clinical relevance, demonstrating that patients with myocardial infarction, coronary artery disease, atrial fibrillation, and heart failure harbor distinct microbial and metabolite signatures. However, these findings vary across populations due to differences in diet, lifestyle, host genetics, medication exposure, and environmental transitions. Despite taxonomic variability, several functional pathways, most notably short-chain fatty acid production, bile acid biotransformation, and aromatic amino acid metabolism generating molecules such as trimethylamine-N-oxide and phenylacetylglutamine, consistently associate with cardiovascular risk. At the same time, population-specific features, including glycan-microbe interactions shaped by ABO and FUT2 genotypes, diet-responsive metabolite profiles, and variable drug-microbiome interactions, highlight the importance of genetic and environmental context. By integrating cross-species and cross-population evidence, this review outlines a framework for identifying robust microbial pathways, clarifying their translational boundaries, and guiding the development of microbiota-informed diagnostics and interventions that account for biological, cultural, and environmental diversity.