Abstract
Cardiovascular diseases remain the leading global cause of morbidity and mortality, placing an escalating burden on health care systems and economies. While the gut microbiota is well recognized in atherosclerosis and cardiometabolic disorders, its influence on myocardial injury, repair, and regeneration is only beginning to emerge. Growing evidence reveals that gut microbes and their metabolites regulate myocardial health through intricate cross-organ networks, including the gut-brain-heart, gut-liver-heart, and gut-lung-heart axes. These findings suggest that the heart plays a key role in systemic host-microbe communication. Advances in metagenomics, metabolomics, and single-cell transcriptomics are now defining the molecular and cellular pathways by which microbial metabolites modulate immune tone, endothelial integrity, metabolic resilience, and cardiomyocyte survival. Studies in gnotobiotic models have established causal links between specific microbial taxa and myocardial outcomes while illuminating their roles in fibrosis resolution, angiogenesis, and regeneration. In this review, we synthesize current knowledge on the bidirectional gut-heart dialogue, emphasizing immunometabolic signaling, cross-organ integration, and regenerative mechanisms. We propose that coupling high-resolution multiomics with mechanistic modeling in controlled microbial systems will be pivotal for next-generation, microbiota-informed diagnostics, and therapeutics. We explore the emerging role of the gut-myocardium axis as both a driver of disease and as a promising modifiable therapeutic target and highlight a new frontier in precision cardiovascular medicine, with the potential to transform strategies for prevention, repair, and tissue regeneration.