From stem cell therapy to precision regenerative cardiology: integrating the gut microbiota and multi-omics in myocardial infarction

Myocardial infarction (MI) remains a major cause of heart failure because extensive cardiomyocyte loss exceeds the limited regenerative capacity of the adult heart. Adult progenitor cell- and mesenchymal stem cell-based therapies promote cardiac repair predominantly through paracrine, immunomodulatory, angiogenic, cytoprotective, and extracellular matrix-regulatory mechanisms, whereas pluripotent stem cell derived cardiomyocytes (PSC-CMs) therapy aims to replace lost contractile cells through myocardial remuscularization. However, outcomes of adult-cell therapies remain inconsistent, and clinical evidence for PSC-CMs therapy remains preliminary, indicating that regenerative efficacy may depend on both therapeutic-product characteristics and the recipient environment. This review examines myocardial regeneration through the concept of a post-infarction regenerative microenvironment shaped by inflammation, fibrosis, vascular integrity, metabolic adaptation, and intercellular communication. We discuss recent advances in stem cell preconditioning, product purification and maturation, genetic engineering, biomaterial-assisted delivery, extracellular vesicle (EV) therapeutics, and the early clinical translation of PSC-CMs and cell-derived secretome products. Particular attention is given to the gut–heart axis as a potential systemic regulator of post-infarction repair. Clinical and experimental studies indicate that MI is accompanied by intestinal injury and time-dependent changes in microbial composition and metabolism. Short-chain fatty acids, particularly butyrate, can support inflammatory resolution, mitochondrial function, vascular homeostasis, and tissue repair, whereas trimethylamine N-oxide can promote endothelial dysfunction, inflammasome activation, oxidative stress, fibrosis, and adverse remodeling. However, these effects have been demonstrated predominantly in experimental settings. Microbial signals may also influence stem/progenitor cell differentiation, immunomodulatory activity, and secretory properties. Nevertheless, direct evidence that the gut microbiota or microbial metabolites determine the efficacy or optimal timing of stemcell therapy after MI remains scarce. Next-generation sequencing and integrated multi-omics provide tools for investigating these relationships by linking microbial function with host responses, therapeutic cell heterogeneity, spatial tissue organization, EV cargo, and cardiac outcomes. Collectively, current evidence supports integrating microbial metabolism, host responses, and regenerative cell function within a unified framework for precision regenerative cardiology. Although direct causal evidence remains limited, this framework provides a rationale for longitudinal and mechanistically controlled studies that jointly assess microbiome profiles, microbial metabolites, therapeutic-product characteristics, and cardiac outcomes. Such studies may enable biomarker-informed patient stratification, optimization of the recipient environment, and rational ex vivo metabolite programming of regenerative products.