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A growing body of evidence implicates the gut microbiota and its metabolites as key modulators of systemic metabolic homeostasis, influencing energy metabolism, inflammation, and oxidative stress. The gut microbiota emerges as a novel regulator of cardiac remodeling and metabolic reprogramming in DCM through the gut\u2013heart axis. This review aims to synthesize current mechanistic insights into how gut microbiota and its bioactive metabolites contribute to metabolic reprogramming in DCM. It further evaluates the potential of microbiota\u2010targeted interventions as emerging therapeutic strategies to mitigate disease progression and restore cardiac homeostasis. A narrative, mechanistically focused literature review was conducted using PubMed and Web of Science databases. It covered experimental, preclinical, and translational studies up to April 2025. Articles were selected based on relevance to gut microbial metabolism, host cardiac metabolic pathways, and therapeutic interventions linked to DCM. Gut microbiota\u2010derived metabolites\u2014including short\u2010chain fatty acids (SCFAs), trimethylamine N\u2010oxide (TMAO), bile acids, lipopolysaccharides (LPS), tryptophan catabolites, and hydrogen sulfide\u2014modulate cardiometabolic pathways via epigenetic regulation, altered energy substrate utilization, inflammatory signaling, and mitochondrial oxidative stress. These metabolites influence insulin resistance, lipid accumulation, mitochondrial dynamics, and cardiac fibrosis. Therapeutic strategies such as dietary modulation, probiotics, prebiotics, fecal microbiota transplantation, and drugs like SGLT2 inhibitors and GLP\u20101 receptor agonists have shown promising effects in modulating gut microbiota composition and alleviating DCM phenotypes in animal models. However, clinical evidence remains limited. The gut microbiota plays a pivotal role in the pathogenesis and potential treatment of DCM through its ability to reprogram host metabolism and inflammation. While preclinical data are compelling, further translational research\u2014including humanized models and multi\u2010omics integration\u2014is required to validate microbiota\u2010targeted therapies for cardiovascular applications. Targeting the microbiota\u2013metabolite axis offers an innovative therapeutic avenue for personalized intervention in diabetic heart disease.<\/jats:p>","DOI":"10.1096\/fj.202501579rr","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T12:13:57Z","timestamp":1756901637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Gut Microbiota\u2010Derived Metabolites Orchestrate Metabolic Reprogramming in Diabetic Cardiomyopathy: Mechanisms and Therapeutic Frontiers"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9406-2891","authenticated-orcid":false,"given":"Jing\u2010yu","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine The First Hospital of Jilin University  Changchun 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