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Dysbiosis contributes to systemic inflammation, endothelial dysfunction, and adverse cardiac remodeling via microbial metabolites such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs). However, the therapeutic intersection between the gut microbiota and pharmacological interventions remains insufficiently integrated. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), a cornerstone of T2DM management, confer cardioprotective effects that may involve microbiota-mediated pathways. This review provides a novel synthesis of how SGLT2is influence gut ecology, specifically through altered glucose excretion and osmotic shifts, to potentially restore SCFA-producing taxa. By delineating the structural transitions from gut physiology to SGLT2i-modulated cardiac outcomes, we emphasize the gut\u2013heart axis as a pivotal therapeutic target. This focused framework offers new insights into the triadic interplay between microbiome stability and cardiometabolic health, moving beyond traditional glucose-centric paradigms.<\/jats:p>","DOI":"10.3390\/ijms27094101","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T01:12:09Z","timestamp":1777857129000},"page":"4101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the Gut\u2013Heart Axis in Diabetic Heart Failure: Microbiota and SGLT2is as Converging Therapeutic Frontiers"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7712-8331","authenticated-orcid":false,"given":"Yen","family":"Chu","sequence":"first","affiliation":[{"name":"Division of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"Laboratory of Cardiovascular Physiology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"Department of Research and Development, Chang Gung Memorial Hospital Linkou Branch, No. 5, Fuxing St., Guishan Dist., Taoyuan 33305, Taiwan"},{"name":"Department of Nursing, College of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Rd., Guishan Dist., Taoyuan 33303, Taiwan"},{"name":"Graduate Institute of Traditional Chinese Medicine, The Medical College, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Hsiung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nursing, College of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Rd., Guishan Dist., Taoyuan 33303, Taiwan"},{"name":"Department of Laboratory Medicine, Section of Clinical Serology and Immunology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2069-3636","authenticated-orcid":false,"given":"Chi-Nan","family":"Tseng","sequence":"additional","affiliation":[{"name":"Division of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"Laboratory of Cardiovascular Physiology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"Department of Research and Development, Chang Gung Memorial Hospital Linkou Branch, No. 5, Fuxing St., Guishan Dist., Taoyuan 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1186\/s12933-024-02358-0","article-title":"DIABETIC-IC study Investigators. 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