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We analyzed 85 patients treated with canagliflozin and 85 controls over 26 weeks to explore whether the gut microbiome and its metabolites contribute to renoprotection. Canagliflozin remodeled the gut microbiota, notably enriching\n                    <jats:italic>Roseburia intestinalis<\/jats:italic>\n                    and increasing plasma melibiose levels. In mice, canagliflozin alleviated glomerular endothelial injury and albuminuria. Similar effects were replicated by fecal microbiota transplantation,\n                    <jats:italic>Roseburia intestinalis<\/jats:italic>\n                    , or melibiose administration. Mechanistically, melibiose bound to and activated glyoxalase 1, reduced methylglyoxal, and suppressed the AGE\u2010RAGE pathway, preserving glomerular endothelial integrity. Furthermore, oral melibiose precursor supplementation reduced albuminuria in patients with early\u2010stage DKD. These findings suggest the involvement of a gut\u2010kidney axis in the renoprotective effects of canagliflozin and indicate that melibiose may serve as a potential therapeutic strategy for DKD.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517222","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T08:11:03Z","timestamp":1779869463000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Canagliflozin Alleviates Diabetic Glomerular Endothelial Injury via Melibiose in a Microbiota\u2010Dependent Manner"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5972-6744","authenticated-orcid":false,"given":"Wei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"},{"name":"Tianjian Laboratory of Advanced Biomedical Sciences  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