Canagliflozin Alleviates Diabetic Glomerular Endothelial Injury via Melibiose in a Microbiota‐Dependent Manner
Canagliflozin reduces albuminuria in patients with diabetic kidney disease (DKD) beyond its glucose-lowering effect, but the mechanisms remain unclear. 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 Roseburia intestinalis and increasing plasma melibiose levels. In mice, canagliflozin alleviated glomerular endothelial injury and albuminuria. Similar effects were replicated by fecal microbiota transplantation, Roseburia intestinalis, or melibiose administration. Mechanistically, melibiose bound to and activated glyoxalase 1, reduced methylglyoxal, and suppressed the AGE-RAGE pathway, preserving glomerular endothelial integrity. Furthermore, oral melibiose precursor supplementation reduced albuminuria in patients with early-stage DKD. These findings suggest the involvement of a gut-kidney axis in the renoprotective effects of canagliflozin and indicate that melibiose may serve as a potential therapeutic strategy for DKD.
Authors
- HUANG Ting
- C. Li
- Qiubo Zhao
- Xunjie Fan (ORCID: https://orcid.org/0000-0003-3973-4127)
- X X
- Zhi Qin (ORCID: https://orcid.org/0000-0002-4416-9356)
- Fangyi Wei (ORCID: https://orcid.org/0000-0003-0564-0843)
- Shengnan Ma
- Wenwen Guo
- Wei Zhang (ORCID: https://orcid.org/0000-0001-7800-3189)
- Dongming Zhang (ORCID: https://orcid.org/0000-0001-7175-1811)
- Yuanyuan Luo (ORCID: https://orcid.org/0000-0002-6269-2124)
- Yanhong Zhou (ORCID: https://orcid.org/0000-0003-3587-3031)
- Yingjun Yang (ORCID: https://orcid.org/0000-0002-9078-4245)
- Zhiqiang Kang (ORCID: https://orcid.org/0009-0009-8410-1688)
- Guolan Xing
- Fengmei Xu
- Yanhong Sang
- Lin Zhao
- Yanxia Liu
- Jiao Wang
- Mingwei Shao
- Chunhua Song
- Lianwei Wang
- Qingzhu Wang
- Jun Li
- Yi Song
- Shumin Song
- Guijun Qin (ORCID: https://orcid.org/0000-0002-2503-7534)
- Yanyan Zhao
- Dan Zhao
- Feng Guo
Institutions
- Ruijin Hospital (CN)
- Zhengzhou University (CN)
- Hefei Design and Research Institute of Coal Industry (China) (CN)
- Zhumadian Central Hospital (CN)
- Zhengzhou University of Science and Technology (CN)
- Second Affiliated Hospital of Zhengzhou University (CN)
- Fifth Affiliated Hospital of Zhengzhou University (CN)
- Zhengzhou Central Hospital (CN)
- Zhengzhou People's Hospital (CN)
- Xinxiang Central Hospital (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Henan Provincial Center for Disease Control and Prevention (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1002/advs.202517222
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Henan Province