Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Jiajia Wu; Yan Chen; Huinan Yang; Leyi Gu; Zhaohui Ni; Shan Mou; Jianxiao Shen; Xiajing Che

doi:10.3389/fendo.2023.1026040

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Front Endocrinol (Lausanne). 2023 Jan 26:14:1026040. doi: 10.3389/fendo.2023.1026040. eCollection 2023.

Authors

Jiajia Wu¹, Yan Chen², Huinan Yang³, Leyi Gu¹, Zhaohui Ni¹, Shan Mou¹, Jianxiao Shen¹, Xiajing Che¹

Affiliations

¹ Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ School of Energy and Power Engineering, University of Shanghai for Science and Technology, Shanghai, China.

Abstract

Background: The intestinal microbiota disorder gradually aggravates during the progression of diabetes. Dapagliflozin (DAPA) can improve diabetes and diabetic kidney disease(DKD). However, whether the gut microbiota plays a role in the protection of DAPA for DKD remains unclear.

Methods: To investigate the effects of DAPA on DKD and gut microbiota composition during disease progression, in our study, we performed 16S rRNA gene sequencing on fecal samples from db/m mice (control group), db/db mice (DKD model group), and those treated with DAPA (treat group) at three timepoints of 14weeks\18weeks\22weeks.

Results: We found that DAPA remarkably prevented weight loss and lowered fasting blood glucose in db/db mice during disease progression, eventually delaying the progression of DKD. Intriguingly, the study strongly suggested that there is gradually aggravated dysbacteriosis and increased bile acid during the development of DKD. More importantly, comparisons of relative abundance at the phylum level and partial least squares-discriminant analysis (PLS-DA) plots roughly reflected that the effect of DAPA on modulating the flora of db/db mice increased with time. Specifically, the relative abundance of the dominant Firmicutes and Bacteroidetes was not meaningfully changed among groups at 14 weeks as previous studies described. Interestingly, they were gradually altered in the treat group compared to the model group with a more protracted intervention of 18 weeks and 22 weeks. Furthermore, the decrease of Lactobacillus and the increase of norank_f:Muribaculaceae could account for the differences at the phylum level observed between the treat group and the model group at 18 weeks and 22 weeks.

Conclusion: We firstly found that the protective effect of DAPA on DKD may be related to the dynamic improvement of the gut microbiota over time, possibly associated with the impact of DAPA on the bile acid pool and its antioxidation effect.

Keywords: Lactobacillus; Muribaculaceae; bile acid; dapagliflozin; diabetes kidney disease (DKD); therapeutic targets.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus*
Diabetic Nephropathies* / drug therapy
Diabetic Nephropathies* / genetics
Disease Progression
Gastrointestinal Microbiome*
Glucose
Mice
RNA, Ribosomal, 16S / genetics
Sodium
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology

Substances

dapagliflozin
Glucose
RNA, Ribosomal, 16S
Sodium
Sodium-Glucose Transporter 2 Inhibitors

Grants and funding

This work was supported in part by grants from KYJ202206-0003-8; the National Natural Science Foundation of China (No. 81700586, 82070693, 81770668, 81970574); Clinical Research Plan of SHDC (No. SHDC2020CR3029B); Shanghai Municipal Planning Commission of science and Research (No.ZXYXZ-201904, No.20194Y0332, No.ZHYY-ZXYJHZX-202014); Science and Technology Commission of Shanghai Municipality (No.20ZR1432600, 13401906100); Shanghai JiaoTong University (No. YG2022ZD004).We would like to appreciate the assistance of the Innovative Research Team of High-Level Local Universities in Shanghai.