Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study

Shuxiang Yan; Hua Wang; Baiyu Feng; Lin Ye; Anqun Chen

doi:10.3389/fimmu.2024.1332757

Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study

Front Immunol. 2024 Mar 8:15:1332757. doi: 10.3389/fimmu.2024.1332757. eCollection 2024.

Authors

Shuxiang Yan¹, Hua Wang^{2

3}, Baiyu Feng¹, Lin Ye¹, Anqun Chen¹

Affiliations

¹ Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China.
² Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
³ Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.

Abstract

Objective: Emerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM).

Methods: We used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results.

Results: It was showed that Class Verrucomicrobiae [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,PFDR=0.0018], Order Verrucomicrobiales (OR=1.5651, 95%CI: 1.1810-2.0742, PFDR=0.0018) and Family Verrucomicrobiaceae (OR=1.3956, 95%CI:1.0336-1.8844, PFDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class Verrucomimicrobiae (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order Verrucomimicrobiae (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), Rhodospirillales (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family Verrucomicroniaceae (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The Eubacteriumprotogenes (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy.

Conclusions: At the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.

Keywords: Mendelian randomization; diabetic nephropathy; gut microbiota; gut-kidney axis; type 1 diabetic mellitus; type 2 diabetic mellitus.

Publication types

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

MeSH terms

Diabetes Mellitus, Type 1*
Diabetes Mellitus, Type 2*
Diabetic Nephropathies*
Gastrointestinal Microbiome*
Humans
Mendelian Randomization Analysis
Reproducibility of Results

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study received financial support from the National Natural Science Foundation for Excellent Young Scholars (Grant No. 82222013) and the Natural Science Foundation for Distinguished Young Scholars of Hunan Province (Grant No. 2021JJ10075).