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

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 [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,FDR=0.0018], Order (OR=1.5651, 95%CI: 1.1810-2.0742, FDR=0.0018) and Family (OR=1.3956, 95%CI:1.0336-1.8844, FDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The (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.