BACKGROUND: Increasing evidence indicates that statins may increase the risk of developing diabetic nephropathy (DN). As the gut-kidney axis concept gains traction, it remains unclear whether statins contribute to the onset and progression of DN by modulating gut microbiota. OBJECTIVE: To investigate the association between statins and DN and the proportion of this association mediated through gut microbiota. METHOD: This study utilized a two-sample Mendelian randomization (MR) approach and a cross-sectional observational design to investigate the causal relationships among statins, 473 gut microbiota, and DN. Furthermore, mediation MR analysis was employed to explore the potential mediating effects of gut microbiota in the statins-DN relationship. RESULTS: HMGCR inhibitors were causally linked to the increased incidence of DN (odds ratio [OR]: 0.732, 95% confidence interval [CI] 0.647, 0.828, P CONCLUSION: Statins may become a risk factor for DN by increasing or decreasing the abundance of specific gut microbiota. These specific gut bacteria have the potential to become a new indicator for guiding the clinical use of statins in diabetic patients.