Gut microbiota and diabetic neuropathy/peripheral artery disease: A two-sample Mendelian randomization study investigating risk factors for diabetic foot ulcers

Diabetic foot ulcers (DFUs) represent a significant complication affecting the lower extremities in individuals with diabetes. The development and progression of DFUs are primarily influenced by diabetic neuropathy (DN) and diabetic peripheral artery disease (DPAD). Recent studies indicate a novel link between the gut microbiota and these risk factors. However, it remains unclear whether a causal relationship exists between them. We obtained data on gut microbiota, derived from publicly available genome-wide association studies. Additionally, we included data on DN, diabetic polyneuropathy (DPN), and DPAD from the FinnGen consortium, considering these conditions as primary risk factors for the onset of DFUs. We employed the inverse variance weighting method for the primary effect analysis and conducted 3 sensitivity tests to ensure the robustness of the results. Our analysis revealed that 7 genera are associated with DN, 8 are associated with DPN, and 12 are associated with DPAD. Notably, the Lachnospiraceae emerged as a common risk factor for both DN [OR = 1.392, 95% CI (1.031, 1.880), P = .031] and DPAD [OR = 1.152, 95% CI (1.019, 1.303), P = .024]. Conversely, the Acidaminococcaceae was identified as a shared protective factor against both DPN [OR = 0.620, 95% CI (0.460, 0.837), P = .002] and DPAD [OR = 0.814, 95% CI (0.691, 0.959), P = .014]. The sensitivity analysis indicated minimal evidence of bias in this study. Our research findings suggest a potential causal relationship between gut microbiota and the key risk factors for developing DFUs. This suggests that early detection and prevention of this serious diabetic complication might be achievable through gut microbiota modulation.