Gut microbiota dysbiosis contributes to diabetic nephropathy via affecting renal lipid deposition and inflammatory responses

BACKGROUND: Diabetic nephropathy (DN) patients exhibit distinct patterns of gut microbiota dysbiosis. Nevertheless, the causal relationship between gut microbiota dysbiosis and DN pathogenesis remains to be established. METHODS: Fecal microbiota transplantation (FMT) was performed using donor samples from both DN patients and diabetic controls, with healthy donor microbiota serving as the control intervention in STZ/high-fat diet-induced DN model. Renal function was assessed by measuring biochemical indicators such as urinary protein and serum creatinine. Renal pathological changes were observed using PAS staining and Masson staining, and the composition of the intestinal microbiota was analyzed by 16 S rRNA sequencing. Furthermore, the effects of FMT-HC on renal gene expression and lipid metabolism were investigated through transcriptome sequencing, Western blotting, and Oil Red O staining. RESULTS: Compared with the control group, the renal function of mice with DN microbiota transplantation was significantly deteriorated, as evidenced by increased proteinuria and aggravated renal tubular interstitial fibrosis, accompanied by impaired intestinal barrier function and reduced abundance of Lactobacillus. After FMT-HC intervention, renal injury in DN mice was significantly alleviated, lipid deposition was reduced, inflammatory responses were downregulated, and beneficial bacteria such as L. johnsonii were significantly enriched in the intestine. In addition, RNA seq revealed that FMT-HC exert a protective effect on diabetic nephropathy by regulating the PPAR signaling pathway, thereby improving renal lipid metabolism disorders. CONCLUSION: This study demonstrates that gut microbiota dysbiosis contributes to diabetic nephropathy. The regulation of renal lipid deposition and inflammatory responses might involve the process of DN.