Endocrine Abstracts

JOINT520

Objective: Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, with complex pathogenesis and limited effectiveness of current prevention and treatment strategies. Identifying novel therapeutic approaches and their molecular targets is therefore of critical clinical significance. This study aims to investigate the therapeutic effects and underlying mechanisms of fecal microbiota transplantation (FMT) in the prevention and treatment of DKD.

Methods: This study was conducted across population, animal, and cellular levels. Metagenomics, serum metabolomics, and tryptophan-targeted metabolomics were employed to analyze changes in gut microbiota composition and serum metabolic flux in both human subjects and DKD mouse models. An 18-week FMT treatment was administered to db/db mice, during which dynamic changes in glucose and lipid metabolism, renal function, and inflammatory markers were evaluated. Renal tissues were collected for transcriptomic sequencing and pathological analysis. Molecular biological techniques, including western blotting, immunoprecipitation, luciferase reporter assays, and gene overexpression/knockdown, were used to further explore the molecular mechanisms underlying the effects of FMT in ameliorating DKD.

Results: FMT effectively improved glucose and lipid metabolism disorders, reduced urinary microalbumin levels, delayed renal function decline, and alleviated renal inflammatory infiltration in db/db mice. In addition, FMT normalized the altered gut microbiota composition and structure in db/db mice, particularly restoring microbial populations associated with gut tryptophan metabolism. This intervention significantly modulated the abnormal serum tryptophan metabolic flux observed in db/db mice. Elevated serum levels of indole-3-acetic acid (IAA) in the DKD state were closely associated with metabolic disorders and renal dysfunction. Mechanistically, IAA promoted NEMO SUMOylation, leading to activation of the NF-κB signaling pathway, which further exacerbated renal inflammatory damage. FMT reduced IAA production, suppressed the activation of the miR-145a-5p/SENP2 signaling axis, inhibited NEMO SUMOylation, and mitigated the excessive activation of the NF-κB inflammatory signaling pathway.

Conclusion: In DKD, increased NEMO SUMOylation activates the NF-κB signaling pathway, resulting in renal inflammatory injury. The gut-derived tryptophan metabolite IAA upregulates renal miR-145a-5p expression, which further enhances NEMO SUMOylation via the miR-145a-5p/SENP2 axis, aggravating inflammatory damage. FMT alleviates DKD and its associated inflammatory injuries by regulating gut tryptophan metabolism, reducing IAA production, and inhibiting the miR-145a-5p/SENP2/NEMO-SUMOylation axis.