Background Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, and current pharmacotherapies provide limited renal protection. Qitu Qushi Formula (QTQSF), a traditional Chinese medicine prescription, has shown therapeutic potential in DKD, but its underlying mechanisms remain unclear. This study aimed to elucidate whether QTQSF alleviates DKD via gut microbiota-mediated pathways. Methods Clinical, animal, and cellular studies were integrated to investigate the therapeutic effects of QTQSF. Clinical samples from 30 patients with type 2 DKD received QTQSF treatment for 6 months was used to assess renal function and gut microbiota. To explore microbiota-mediated mechanisms, db/db mice, pseudo-germ-free models, and fecal microbiota transplantation (FMT) were utilized. Multi-omics analyses, including 16S rRNA sequencing, untargeted and targeted metabolomics, and transcriptomics, were conducted to uncover key pathways underlying QTQSF’s efficacy. Results QTQSF significantly improved renal function and remodeled gut microbial composition in DKD patients. In db/db mice, QTQSF reduced albuminuria, fibrosis, and apoptosis, whereas these protective effects were attenuated after gut microbiota depletion. FMT supported that gut microbiota mediated the renoprotective effects of QTQSF. Integrated multi-omics analyses revealed that QTQSF enhanced microbial tryptophan metabolism and increased the gut microbiota-derived metabolite indole-3-propionic acid (IPA). Elevated IPA levels were associated with regulation of the renal Sirt1/FoxO1 pathway, which was further validated in podocytes as a key mechanism underlying the anti-apoptotic effects. Conclusion QTQSF may ameliorate DKD by enhancing gut microbiota-derived IPA production and regulating the Sirt1/FoxO1 signaling pathway, thereby attenuating renal injury. These findings provide mechanistic insight into the renoprotective effects of QTQSF and highlight a gut microbiota–metabolite–host signaling axis in DKD.
W et al. (Tue,) studied this question.
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