Triptolide improves microbial dysbiosis and metabolite disorder in db/db mice.

BACKGROUND: Diabetic kidney disease (DKD) is an increasing global public health problem. Triptolide (TP) has a good therapeutic effect on DKD and is widely used in China. However, the mechanism of TP is still unclear. METHODS: Db/db mice models were subjected to TP for 12 weeks. UHPLC-QE-MS and 16S rRNA amplicon sequencing were used to investigate the correlations between the metabolome, microbiome, and DKD-related indicators under DKD condition. RESULTS: TP demonstrated significant nephroprotective effects in db/db mice, ameliorated renal functional impairment and structural damage while attenuated inflammatory responses associated with DKD. Notably, TP administration effectively restored gut microbiota dysbiosis in db/db mice. Comparative analysis identified ten altered microbial taxa across groups, including Bifidobacterium, Erysipelotrichaceae_U-CG003, Herminiimonas, Domibacillus, Methylobacterium-Methylorubrum, Phascolarctobacterium, Dorea, Ralstonia, UCG-002, and Dubosiella, suggesting their potential utility as discriminative biomarkers for DKD progression and therapeutic response. Metabolomic profiling revealed 11 significantly perturbed metabolites, with small molecule pathway database (SMPDB) enrichment analysis highlighting three critical metabolic pathways: vitamin K metabolism, propionate metabolism, and steroid biosynthesis. Mechanistic investigations suggest that TP may reduce the inflammatory response through the JNK/STAT/P53 pathway, regulate the changes of intestinal flora, and correct renal metabolic disorders to exert renal protection. CONCLUSION: TP may play a renal protective role by regulating the changes of intestinal microflora and correcting renal metabolic disorders, which may be related to the JNK/STAT/P53 pathway involved in reducing the inflammatory response. In addition, Vitamin K2 has a synergistic anti-inflammatory effect with TP.