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

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. 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. 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. 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. A healthy and balanced relationship between the gut and the host is crucial for maintaining the health of the host, and dysbiosis of this bidirectional crosstalk is implicated in the pathogenesis of DKD. Bacterial genera and metabolites were significantly altered and restored to normal levels after Triptolide treatment. Triptolide 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.糖尿病肾病（Diabetic kidney disease，DKD）已成为日益严峻的全球性公共卫生问题。雷公藤内酯（Triptolide，TP）对DKD具有良好的治疗效果，在我国临床应用广泛，但其具体作用机制尚未完全阐明。 本研究以db/db小鼠模型为研究对象，给予雷公藤内酯干预12周。采用超高效液相色谱-四级杆-静电场轨道阱质谱（UHPLC-QE-MS）与16S rRNA扩增子测序技术，探究糖尿病肾病状态下代谢组、微生物组与DKD相关指标间的关联。 雷公藤内酯在db/db小鼠中展现出显著的肾脏保护作用：可改善肾功能损伤与肾脏结构破坏，同时减轻DKD相关的炎症反应。值得注意的是，雷公藤内酯给药可有效修复db/db小鼠的肠道菌群失调。组间比较分析共鉴定出10个差异微生物类群，包括双歧杆菌属（Bifidobacterium）、丹毒丝菌科U-CG003（Erysipelotrichaceae_U-CG003）、赫尔曼菌属（Herminiimonas）、多明杆菌属（Domibacillus）、甲基杆菌-甲基红球菌属（Methylobacterium-Methylorubrum）、考拉杆菌属（Phascolarctobacterium）、多尔菌属（Dorea）、罗尔斯通菌属（Ralstonia）、UCG-002以及杜波氏菌属（Dubosiella），提示这些类群可作为DKD进展与治疗响应的潜在鉴别生物标志物。代谢组学分析共鉴定出11个显著扰动的代谢物，通过小分子通路数据库（Small Molecule Pathway Database，SMPDB）富集分析发现3条关键代谢通路：维生素K代谢、丙酸代谢以及类固醇生物合成。机制研究表明，雷公藤内酯可能通过JNK/STAT/P53通路减轻炎症反应、调控肠道菌群结构失衡并纠正肾脏代谢紊乱，从而发挥肾脏保护作用。 雷公藤内酯或可通过调控肠道菌群结构、纠正肾脏代谢紊乱发挥肾脏保护作用，这一过程可能与JNK/STAT/P53通路介导的炎症反应抑制有关。此外，维生素K2可与雷公藤内酯发挥协同抗炎效应。 肠道与宿主间的健康稳态互作对维持宿主健康至关重要，而这种双向串扰的菌群失调与DKD的发病机制密切相关。 经雷公藤内酯干预后，差异的细菌属与代谢物水平可恢复至正常范围。 雷公藤内酯或可通过调控肠道菌群结构、纠正肾脏代谢紊乱发挥肾脏保护作用，这一过程可能与JNK/STAT/P53通路介导的炎症反应抑制有关。