目的 基于代谢组学和肠道菌群多维度整合研究雷公藤红素（celastrol，CEL）抗高尿酸血症肾病（hyperuricemic nephropathy，HN）的作用机制。方法 腺嘌呤联合乙胺丁醇构建HN小鼠模型，设对照组、模型组、非布司他（febuxostat group，FG）组和CEL高、中、低剂量（2.0、1.0、0.5 mg/kg）组，ig给药14 d后，检测小鼠血清尿酸（uric acid，UA）、尿素氮（urea nitrogen，UREA）及肌酐（creatinine，CREA）水平；采用苏木素-伊红（HE）染色法观察肾组织病理变化；收集小鼠粪便，采用16S rDNA高通量测序法检测肠道菌群变化，采用超高液相色谱-四级杆-飞行时间质谱技术检测粪便内源性代谢物水平，结合主成分分析和正交偏最小二乘法-判别分析对差异代谢物进行筛选和鉴定，进而利用MetaAnalyst数据库进行代谢通路分析，并进行肠道菌群和差异代谢物相关性分析。结果 各剂量CEL均可降低HN小鼠的血清UA水平，其中，高剂量CEL可显著降低HN小鼠的血清UREA、CREA水平（P＜0.01、0.001），具有较好的肾保护作用，可改善肾组织病理损伤；共鉴定出45个差异代谢物，涉及6条关键代谢通路，提示CEL可能通过调节谷氨酰胺、亚油酸代谢、谷氨酸代谢、嘧啶代谢、组氨酸代谢、磷酸戊糖途径和精氨酸生物合成发挥作用；CEL各剂量组菌群结构有向对照组恢复的趋势，其中乳酸菌属、螺杆菌属、另枝菌属、葡萄球菌属、拟普雷沃氏菌属及拟杆菌属发生显著变化。结论 CEL可能通过影响氨基酸、能量及脂质等代谢通路并调控肠道菌群结构，而发挥治疗HN作用。

Objective To investigate the effect of celastrol (CEL) on hyperuricemic nephropathy (HN) based on multi-dimensional strategy of metabolomics and integration of intestinal flora. Methods Adenine combined with ethylamine butanol intragastric administered mice were used as research objects. Control group, model group, febuxostat group, CEL high-, medium- and low-dose (2.0, 1.0, 0.5 mg/kg) groups were established. After 14 d of corresponding drug treatment, serum uric acid (UA), urea nitrogen (UREA) and creatinine (CREA) levels in each group were detected. Hematoxylin-eosin staining was used to observe pathological changes in kidney tissue. Changes in the intestinal flora of mice were detected by high throughput 16S rDNA sequencing technology. Ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry technology was used to detect level of fecal endogenous metabolites in mice, and principal component analysis and orthogonal partial least squares-discriminant analysis were used to screen and identify differential metabolites. MetaAnalyst platform was used for metabolic pathway analysis, while correlation analysis of intestinal microflora and differentiated metabolites was constructed. Results All doses of CEL can effectively reduce serum UA levels in HN mice. Notably, high-dose of CEL can significantly reduce serum UREA and CREA levels (P < 0.01, 0.001), demonstrating significant renal protection and improvement in renal tissue pathological damage. A total of 45 potential biomarkers were identified, and a total of six pathways are closely related to HN. CEL was closely associated with alterations in glutamine, linoleic acid metabolism, glutamate metabolism, pyrimidine metabolism, histidine metabolism, pentose phosphate pathway, and arginine biosynthesis. The microflora of each CEL dose group had a tendency to recover from that of the control group, in which Lactobacillus, Helicobacter, Alistipes, Staphylococcus, Alloprevotella and Bacteroides had significant changes. Conclusion CEL can modify metabolic pathways such as amino acids, energy, and lipids, and it can also regulate the structure of intestinal flora, thereby playing a role in the treatment of HN.

R285.5

国家自然科学基金项目(81801086);四川省自然科学基金项目(2022NSFSC1574);西南民族大学中央高校基本科研业务费专项资金优秀培养工程项目(2023NYXXS078)