基于肠道菌群结合代谢组学探讨新型IDO1抑制剂与淫羊藿苷元组合物对糖尿病肾病的作用机制  

Mechanism of action of a novel IDO1 inhibitor and icartin combinationon diabetic nephropathy based on intestinal flora combined with metabolomics

作　　者：李梦 崔德宇 刘译璠 徐燕 沈萌萌 卢小艳 姚景春 LI Meng;CUI De-yu;LIU Yi-fan;XU Yan;SHEN Meng-meng;LU Xiao-yan;YAO Jing-chun(Ocean University of China School of Medicine and Pharmacy,Qingdao Shandong 266100,China;Key Laboratory of Immunopharmacology and Toxicology of Natural Medicines in Linyi City,Linyi Shandong 273400,China;State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine,Lunan Pharmaceutical Group Co.LTD,Linyi Shandong 276005,China)

机构地区：[1]中国海洋大学医药学院,山东青岛266100 [2]临沂市天然药物免疫药理毒理重点实验室,山东临沂273400 [3]鲁南制药集团股份有限公司经方与现代中药融合创新全国重点实验室,山东临沂276005

出　　处：《中国药理学通报》2025年第3期528-537,共10页Chinese Pharmacological Bulletin

基　　金：山东省自然科学基金创新发展联合基金项目(No ZR2022LZY021)。

摘　　要：目的研究IDO-1抑制剂(3-047)与淫羊藿苷元(Y003)质量比为1∶1.6的组合物对db/db小鼠糖尿病肾病的保护作用及其作用机制。方法db/db小鼠给药治疗24周后,在考察其肾脏保护作用的同时,进一步使用16S rDNA基因测序联合非靶向代谢组学,从“微生物-肠-肾”轴的角度探究3-047与Y003组合物改善糖尿病肾病的机制。结果与对照组相比,模型组小鼠FBG、Scr、BUN、TC、TG、LDL-C水平明显升高,HDL-C水平降低(P<0.05),尿白蛋白排泄率明显增加,肾小球基底膜增厚与系膜扩张,氧化应激损伤加重,肠道菌群丰度降低、结构与功能紊乱,而3-047与Y003组合物可不同程度的改善上述状况,明显增加 Alloprevotella、Alistipes和Dubosiella 等的相对丰度,降低 Ligilactobacillus、Dubosiella和Lactococcus 等的相对丰度。代谢组学共筛选出11种具有显著性差异的生物标志物,并富集到丙氨酸、酪氨酸与色氨酸生物合成,不饱和脂肪酸生物合成等途径。 结论 3-047与Y003的组合物可通过调节肠道菌群和相关氨基酸代谢改善糖脂代谢紊乱、减轻肾组织结构和功能损伤、缓解氧化应激,进而实现对糖尿病肾病小鼠的保护作用,证明肠道菌群和相关代谢产物是治疗糖尿病肾病的潜在靶点。Aim To study the protective effect of a combination of IDO-1 inhibitor(3-047)with Icartin(Y003)at a mass ratio of 1∶1.6 on diabetic nephropathy in db/db mice and its mechanism of action.Methods After 24 weeks of treatment in db/db mice,on the basis of pharmacodynamic evaluation,16S rDNA gene sequencing combined with untargeted metabolomics was used to further investigate the mechanism of improvement of diabetic nephropathy from the perspective of the"microbial-intestinal-nephrotic"axis by the combination of 3-047 and Y003.Results Compared with the control group,mice in the model group showed significantly higher levels of FBG,Scr,BUN,TC,TG,LDL-C,lower levels of HDL-C(P<0.05),significantly increased urinary albumin excretion rate,thickening of the glomerular basement membrane and dilatation of the tunica albuginea,aggravation of oxidative stress damage,lower abundance,structural and functional disorders of the intestinal flora.The combination of 3-047 and Y003 could improve the above conditions to different degrees,significantly increase the relative abundance of Alloprevotella,Alistipes and Dubosiella,and decrease the relative abundance of Ligilactobacillus,Dubosiella and Lactococcus.A total of 11 biomarkers with significant differences were screened by metabolomics and enriched to the pathways of alanine,tyrosine and tryptophan biosynthesis,and unsaturated fatty acid biosynthesis.Conclusions The combination of 3-047 and Y003 could improve the disorders of glucose-lipid metabolism,reduce the structural and functional damage of renal tissues,and alleviate oxidative stress by regulating the intestinal flora and related amino acid metabolism,and thus achieve a protective effect on mice with diabetic nephropathy,demonstrating that the intestinal flora and the related metabolites are potential targets for the treatment of diabetic nephropathy.

关 键 词：糖尿病肾病 肠道菌群 代谢组学 IDO-1抑制剂 淫羊藿苷元 氧化应激 

分 类 号：R-332[医药卫生] R322.45R322.61R349.1R587.2R692.39