基于孟德尔随机化法和生物信息学的肠道菌群与巨细胞动脉炎的因果关系及其治疗策略研究  

Study on the causal relationship between gut microbiota and giant cell arteritis and its treatment strategies based on mendelian randomization and bioinformatics

作　　者：雷周璇 熊哲铭 葛晶鑫 叶灵 张卉 舒显奎 杨艳芳 吴和珍 刘博 Lei Zhouxuan;Xiong Zheming;Ge Jingxin;Ye Ling;Zhang Hui;Shu Xiankui;Yang Yanfang;Wu Hezhen;Liu Bo(Faculty of Pharmacy,Hubei University of Chinese Medicine,Wuhan 430065,China)

机构地区：[1]湖北中医药大学药学院,武汉430065

出　　处：《中华风湿病学杂志》2025年第1期38-47,I0005,共11页Chinese Journal of Rheumatology

基　　金：武汉市知识创新计划(2022020801010419)。

摘　　要：目的探讨肠道菌群与巨细胞动脉炎(GCA)的关系,并寻找潜在的治疗策略。方法肠道微生物群数据使用MiBioGen联盟的全基因组关联研究(GWAS)获得,GCA数据使用FinnGen联盟公开GWAS获得。利用两样本孟德尔随机化(MR)分析评估肠道微生物群和GCA的因果关系,使用逆方差加权(IVW),加权中位数法、MR-Egger回归、简单模式和加权模式估算效应,利用异质性检验以及水平多效性检验评估结果,利用多重假设性检验排除假阳性结果。所有分析均通过R语言中的TwoSampleMR和MRPRESSO软件包4.3.0完成。分析肠道菌群数据,再进行网络药理学分析及分子对接验证。结果IVW模拟结果显示13种与GCA相关的肠道微生物群,其中Lachnospiraceae显著降低了GCA的风险[nSNP=16,OR值(95%CI)=0.32(0.16,0.63),β=-1.15,灵敏度(Se)=0.35,P=0.001,错误发现率<0.05],且无异质性(Cochran′s Q=13.42,P=0.490)以及无水平多效性(Se=0.07,P=0.370),进一步利用文献检索以及计算机模拟对接,染料木黄酮与MMP2结合能为-43.1 kJ/mol。结论肠道菌群中的Lachnospiraceae与GCA呈负相关,且染料木黄酮可能通过MMP2靶点调节Lachnospiraceae丰度起到治疗GCA的作用,为临床治疗巨细胞动脉炎提供了新的思路。ObjectiveTo explore the relationship between gut microbiota and giant cell arteritis(GCA),and to identifyits potential therapeutic strategies.MethodsGut microbiota data were obtained from the MiBioGen consortium genome-wide association study(GWAS),and GCA data were obtained from the FinnGen consortium public GWAS.Causal associations between gut microbiota and GCA were assessed using two-sample Mendelian randomization(MR)analyses,including inverse-variance weighted(IVW),weighted median,MR-Egger regression,simple mode,and weighted mode methods.Heterogeneity and horizontal pleiotropy were evaluated,and false positive results were excluded by using the Benjamini-Hochberg(BH)method of multiple hypothesis testing.All analyses were completed using the TwoSampleMR and MRPRESSO software packages(version 4.3.0)in R language.The analysis of the intestinal flora data,followed by conducting network pharmacology analysis were carried out by Cytoscape 3.9.1 and perform molecular docking verification was performed with AutoDock Vina software.ResultsIVW simulations revealed 13 gut microbiota taxa were associated with GCA,of which Lachnospiraceae was significantly negatively associated with GCA risk[nSNP=16,OR(95%CI)=0.32(0.16,0.63),β=-1.15,Se=0.35,P=0.001,FDR<0.05],and there was no heterogeneity(Cochran′s Q test,Q=13.42,P=0.490)as well as horizontal pleiotropy(P=0.370).Further literature search and computer simulation docking analysis showed that genistein binds to MMP2 with a binding energy of-43.1 kJ/mol.Conclusion Lachnospiraceae in the gut microbiota was is negatively associated with GCA,and genistein may be able to regulate the abundance of Lachnospiraceae through the MMP2 target to treat GCA,providing a new therapeutic approach for giant cell arteritis.

关 键 词：巨细胞动脉炎 胃肠道微生物组 肠道微生物群 自身免疫性疾病 染料木黄酮 

分 类 号：R593.2[医药卫生—内科学]