肠道微生物与便秘的双向孟德尔随机化研究

Bidirectional Mendelian randomization study on gut microbiota and constipation

目的采用孟德尔随机化(MR)研究方法分析肠道微生物与便秘的因果关系。方法肠道微生物遗传变异数据来自微生物基因组联盟数据库,便秘遗传变异数据来自综合流行病学小组开放全基因组关联研究数据库;采用逆方差加权法,以肠道微生物相关的2511个单核苷酸多态性(SNP)为工具变量,便秘为研究结局,进行正向MR分析;以便秘相关的13个SNP为工具变量,肠道微生物为研究结局,进行反向MR分析。采用Cochran检验评估异质性,MR Steiger检验反向因果的SNP,MR-PRESSO检验和MR-Egger回归法检验水平多效性,采用留一法检验结果的稳健性。结果正向MR分析结果显示,宿主遗传驱动的粪球菌属1丰度升高,便秘风险降低(OR=0.791,95%CI:0.709~0.884);宿主遗传驱动的拟杆菌门丰度升高,便秘风险增加(OR=1.240,95%CI:1.102~1.394)。Cochran检验显示不存在异质性(均P>0.05),MR Steiger检验未发现反向因果的SNP,MR-PRESSO检验和MR-Egger回归法未发现工具变量的水平多效性(均P>0.05),留一法检验显示结果稳健。反向MR分析未发现反向因果关系(均P>0.05)。结论肠道微生物中的粪球菌属1、拟杆菌门与便秘有关。

Objective To investigate the causal relationship between gut microbiota and constipation using Mendelian randomization(MR)method.Methods Genetic variation data of gut microbiota were obtained from the MiBioGen Con⁃sortium database.The genetic variation data of constipation were sourced from the IEU Open GWAS database.A for⁃ward MR analysis was performed using the inverse-variance weighted(IVW)method with 2511 SNPs associated with gut microbiota as instrumental variables,and constipation as study outcome,and a reverse MR analysis was performed with 13 microbiota-associated SNPs as instrumental variables and gut microbiota as study outcome.The heterogeneity was assessed using the Cochran test,reverse causation of SNP were examined using MR Steiger test,and the horizontal pleiotropy was assessed using the MR-PRESSO test and MR-Egger regression.In addition,the robustness of the results was verified with the leave-one-out.Results Forward MR analysis results showed that an increased abundance of ge⁃nus Coprococcus1 driven by host genetics was associated with a decreased risk of constipation(OR=0.791,95%CI:0.709-0.884),and increased abundance of phylum Bacteroidetes driven by host genetics was associated with an in⁃creased risk of constipation(OR=1.240,95%CI:1.102-1.394).Cochran test detected no heterogeneity(both P>0.05),MR Steiger test was not revealed reverse causation of SNP,and neither the MR-PRESSO test nor the MR-Egger regres⁃sion revealed horizontal pleiotropy of instrumental variables(all P>0.05),and the leave-one-out method confirmed the robustness of results.Reverse MR analysis showed no association between gut microbiota and constipation(both P>0.05).Conclusion Genus Coprococcus1 and phylum Bacteroidetes in the gut microbiota are associated with constipation.