特定肠道菌群和骨质疏松症的因果关系

The causal relationship between specific gut microbiota and osteoporosis

目的采用孟德尔随机化分析方法来研究特定肠道菌群与骨质疏松症发病风险的因果关系。方法获取肠道菌群与骨质疏松症的全基因组关联研究数据,将单核苷酸多态性(SNP)作为工具变量并选择敏感的SNPs进行分析。通过逆方差加权法(IVW)、加权中位数法(WM)、MR-Egger回归法进行两样本孟德尔随机化分析,以OR值检验肠道菌群与骨质疏松症之间的因果关系,并完成敏感性和多效性检验。结果筛选到1531个SNPs作为工具变量,狭义梭菌属1、粪球菌属3、粪杆菌属、纺锤链杆菌属、考拉杆菌属、瘤胃球菌科NK4A214群、塞利单胞菌属与骨质疏松症的孟德尔随机化分析结果显示,IVW法的OR值分别为1.291(95%CI 1.037~1.607,P=0.022)、0.627(95%CI 0.440~0.894,P=0.010)、1.520(95%CI 1.125~2.054,P=0.006)、1.271(95%CI 1.037~1.558,P=0.021)、0.801(95%CI 0.674~0.951,P=0.012)、1.220(95%CI 1.010~1.473,P=0.039)、0.854(95%CI 0.744~0.979,P=0.024),表明肠道菌群与骨质疏松症之间存在因果关系。IVW(P>0.05)和MR-Egger回归(P>0.05)的CochranQ检验表明SNPs并不存在异质性。MR-Egger法的egger_intercept和0差异无统计学意义(P>0.05),SNPs不存在水平多效性。结论狭义梭菌属1、粪球菌属3、粪杆菌属、纺锤链杆菌属、考拉杆菌属、瘤胃球菌科NK4A214群、塞利单胞菌属与骨质疏松症之间存在因果关系,为探讨肠道菌群介导的骨质疏松症的发病机制提供了新的认知。

Objective To investigate the causal relationship between the gut microbiota and the risk of osteoporosis by adopting Mendelian randomization(MR)analysis approach.Methods The data was obtained from a genomewide association study(GWAS)on the gut microbiota and osteoporosis.The single nucleotide polymorphism(SNP)was used as instrumental variables and SNPs that were sensitive to the gut microbiota were selected for analysis.Two-sample MR analyses were performed using IVW,WM,and MR-Egger regression methods to estimate the causal relation⁃ship between the gut microbiota and osteoporosis,with odds ratios(OR)as the effect size estimates.Sensitivity and pleiotropy tests were conducted to evaluate the robustness and potential bias of the results.Results A total of 1531 SNPs were included as instru⁃mental variables in this study.The Mendelian randomization analysis revealed a causal relationship between Clostridiumsensustricto1,Coprococcus 3,Faecalibacterium,Fusicatenibacter,Phascolarctobacterium,Ruminococcaceae NK4A214 group,Sellimonas,and osteoporosis.The odds ratios(OR)estimated by the random-ef⁃fects model IVW method were 1.291(95%CI 1.037-1.607,P=0.022),0.627(95%CI 0.440-0.894,P=0.010),1.520(95%CI 1.125-2.054,P=0.006),1.271(95%CI 1.037-1.558,P=0.021),0.801(95%CI 0.674-0.951,P=0.012),1.220(95%CI 1.010-1.473,P=0.039),and 0.854(95%CI 0.744-0.979,P=0.024),respectively.These results indicate a causal relationship between the gut microbi⁃ota and osteoporosis.The Cochran Q test for IVW(P>0.05)and MR-Egger regression(P>0.05)indicated no heterogeneity among the SNPs.The MR-Egger method showed that the egger-intercept was not significantly different from zero(P>0.05),suggesting no horizontal pleiotropy among the SNPs.Conclusion This study suggests a causal relationship between seven bacterial genera(Clostridiumsensustricto1,Coprococcus3,Faecalibacterium,Fusicatenibacter,Phascolarctobacterium,Ruminococcaceae NK4A214 group,Sellimonas)and osteoporosis,providing new insights into the pathogenesis of intestinal microbiota mediated osteoporosis.