【摘要】 背景：药物相关性骨坏死是一类应用药物后出现的严重不良反应。大量的证据表明，肠道菌群与药物相关性骨坏死有关。然而，肠道菌群对药物相关性骨坏死的因果关系尚不清楚。目的：采用孟德尔随机化方法来评估肠道菌群与药物相关性骨坏死风险之间的潜在因果关系。方法：使用Mi Bio Gen联盟肠道菌群的全基因组关联分析(GWAS)汇总统计数据(n=13 266)和芬兰R9数据库中药物相关性骨坏死的GWAS数据(264例药物相关性骨坏死患者和377 013例健康对照者)。采用逆方差加权法、MR-Egger回归法、加权中位数法、加权模型法和简单模型法来研究肠道菌群与药物相关性骨坏死之间的因果关系。敏感性分析用于检验孟德尔随机化分析结果是否可靠。反向孟德尔随机化以全部肠道菌群作为结局进行效应分析和敏感性分析。结果与结论：(1)逆方差加权法结果显示，黏胶球形菌门、黏胶球形菌纲、黑色素杆菌纲、嗜胃杆菌目、红螺菌目、食物谷菌目和双歧杆菌属与药物相关性骨坏死呈直接的正向因果关联；甲烷杆菌纲、芽孢杆菌目、甲烷杆菌目、毛螺菌科、甲烷杆菌科、霍尔德曼氏菌属、毛螺菌属(UCG010)、厌氧杆菌和泰泽氏菌属与药物相关性骨坏死呈直接的负向因果关联。(2)反向孟德尔随机化结果显示，药物相关性骨坏死与梭菌科、消化链球菌科、链球菌科、梭状芽胞杆属和链球菌属呈直接的负向因果关联，与艾森伯格菌属呈直接的正向因果关联。(3)双向敏感性分析均未发现存在异质性或水平多效性。(4)结果证实，肠道菌群作为暴露，药物相关性骨坏死作为结局，7种细菌性状对药物相关性骨坏死呈正相关因果关系，9种细菌性状对药物相关性骨坏死呈负相关因果关系；药物相关性骨坏死作为暴露，肠道菌群作为结局，药物相关性骨坏死与5种细菌性状有负相关因果关系，与1种细菌性状有正相关因果关系。改变肠道菌群的多样性和组成，有望改善药物相关性骨坏死的发病与预后，为骨科疾病的研究提供了思路。更多还原

【Abstract】 BACKGROUND: Osteonecrosis due to drugs is a serious adverse reaction occurring after the application of such drugs. Increasing evidence suggests that the gut microbiota composition is associated with osteonecrosis due to drugs. However, the causal relationship of the gut microbiota to osteonecrosis due to drugs is still unclear.OBJECTIVE: To evaluate the potential causal relationship between the gut microbiota and the risk of osteonecrosis due to drugs using the Mendelian randomization method.METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genomewide association study meta-analysis(n=13 266) conducted by the Mi Bio Gen consortium as well as the summary statistics of osteonecrosis due to drugs obtained from the Finn Gen consortium R9 release data(264 cases and 377 013 controls). Inverse variance weighted, MR-Egger, weighted median, weighted model and simple model were used to examine the causal association between gut microbiota and osteonecrosis due to drugs. Sensitivity analysis was used to test whether the results of the Mendelian randomization analysis were reliable. Reverse Mendelian randomization analysis was performed on all the bacteria as an outcome for effect analysis and sensitivity analysis.RESULTS AND CONCLUSION: Inverse variance weighted estimates suggested that Lentisphaerae(phylum), Lentisphaeria(class), Melainabacteria(class), Gastranaerophilales(order), Rhodospirillales(order), Victivallales(order) and Bifidobacterium(genus) had protective causal effects on osteonecrosis due to drugs. Methanobacteria(class), Bacillales(order), Methanobacteriaceae(family), Lachnospiraceae(family), Methanobacteriales(order), Holdemania(genus), Holdemania(UCG010 group)(genus), Odoribacter(genus) and Tyzzerella3(genus) had negative causal effects on osteonecrosis due to drugs. According to the results of reverse Mendelian randomization analysis, Clostridiaceae1(family), Peptostreptococcaceae(family), Streptococcaceae(family), Clostridiumsensustricto1(genus) and Streptococcus(genus) showed negative causal effects on osteonecrosis due to drugs. However, Eisenbergiella(genus) showed protective causal effects on osteonecrosis due to drugs. None of the bidirectional sensitivity analysis revealed heterogeneity or horizontal pleiotropy. When gut microbiota were used as exposure and osteonecrosis due to drugs as the outcome, Mendelian randomization analysis found that seven bacterial traits were positively correlated to osteonecrosis due to drugs, nine bacterial traits were negatively related to osteonecrosis due to drugs. When osteonecrosis due to drugs were used as exposure and gut microbiota as the outcome, reverse Mendelian randomization analysis found a negative correlated relationship with five bacterial traits and a positive causal relationship with one bacterial trait. By changing the diversity and composition of gut microbiota, it is expected to improve the incidence and prognosis of osteonecrosis due to drugs, providing new ideas for the study of orthopedic diseases.更多还原