基于孟德尔随机化探讨肠道菌群与胆囊炎的因果关系

Exploring the Causal Relationship between Intestinal Flora and Cholecystitis Based on Mendelian Randomisation

摘要: 目的：采用孟德尔随机化方法来探索肠道菌群与胆囊炎之间是否存在因果关系。方法：从MiBioGen联盟中选择合适的单核苷酸多态性(single nucleotide polymorphisms, SNPs)作为工具变量与IEU数据库中胆囊炎的GWAS数据进行孟德尔随机化分析。采用MR-Egger回归法、加权中位数法、逆方差加权法(inverse variance weighted, IVW)、加权模型法和简单模型法，来研究肠道菌群与胆囊炎之间的因果关系。敏感性分析用于检验分析结果的可靠性。结果：(1) IVW结果显示，黏胶球形菌门(Beta = 0.066, 95% CI: 1.003~1.139, P = 0.041)，梭状芽孢杆菌属1 (Beta = 0.142, 95% CI: 1.024~1.297, P = 0.018)，与胆囊炎发病呈正相关；甲烷杆菌纲、目、科(Beta = −0.068, 95% CI: 0.874~0.999, P = 0.047)，瘤胃球菌科(Beta = −0.152, 95% CI: 0.741~0.997, P = 0.045)，毛螺菌属UCG010组(Beta = −0.152, 95% CI: 0.759~0.973, P = 0.016)，瘤胃球菌属NK4A214组(Beta = −0.132, 95% CI: 0.780~0.985, P = 0.027)，与胆囊炎发病呈负相关。(2) 敏感性分析均未发现存在异质性或水平多效性。(3) 胆囊炎与肠道菌群无反向孟德尔随机化因果关系。结论：黏胶球形菌门和梭状芽孢杆菌属1丰度的增加可能增加胆囊炎患病风险，而甲烷杆菌纲、目、科，瘤胃球菌科、毛螺菌属UCG010组以及瘤胃球菌属NK4A214组丰度的增加可能对胆囊炎具有抑制作用。这些发现为肠道菌群在胆囊炎发病机制中的潜在作用提供了新的因果证据，并为未来的干预研究提供了理论依据。

Abstract: Objective: Mendelian randomization was used to explore whether there is a causal relationship between intestinal flora and cholecystitis. Methods: Appropriate single nucleotide polymorphisms (SNPs) were selected from the MiBioGen consortium as instrumental variables for Mendelian randomization analysis with GWAS data of cholecystitis in the IEU database. MR-Egger regression, weighted median, inverse variance weighted (IVW), weighted modeling, and simple modeling were used to investigate the causal relationship between gut flora and cholecystitis. Sensitivity analysis was used to test the reliability of the analyzed results. Results: (1) The IVW results showed that the phylum Lentisphaerae (Beta = 0.066, 95% CI: 1.003~1.139, P = 0.041) and the genus Clostridiumsensustricto 1 (Beta = 0.142, 95% CI: 1.024~1.297, P = 0.018), were positively correlated with the onset of cholecystitis; and that the phylum Methanobacteria, order and family (Beta = −0.068, 95% CI: 0.874~0.999, P = 0.047), the family Rumococcaceae (Beta = −0.152, 95% CI: 0.741~0.997, P = 0.045), the genus Lachnospiraceae UCG010 (Beta = −0.152, 95% CI: 0.759~0.973, P = 0.016), the genus Ruminococcaceae NK4A214 group (Beta = −0.132, 95% CI: 0.780~0.985, P = 0.027), were negatively associated with the development of cholecystitis. (2) None of the sensitivity analyses showed the presence of heterogeneity or horizontal pleiotropy. (3) No reverse Mendelian randomised causality between cholecystitisand gut flora. Conclusion: Increased abundance of the phylum Lentisphaerae and the genus Clostridiumsensustricto 1 may increase the risk of developing biliary flatulence, whereas increased abundance of the phylum Methanobacteria, order and family, the family Rumococcaceae, the family Ruminococcaceae, the genus Lachnospiraceae UCG010, and the genus Ruminococcaceae NK4A214 group, may have a protective effect against biliary flatulence. These findings provide new causal evidence for the potential role of gut flora in the pathogenesis of biliary flatulence and provide a theoretical basis for future intervention studies.