肠道菌群和血浆脂质组与胃癌之间的关联：一项中介孟德尔随机化研究

Associations of Gut Microbiota and Plasma Lipidome with Gastric Cancer: A Mediation Mendelian Randomization Study

摘要: 目的：采用孟德尔随机化方法(MR)研究肠道菌群与胃癌之间的因果关系，并探讨血浆脂质组在其中潜在的中介作用。方法：本研究通过访问GWAS Catalog及IEU OpenGWAS项目数据库收集肠道菌群、血浆脂质组以及胃癌的样本数据。通过双样本双向MR，筛选出与胃癌存在正向因果关系的肠道菌群。通过两步孟德尔随机化(Two-Step MR)筛选出在肠道菌群与胃癌之间起到中介作用的脂质并计算其中介效应及中介比例。结果：本研究通过双样本双向MR分析发现共有4种肠道菌群和8条菌群代谢通路与胃癌存在正向因果关系。在血浆脂质组与胃癌的MR分析结果中，有4种脂质与胃癌显著相关。Two-Step MR分析结果显示，粪拟杆菌与胃癌之间存在显著的因果关系，磷脂酰胆碱(18:0_22:6)在其中起到中介作用[中介比例 = 7.51%，95%CI (−1.84%, 16.87%)]。同时，L-苯丙氨酸生物合成通路的丰度与胃癌之间也存在显著的因果关系，磷脂酰胆碱(O-16:0_18:1)在其中起到中介作用[中介比例 = −13.57%，95%CI (−30.65%, 3.50%)]。结论：本研究结果揭示了肠道菌群与胃癌之间的因果关系，证实了两种肠道菌群及代谢通路对胃癌的影响受到两种脂质的介导，为胃癌的防治策略提供了新的思路和方法。

Abstract: Objective: To investigate the causal relationship between gut microbiota and gastric cancer using Mendelian randomization (MR) and explore the potential mediating role of plasma lipidome in this association. Methods: Data on gut microbiota, plasma lipidome, and gastric cancer were collected from the GWAS Catalog and IEU OpenGWAS Project databases. Two-sample bidirectional MR was applied to identify gut microbiota with positive causal effects on gastric cancer. Two-Step MR was used to screen lipids mediating the relationship between gut microbiota and gastric cancer, and to calculate mediation effects and proportions. Results: Two-sample bidirectional MR analysis identified 4 gut microbiota species and 8 microbial metabolic pathways with positive causal relationships to gastric cancer. Four plasma lipids were significantly associated with gastric cancer in MR analysis. Two-Step MR results showed that Bacteroides faecis had a significant causal effect on gastric cancer, mediated by phosphatidylcholine (18:0_22:6) [mediation proportion: 7.51%, 95%CI (−1.84%, 16.87%)]. Additionally, the L-phenylalanine biosynthesis pathway was significantly associated with gastric cancer, with phosphatidylcholine (O-16:0_18:1) acting as a mediator [mediation proportion: −13.57%, 95%CI (−30.65%, 3.50%)]. Conclusion: This study reveals causal relationships between gut microbiota and gastric cancer, and confirms that the effects of two gut microbiota species and metabolic pathways on gastric cancer are mediated by two lipids, providing new insights and methods for gastric cancer prevention and treatment.