目的 基于“肠-胞宫轴”采用孟德尔随机化（Mendelian randomization，MR）探讨东亚人群肠道菌群与妇科癌症之间的遗传因果效应，并筛选调控肠道菌群介导妇科癌症发生发展高风险基因的单体化合物、中药及方剂。方法 以逆方差加权法为主要评估方法，通过东亚人群的肠道菌群与妇科癌症的全基因组关联研究汇总数据进行双向两样本MR分析。对工具变量邻近关联基因进行功能富集分析以探析肠道菌群介导妇科癌症发生发展的生物学过程。通过SoFDA数据库进行中药方剂的富集分析。通过GEO数据库和UCSC XENA数据库挖掘和验证肠道菌群介导妇科癌症发生发展的关键风险基因。通过CTD数据库和COREMINE数据库得到对相应风险基因具有潜在调控作用的单体化合物及中药，分子对接验证其结合性能。结果MR分析发现了4个与卵巢癌发生风险升高相关的肠道微生物、7个与宫颈癌发生风险升高相关的肠道微生物、3个与子宫内膜癌发生风险升高相关的肠道微生物。肠道菌群介导妇科癌症发生发展相关基因显著富集在Ras相关蛋白1（Ras-related protein 1，Rap1）、磷脂酰肌醇-3-羟激酶（phosphatidylinositol-3-hydroxykinase，PI3K）/蛋白激酶B（protein kinase B，Akt）信号通路、三酰甘油稳态、RNA代谢及结合调节、抗原加工及呈递、表皮发育等生物学过程及通路。肠道菌群介导妇科癌症发生发展相关基因显著富集在温补脾肾类方和疏肝行气类方。验证得到17个肠道菌群介导妇科癌症发生发展的高风险基因。筛选得到15个单体化合物靶向9个高风险基因的调控作用关系，57味中药靶向12个高风险基因的调控作用关系。分子对接显示单体化合物与高风险靶点基因具有良好结合性能。结论 基于MR发现14种肠道菌群与妇科癌症发生发展高风险存在因果关联，其机制可能与脂质代谢稳态、Ras、PI3K/Akt等通路相关。槲皮素、齐墩果酸、山柰酚可能是调控高风险基因的关键单体化合物，鹿茸、山茱萸、淫羊藿可能是调控高风险基因的关键中药，温补脾肾类方和疏肝行气类方可能是通过调节肠道菌群来防治妇科癌症的重要中药方剂；丰富了“肠-胞宫轴”生物学基础，深化了妇科癌症的病因学认识，并为中医药调控肠道菌群防治妇科癌症提供了新的方向。

Objective To investigate the genetic causality between gut microbiota and gynecological cancers in East Asian populations based on the gut-uterus with appendages axis using Mendelian randomization (MR), and to screen for monomers, Chinese medicines and prescriptions that regulate genes with high risk for the development of gynecological cancers mediated by gut microbiota. Methods Bidirectional two-sample MR analysis was performed using pooled data from a genome-wide association study of gut microbiota and gynecological cancer in an East Asian population, with inverse-variance weighting as the primary method of assessing genetic causal effects. Functional enrichment analysis of instrumental variables adjacent to associated genes was used to explore the biological process of gut microbiota mediating gynecological cancer development. Enrichment analysis of traditional Chinese medicine prescriptions was carried out through SoFDA database. GEO database and UCSC XENA database were used to mine and verify the key risk genes for gut microbiota mediating gynecologic cancer development. Monomers and traditional Chinese medicines with regulatory effects on corresponding risk genes were obtained from CTD database and COREMINE database, and their binding properties were verified by molecular docking. Results MR analysis identified four intestinal microorganisms associated with an elevated risk of ovarian cancer development, seven intestinal microorganisms associated with an elevated risk of cervical cancer development, and three intestinal microorganisms associated with an increased risk of endometrial cancer development. Genes related to gut microbiota mediating gynecological cancer development were significantly enriched in biological processes and pathways such as Rap1, phosphatidylinositol-3-hydroxykinase (PI3K)/protein kinase B (Akt) signaling pathway, triglyceride homeostasis, regulation of RNA metabolism and binding, antigen processing and presentation and epidermal development. The gut microbiota mediated the occurrence and development of gynecological cancer-related genes, which were significantly enriched in warming and tonifying the spleen and kidney formulas and soothing the liver and promoting the flow of qi formulas. A total of 17 high-risk genes of gut microbiota mediating gynecological cancer development were validated. The regulatory relationships of 15 monomer compounds targeting nine high-risk genes and 57 traditional Chinese medicines targeting 12 high-risk genes were screened. Molecular docking showed that monomer compounds had good binding performance with high-risk target genes. Conclusion Based on MR analysis, a causal association was found between 14 gut microbiota and a high risk of gynecological cancer development, the mechanism of which may be related to lipid metabolism homeostasis, Ras, PI3K/Akt and other pathways. Quercetin, oleanolic acid, and kaempferol may be key monomer compounds regulating high-risk genes. Lurong (Cervi Cornu Pantotrichum), Shanzhuyu (Corni Fructus), Yinyanghuo (Epimedii Folium) may be key traditional Chinese medicines regulating high-risk genes. Warming and tonifying the spleen and kidney formulas, along with soothing the liver and promoting the flow of qi formulas, may be important Chinese medicine prescriptions to prevent and treat gynecological cancers by improving intestinal microbiota. This study enriches the biological foundation of the “gut-uterus with appendages axis”, deepens the understanding of the etiology and pathogenesis of gynecological cancers, and provides a new direction for the regulation of gut microbiota by traditional Chinese medicine in the prevention and control of gynecological cancers.

Q811.4;R285

国家自然科学基金面上项目（82374504）；广东省中医药管理局科研项目（20221174）