目的 基于“腸-胞宮軸”采用孟德爾隨機(jī)化（Mendelian randomization，MR）探討東亞人群腸道菌群與婦科癌癥之間的遺傳因果效應(yīng)，并篩選調(diào)控腸道菌群介導(dǎo)婦科癌癥發(fā)生發(fā)展高風(fēng)險基因的單體化合物、中藥及方劑。方法 以逆方差加權(quán)法為主要評估方法，通過東亞人群的腸道菌群與婦科癌癥的全基因組關(guān)聯(lián)研究匯總數(shù)據(jù)進(jìn)行雙向兩樣本MR分析。對工具變量鄰近關(guān)聯(lián)基因進(jìn)行功能富集分析以探析腸道菌群介導(dǎo)婦科癌癥發(fā)生發(fā)展的生物學(xué)過程。通過SoFDA數(shù)據(jù)庫進(jìn)行中藥方劑的富集分析。通過GEO數(shù)據(jù)庫和UCSC XENA數(shù)據(jù)庫挖掘和驗證腸道菌群介導(dǎo)婦科癌癥發(fā)生發(fā)展的關(guān)鍵風(fēng)險基因。通過CTD數(shù)據(jù)庫和COREMINE數(shù)據(jù)庫得到對相應(yīng)風(fēng)險基因具有潛在調(diào)控作用的單體化合物及中藥，分子對接驗證其結(jié)合性能。結(jié)果MR分析發(fā)現(xiàn)了4個與卵巢癌發(fā)生風(fēng)險升高相關(guān)的腸道微生物、7個與宮頸癌發(fā)生風(fēng)險升高相關(guān)的腸道微生物、3個與子宮內(nèi)膜癌發(fā)生風(fēng)險升高相關(guān)的腸道微生物。腸道菌群介導(dǎo)婦科癌癥發(fā)生發(fā)展相關(guān)基因顯著富集在Ras相關(guān)蛋白1（Ras-related protein 1，Rap1）、磷脂酰肌醇-3-羥激酶（phosphatidylinositol-3-hydroxykinase，PI3K）/蛋白激酶B（protein kinase B，Akt）信號通路、三酰甘油穩(wěn)態(tài)、RNA代謝及結(jié)合調(diào)節(jié)、抗原加工及呈遞、表皮發(fā)育等生物學(xué)過程及通路。腸道菌群介導(dǎo)婦科癌癥發(fā)生發(fā)展相關(guān)基因顯著富集在溫補(bǔ)脾腎類方和疏肝行氣類方。驗證得到17個腸道菌群介導(dǎo)婦科癌癥發(fā)生發(fā)展的高風(fēng)險基因。篩選得到15個單體化合物靶向9個高風(fēng)險基因的調(diào)控作用關(guān)系，57味中藥靶向12個高風(fēng)險基因的調(diào)控作用關(guān)系。分子對接顯示單體化合物與高風(fēng)險靶點(diǎn)基因具有良好結(jié)合性能。結(jié)論 基于MR發(fā)現(xiàn)14種腸道菌群與婦科癌癥發(fā)生發(fā)展高風(fēng)險存在因果關(guān)聯(lián)，其機(jī)制可能與脂質(zhì)代謝穩(wěn)態(tài)、Ras、PI3K/Akt等通路相關(guān)。槲皮素、齊墩果酸、山柰酚可能是調(diào)控高風(fēng)險基因的關(guān)鍵單體化合物，鹿茸、山茱萸、淫羊藿可能是調(diào)控高風(fēng)險基因的關(guān)鍵中藥，溫補(bǔ)脾腎類方和疏肝行氣類方可能是通過調(diào)節(jié)腸道菌群來防治婦科癌癥的重要中藥方劑；豐富了“腸-胞宮軸”生物學(xué)基礎(chǔ)，深化了婦科癌癥的病因?qū)W認(rèn)識，并為中醫(yī)藥調(diào)控腸道菌群防治婦科癌癥提供了新的方向。

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

國家自然科學(xué)基金面上項目（82374504）；廣東省中醫(yī)藥管理局科研項目（20221174）