目的 采用孟德尔随机化（mendelian randomization，MR）的方法探索与支气管哮喘存在遗传因果关联的肠道菌群，探析“肠-肺轴”干预哮喘的生物学基础，预测对其具有调控作用的中药。方法 获取肠道菌群和哮喘的全基因组关联研究数据（genome-wide association study，GWAS）。使用R语言以逆方差加权法（inverse variance weighted，IVW）为主要方法进行MR分析。采用异质性检验、敏感性分析、水平多效性和离群值检验对结果进行质量控制。对单核苷酸多态性（single nucleotide polymorphisms，SNPs）邻近基因进行蛋白质-蛋白质互作（protein-protein interaction，PPI）分析以筛选核心基因，对邻近基因进行功能富集分析以探索肠道菌群介导哮喘发生的潜在机制。使用中药系统药理学数据库与分析平台（Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform，TCMSP）预测对“肠-肺轴”存在潜在治疗作用的化合物与中药，并统计分析潜在干预中药特征。筛选核心中药成分，使用分子对接进行验证。结果 MR分析发现4种肠道菌群——毛状假黄素发酵菌、粪拟杆菌、布劳特氏菌属Blautia obeum、真细菌属Eubacterium ramulus和4条功能路径——同型乳酸发酵路径、辅酶A生物合成路径、葡萄糖和葡萄糖-1-磷酸降解路径、尿囊素降解乙醛酸路径与哮喘具有相对稳定的因果关系。SNPs间无异质性、水平多效性和离群值，敏感性良好。获得以胰岛素基因（insulin，INS）、胰岛素样生长因子2（insulin-like growth factor 2，IGF2）、免疫球蛋白λ样多肽5（immunoglobulin lambda-like polypeptide 5，IGLL5）、胸腺细胞分化抗原1（thy-1 cell surface antigen，THY1）、脂联素（adiponectin,C1Q and collagen domain containing，ADIPOQ）为核心的202个SNPs邻近基因，邻近基因功能主要富集在糖鞘脂生物合成、酪氨酸代谢、苯丙氨酸代谢、环磷酸鸟苷（cyclic guanosine monosphosphate，cGMP）-蛋白激酶G（protein kinase G，PKG）信号通路等路径。获得以芹菜素、油酸、芦丁为代表的15种化合物和以麻黄、红花、银杏叶为代表的254味中药。中药的四气以寒、温为主，五味以苦、甘、辛为主，归经以肝、肺经为主，功效以清热为主。分子对接显示核心中药成分与核心基因具有良好结合效能。结论 基于MR发现8种与哮喘存在因果关联的肠道菌群和功能路径，其机制可能与糖鞘脂生物合成、酪氨酸和苯丙氨酸代谢等信号通路相关。预测麻黄、红花、银杏叶等中药对肠道菌群介导哮喘发生具有潜在调控作用。

Objective To explore the gut microbiota causally associated with bronchial asthma by Mendelian randomization (MR), to investigate the biological basis of the “gut-lung axis” in asthma, and to predict the traditional Chinese medicines (TCM) that may have regulatory effects on it.Methods The genome-wide association study (GWAS) data were obtained on the association between gut microbiota and asthma. MR analysis was performed using R language with inverse variance weighted (IVW) as the main method. Heterogeneity test, sensitivity analysis, horizontal pleiotropy and outlier test were used for quality control of the results. Protein-protein interaction (PPI) analysis was performed on the proximity genes of single nucleotide polymorphisms (SNPs) to screen the core genes, and functional enrichment analysis was performed on the proximity genes to explore the potential mechanisms of asthma mediated by gut microbiota. The TCMSP database was used to predict the potential therapeutic effects of chemical components and Chinese medicines on the “gut-lung axis”, and the characteristics of the potential intervening Chinese medicines were statistically analyzed. The core TCM components were screened and validated using molecular docking.Results MR analysis identified four gut microbiota including Pseudoflavonifractor capillosus, Bacteroides coprocola, Blautia obeum, Eubacterium ramulus, and four functional pathways including homolactic fermentation pathway, coenzyme A biosynthesis pathway, glucose and glucose-1-phosphate degradation pathway and allantoin degradation to glyoxylate pathway had relatively stable causal relationships with asthma. There was no heterogeneity, horizontal pleiotropy, or outliers among SNPs, and sensitivity was good. A total of 202 SNPs-proximal geness with insulin (INS), insulin-like growth factor 2 (IGF2), immunoglobulin lambda-like polypeptide 5 (IGLL5), thy-1 cell surface antigen (THY1) and adiponectin, C1Q and collagen domain containing (ADIPOQ) as the core genes were obtained, and the functions of the proximal genes were mainly enriched in the glycosphingolipid biosynthesis, tyrosine metabolism, phenylalanine metabolism, and cyclic guanosine monosphosphate (cGMP)-protein kinase G (PKG) signaling pathway. Fifteen chemical components represented by apigenin, oleic acid and rutin and 254 herbs of TCM represented by Mahuang (Ephedrae Herba), Yinxingye (Ginkgo Folium) and Honghua (Carthami Flos) were obtained. The four qi of the Chinese medicines were mainly cold and warm, the five flavors were mainly bitter, sweet and pungent, the meridian tropism were mainly liver and lung meridians, and the efficacy was mainly heat-clearing. The molecular docking showed that the core TCM components had good binding efficiency with the core genes.Conclusion Based on MR, eight gut microbiota and functional pathways were found to be causally associated with asthma, and their mechanisms may be related to glycosphingolipid biosynthesis, tyrosine and phenylalanine metabolism, and cGMP-PKG signaling pathway. It is predicted that the Chinese herbal medicines such as Ephedrae Herba, Ginkgo Folium and Carthami Flos could potentially regulate the gut microbiota-mediated asthma development.

Q811.4;R285

国家中医药管理局第五批全国中医临床优秀人才研修项目（国中医药人教函[2022]1号）；北京市中医药管理局北京中医药新时代125工程（京中医药科字[2025]2号）；北京中医药大学第三附属医院精诚人才计划（京中三院人[2025]4号）