目的 在“肺与大肠相表里”理论指导下采用孟德尔随机化（Mendelian randomization，MR）明确与肺癌发生具遗传因果效应的肠道菌群，并预测能通过调控肠道菌群干预肺癌的潜在中药。方法 从IEU OpenGWAS数据库获取肠道菌群与肺癌的全基因组关联研究汇总数据。使用R语言TwoSampleMR软件包进行MR分析，以逆方差加权法为主要的遗传因果效应评估方法。对工具变量邻近基因进行功能富集分析以探析相关微生物介导肺癌发生的信号通路。结合CTD和Coremine数据库预测对工具变量邻近基因具有潜在调控作用的中药，统计其性味归经及功效信息。结果 MR分析发现了10个与肺癌发生具遗传因果效应的肠道菌群，其中变形菌门（Proteobacteria）、厚壁菌门（Firmicutes）、毛螺菌科（Lachnospiraceae）、Marvinbryantia、瘤胃球菌科（Ruminococcaceae UCG004）和粪居拟杆菌Bacteroides coprocola菌群与肺癌发生风险降低相关，草酸杆菌科（Oxalobacteraceae）、普氏菌属7（Prevotella 7）、黑臭杆菌属（Odoribacter）和大肠杆菌Escherichia coli菌群与肺癌发生风险升高相关。工具变量邻近基因主要富集在Janus激酶（Janus kinase，JAK）/信号转导和转录激活因子（signal transducer and activator of transcription，STAT）、丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor，PPAR）和磷脂酰肌醇-3-羟激酶（phosphatidylinositol-3-hydroxykinase，PI3K）/蛋白激酶B（protein kinase B，Akt）等信号通路。潜在调控中药四气以温为主，寒、平次之，五味以苦味为主，甘、辛次之，归经以肝为主，肺、脾、胃和肾次之，功效以清热为主，补虚次之，还包含活血、理气、祛风湿、化痰止咳平喘和利水渗湿等。其中映射频率靠前的代表中药包括人参、马齿苋、生姜、姜黄、郁金、白果、五味子和丹参等。结论 基于“肺与大肠相表里”中医经典理论，采用MR分析发现以厚壁菌门、Marvinbryantia和变形菌门为代表的10种肠道菌群可能通过JAK/STAT、MAPK、PPAR和PI3K/Akt等信号通路介导肺癌发生发展。潜在调控中药主要包括清热药、补虚药、活血药和理气药等。丰富了“肺与大肠相表里”的生物学内涵，将为从“肠道菌群”视角探索肺癌的中医药防治策略提供参考。

Objective Under the guidance of the theory of “interior-exterior relationship between lung and large intestine”, Mendelian randomization (MR) was used to identify the intestinal flora that has genetic causal effect on the occurrence of lung cancer, and to predict the potential traditional Chinese medicines (TCMs) that can intervene in lung cancer by regulating the intestinal flora. Methods The present study utilized genome-wide association studies (GWAS) data from the IEU OpenGWAS database to conduct a MR analysis to investigate the causal relationship between intestinal flora and lung cancer. The MR analysis was performed using the TwoSampleMR package of R studio, employing inverse variance weighting as the primary method. Additionally, functional enrichment analysis of the instrumental variables’ adjacent genes was carried out to elucidate the potential pathways. CTD and Coremine database were employed to predict TCMs, and the four qi, five flavors, meridian affinity, and effect of the TCMs were analyzed. Results MR analysis identified 10 intestinal flora with causal effects on lung cancer. Proteobacteria, Firmicutes, Lachnospiraceae, Marvinbryantia, Ruminococcaceae UCG004 and Bacteroides coprocola were related to the reduction of the risk of lung cancer. Oxalobacteraceae, Prevotella 7, Odoribacter and Escherichia coli were associated with an increased risk of lung cancer. The genes were predominantly enriched in Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), peroxisome proliferator activated receptor (PPAR) and phosphatidylinositol-3-hydroxykinase (PI3K)/protein kinase B (Akt) signaling pathways. The four qi of predicted TCM were mainly warm, followed by cold and flat. The five flavors were mainly bitter, followed by sweet and sweet. Liver is the main meridian affinity, followed by lung, spleen, stomach and kidney. The efficacy are mainly to clear heat, tonic, circulate blood and regulate qi, dispel wind-damp, resolve phlegm, relieve cough and asthma, and clear damp and promote diuresis. Among them, the representative TCMs with the highest mapping frequency include Renshen (Ginseng Radix et Rhizoma), Machixian (Portulacae Herba), Shengjiang (Zingiberis Rhizoma Recens), Jianghuang (Curcumae Longae Rhizoma), Yujin (Curcumae Radix), Baiguo (Ginkgo Semen), Wuweizi (Schisandrae Chinensis Fructus) and Danshen (Salviae Miltiorrhizae Radix et Rhizoma). Conclusion Based on the theory of “interior-exterior relationship between lung and large intestine”, a total of 10 intestinal flora may mediate the development of lung cancer through JAK/STAT, MAPK, PPAR and PI3K/Akt signaling pathways using MR analysis. Predicted TCMs mainly include interior heat-clearing medicines, tonic medicines, blood-circulating medicines, and qi-regulating medicines. In general, this study enriched the biological connotation of“interior-exterior relationship between lung and large intestine”, and will provide an important reference for exploring TCM prevention and treatment strategies of lung cancer from the perspective of “intestinal flora”.

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国家自然科学基金项目（82305188）；四川省自然科学基金青年基金（23NSFSC6246）；中国博士后科学基金（2022MD723715）