目的 运用网络药理学探讨肠道微生物代谢物在慢性阻塞性肺疾病（COPD）中的潜在作用机制。方法 从gutMGene数据库获取肠道微生物代谢物及靶点信息，利用相似性集成方法（SEA）和SwissTargetPrediction数据库预测其作用靶点，并通过OMIM、CTD和Genecards数据库收集COPD相关靶点。取交集后，对共同靶点进行基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析，构建蛋白质-蛋白质相互作用（PPI）网络筛选核心靶点，并建立“微生物-底物-代谢物-靶点”网络。对关键代谢物进行成药性评估及分子对接验证。结果 共获得55个代谢物-疾病共同靶点。富集分析显示，代谢物主要参与炎症、氧化应激及凋亡等生物过程，涉及Toll样受体、白细胞介素（IL）-17、磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）等信号通路。PPI及“微生物-底物-代谢物-靶点”网络分析确定肿瘤坏死因子（TNF）、AKT1、IL1B、肿瘤蛋白p53（TP53）、IL6为核心靶点，与30种代谢物、22种底物及64种微生物相互作用。13种代谢物具良好成药性，分子对接证实其与核心靶点能稳定结合。结论 肠道微生物代谢物可能通过调控多个核心靶点和免疫炎症通路，在COPD治疗中发挥关键作用，为后续机制研究提供了理论基础。

Objective To explore the potential mechanism of action of intestinal microbiota metabolites in chronic obstructive pulmonary disease (COPD) by using network pharmacology. Methods Information on intestinal microbial metabolites and their targets was obtained from the gutMGene database. Their action targets were predicted using the SEA and SwissTargetPrediction databases, while COPD-related targets were collected via the OMIM, CTD and Genecards databases. The intersection of these targets was taken, followed by GO and KEGG enrichment analyses performed on the shared targets. A protein-protein interaction (PPI) network was constructed to screen core targets, and a “microbe-substrate-metabolite-target” network was established. Drugability assessment and molecular docking verification were carried out for key metabolites. Results A total of 55 metabolite-disease common targets were obtained. Enrichment analysis showed that the metabolites were mainly involved in biological processes such as inflammation, oxidative stress and apoptosis, and were related to signaling pathways such as Toll-like receptor signaling pathway, IL- 17 signaling pathway, and PI3K-Akt signaling pathway. PPI and “microbe-substrate-metabolite-target” network analysis identified TNF, AKT1, IL1B, TP53, and IL6 as core targets, which interacted with 30 metabolites, 22 substrates and 64 microorganisms. Thirteen metabolites had good drugability, and molecular docking confirmed that they could stably bind to the core targets. Conclusion A total of 55 intestinal microbial metabolites were identified, and it was found that they might play a crucial role in the treatment of COPD by regulating multiple core targets and immune-inflammatory pathways. This provides a theoretical basis for subsequent mechanism research.

R965

国家自然科学基金项目（82505393）