目的 通过逆向网络药理学方法，探究肠道菌群来源的代谢产物在糖尿病心肌病（DCM）与心力衰竭（HF）合并发病过程中发挥作用的分子关联机制并预测潜在的核心干预中药。方法 从gutMGene数据库中提取肠道菌群代谢产物；利用相似集成算法（SEA）与SwissTargetPrediction数据库进行代谢产物靶点预测。从Genecards、OMIM等数据库中获取HF和DCM相关靶点，鉴定出共同靶点。将菌群代谢产物预测靶点与疾病共有靶点取交集，再与gutMGene收集的238个经实验验证的菌群相关靶点二次取交集，获得候选靶基因集。通过蛋白质-蛋白质相互作用（PPI）网络分析、基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析及分子对接技术，验证得到核心靶点。借助SwissADME与ADMETlab2.0工具，完成药物相似性与毒性的评估。通过中药系统药理学数据库与分析平台（TCMSP）数据库反向检索中药化学成分，最终根据活性成分匹配对应中药，并结合性味归经理论阐释其核心作用。结果 获取了251种肠道菌群代谢产物及其作用靶点；筛选得到HF相关靶点16 136个、DCM相关靶点6 445个，鉴定出6 301个疾病共同靶点。通过多层交集与PPI网络分析得到46个核心靶点，PPI结果显示，丝氨酸和苏氨酸激酶1（AKT1）与白细胞介素（IL）-6为核心枢纽蛋白，KEGG通路富集分析表明脂质与动脉粥样硬化信号通路具有关键作用。分子对接实验证实，丁酸盐与AKT1具有较强的结合能力，药物相似性筛选结果显示，丁酸盐与乙酸盐具有良好的应用前景，且二者均无肝毒性与心脏毒性。微生物群-代谢物-靶点-信号通路网络分析强调，罗斯氏菌和梭菌是调控脂质与动脉粥样硬化信号通路的核心菌株。逆向共筛得445种中药，其中度（Degree）值≥6的85种中药多为寒性、苦味； Degree值≥20的中药包括甘草、降香、丹参、延胡索等。结论 阐明了肠道菌群-代谢产物-靶点-信号通路的调控网络在DCM与HF共病中的作用，为利用肠道来源代谢产物治疗DCM合并HF提供了理论框架。并锁定核心中药，核心中药的药性组合契合“本虚标实、痰瘀互结”的中医核心病机，为临床针对该共病辨证组方提供候选药物库、配伍理论支撑及分子机制依据。

Objective To explore the molecular association mechanism of metabolites derived from gut microbiota in the comorbid development of diabetic cardiomyopathy (DCM) and heart failure (HF), and predict potential core intervention Chinese herbal medicines through the method of reverse network pharmacology. Methods Gut microbiota-derived metabolites and their corresponding targets were retrieved from the gutMGene database, with target prediction performed using the Similarity Ensemble Approach (SEA) and SwissTargetPrediction databases. Targets related to HF and DCM were obtained from databases such as Genecards and OMIM, and the common targets were identified. The intersection of the eight predicted microbial metabolites and the common targets of disease was obtained, and then the second intersection was made with the 238 experimentally validated microbialrelated targets collected by gutMGene to obtain a candidate target gene set. Core targets were validated through protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking techniques. Drug similarity and toxicity were evaluated using SwissADME and ADMETlab 2.0 tools. TCM chemical components were retrieved in a reverse manner from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Finally, TCMs were matched based on their active components, and their core pharmacological effects were interpreted in light of the TCM theories of property, flavor, and meridian tropism. Results A total of 251 gut microbiota metabolites and their targets were obtained; 16 136 HF-related targets and 6 445 DCM-related targets were screened, and 6 301 common targets were identified. PPI network analysis yielded 46 core targets, among which AKT1 and IL-6 were identified as core hub proteins. KEGG pathway enrichment analysis indicated that the lipid and atherosclerosis signaling pathway plays a pivotal role. Molecular docking assays confirmed that butyrate exhibits strong binding affinity to AKT1. The drug similarity screening results showed that butyrate and acetate have good application prospects, and neither of them exhibits hepatotoxicity nor cardiotoxicity. Microbemetabolite-target-signaling pathway network analysis emphasized that Roseburia and Clostridium are the core bacterial strains regulating the lipid and atherosclerosis signaling pathway. Reverse screening identified 445 TCMs, among which 85 TCMs with a Degree value ≥ 6 were predominantly characterized by cold property and bitter flavor. TCMs with a Degree value ≥ 20 include Glycyrrhizae Radix et Rhizoma, Dalbergiae Odoriferae Lignum, Salviae Miltiorrhizae Radix et Rhizoma, and Corydalis Rhizoma. Conclusion This study elucidated the role of the regulatory network of gut microbiota-metabolites-targets-signaling pathways in the comorbidity of DCM and HF, providing a theoretical framework for the therapeutic application of gut-derived metabolites in treating DCM complicated with HF. Meanwhile, core TCMs are identified, whose property combinations are consistent with the core TCM pathogenesis of “root deficiency and superficial excess, intermingled phlegm and blood stasis”. These findings offer a candidate drug library, compatibility theoretical support, and molecular mechanistic basis for the syndrome differentiation and formula composition in the clinical management of this comorbidity.

R285.5

甘肃省中医药管理局课题基金资助项目（GZKZ-2025-30）；甘肃省卫生健康行业科技创新重大项目（GSWSQNPY2025-21）；甘肃省自然科学基金资助项目（25JRRA975）；甘肃省药品监督管理局（2025GSMPA054）；兰州市科技局计划项目（2025-2-87）；甘肃中医药大学研究生创新创业项目（2026CXCY-251）