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Although gut microbiota is intimately linked to COPD pathogenesis, associations among the gut microbiota, its derived metabolites, and exacerbation risk in stable COPD patients remain poorly understood. We recruited 74 stable COPD patients (Group A, n = 18; Group B, n = 26; Group E, n = 30) for cross-sectional multi-omics profiling via fecal metagenomic sequencing and untargeted serum metabolomic analyses. Group E exhibited a decreasing trend in alpha diversity compared to Groups A and B. In addition, Group A displayed the most complex bacterial cooperative network, showing lower complexity and connectivity as symptom burden and risk of exacerbations increased. Taxonomically, the family Prevotellaceae was significantly enriched in Group A, while Streptococcaceae and Lactobacillaceae were more abundant in Groups B and E. Among 51 species displaying progressive trends with increasing exacerbation risk, 35 increased (e.g., Clostridium ljungdahlii) and 16 decreased (e.g., Prevotella dentalis). Furthermore, metabolomics analysis revealed that serum O-phosphoethanolamine levels were markedly elevated in Group E and showed a positive correlation with the COPD Assessment Test and modified Medical Research Council dyspnea scale scores. Exploratory mediation analysis suggested that elevated systemic O-phosphoethanolamine levels partially mediated the association between Clostridium ljungdahlii and COPD exacerbation risk. This study establishes significant associations between gut microbiota and phenotypic stratification in stable COPD patients. The identified Clostridium ljungdahlii\/O-phosphoethanolamine axis may be associated with symptom burden and COPD exacerbation risk, provide a basis for further mechanistic studies.<\/jats:p>","DOI":"10.3390\/microorganisms14081673","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:38:54Z","timestamp":1785411534000},"page":"1673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Metagenomic and Metabolomic Profiling Identifies Severity-Specific Gut Microbiota Signatures Across A-B-E Phenotypes in Clinically Stable COPD: A Cross-Sectional Study"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-6702","authenticated-orcid":false,"given":"Renyang","family":"Tong","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"},{"name":"Beijing Key Laboratory of Multimodal Intelligent Diagnosis and Treatment System for Respiratory Diseases, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"An","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"},{"name":"Beijing Key Laboratory of Multimodal Intelligent Diagnosis and Treatment System for Respiratory Diseases, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziting","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshuang","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengmo","family":"Rong","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"},{"name":"Beijing Key Laboratory of Multimodal Intelligent Diagnosis and Treatment System for Respiratory Diseases, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-2500","authenticated-orcid":false,"given":"Yu","family":"An","sequence":"additional","affiliation":[{"name":"Medical Research Center, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-259X","authenticated-orcid":false,"given":"Ruiyue","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, 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