Integrated Metagenomic and Metabolomic Profiling Identifies Severity-Specific Gut Microbiota Signatures Across A-B-E...

The ABE classification is crucial for the management of stable chronic obstructive pulmonary disease (COPD), reflecting disease symptom burden and exacerbation risk. 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.