Airway microbiota and immunity associated with chronic obstructive pulmonary disease severity.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive airflow limitation and chronic inflammation. Although airway microbes and host immunity are known contributors, the molecular mechanisms underlying disease severity remain unclear. This study explores microbial dysbiosis and host immune responses across varying COPD severities. METHODS: We conducted integrated metagenomic and transcriptomic analyses on bronchoalveolar lavage fluid from two cohorts: a discovery cohort and a validation cohort. We investigated microbial diversity, pathogenic bacterial enrichment, and host gene expression patterns. Functional metagenomics was used to assess antibiotic resistance genes. Host-microbe network analyses explored correlations between pathogens and immune-metabolic pathways. Diagnostic models utilizing microbial-immune biomarkers were developed, trained on a subset of the discovery cohort, tested on remaining discovery samples, and validated by quantitative polymerase chain reaction (qPCR) in the validation cohort to distinguish COPD from controls and stratify disease severity. RESULTS: Severe COPD exhibited reduced microbial diversity and an increased presence of pathogenic bacteria, including Moraxella osloensis and Streptococcus species. These pathogens were associated with dysregulated inflammatory signaling, and significant neutrophil activity, evidenced by the formation of Neutrophil Extracellular Traps (NETs), and oxidative stress, which correlated with airway remodeling and a decline in lung function. Functional metagenomics showed a significant increase in antibiotic resistance genes in severe cases, linked to chronic treatment pressures. Host-microbe network analyses revealed strong correlations between these pathogens and disrupted immune-metabolic pathways, such as altered energy metabolism and inflammatory cascades, consistent across both cohorts. Diagnostic models based on microbial-immune biomarkers demonstrated high accuracy in differentiating COPD patients from controls and in stratifying disease severity. CONCLUSIONS: This study identifies microbial and immune signatures associated with COPD severity, providing mechanistic insights into its pathophysiology. The findings may inform precision medicine strategies by targeting airway dysbiosis and immune dysregulation. While causal relationships could not be established in this cross-sectional study, the findings provide a foundation for future mechanistic investigations using advanced in vitro and in vivo models.