RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality and health care costs. Cigarette smoke is a causative factor, however not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advance stages. OBJECTIVE: Here we investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. METHODS: We recruited 57 patients with >10 pack year smoking history: 26 had physiological evidence of COPD, 31 had normal lung function (smoker controls). Bronchoscopy sampled the upper airways (UA), lower airways (BAL) and environmental background (BKG). Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. MEASUREMENTS/MAIN RESULTS: Compared with smoker controls, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1 and MUC4 in mild-to-moderate COPD. Finally, in a pre-clinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury revealing transcriptomic signatures similar to those observed in human COPD subjects. CONCLUSIONS: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.
