• Imran Sulaiman, Benjamin G Wu, Matthew Chung, Bradley Isaacs, Jun-Chieh J Tsay, Meredith Holub, Clea R Barnett, Benjamin Kwok, Matthias C Kugler, Jake G Natalini, Shivani Singh, Yonghua Li, Rosemary Schluger, Joseph Carpenito, Destiny Collazo, Luisanny Perez, Yaa Kyeremateng, Miao Chang, Christina D Campbell, Philip M Hansbro, Beno W Oppenheimer, Kenneth I Berger, Roberta M Goldring, Sergei B Koralov, Michael D Weiden, Rui Xiao, Jeanine D'Armiento, Jose C Clemente, Elodie Ghedin, and Leopoldo N Segal.
• Division of Pulmonary and Critical Care Medicine.
• Am. J. Respir. Crit. Care Med. 2023 Nov 15; 208 (10): 110111141101-1114.

AbstractRationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare 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 advanced stages. Objectives: 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 a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. 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 and Main Results: Compared with smoker control subjects, 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 preclinical 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 subjects with COPD. 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.

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