Airway dysbiosis accelerates lung function decline in chronic obstructive pulmonary disease

• Published in: Cell host & microbe 2023-06, Vol.31 (6), p.1054-1070.e9
• Main Authors: Liang, Weijie, Yang, Yuqiong, Gong, Shenhai, Wei, Mingyuan, Ma, Yingfei, Feng, Ruipei, Gao, Jingyuan, Liu, Xiaomin, Tu, Fuyi, Ma, Wei, Yi, Xinzhu, Liang, Zhenyu, Wang, Fengyan, Wang, Lingwei, Chen, Dandan, Shu, Wensheng, Miller, Bruce E., Tal-Singer, Ruth, Donaldson, Gavin C., Wedzicha, Jadwiga A., Singh, Dave, Wilkinson, Tom M.A., Brightling, Christopher E., Chen, Rongchang, Zhong, Nanshan, Wang, Zhang
• Format: Article
• Language: English
• Subjects: airway microbiome; Animals; bacteriophage; COPD; Disease Progression; Dysbiosis; Forced Expiratory Volume; homocysteine; Humans; Lung; lung function decline; Mice; multi-omics; Pulmonary Disease, Chronic Obstructive; Staphylococcus aureus
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2023.04.018

Progressive lung function decline is a hallmark of chronic obstructive pulmonary disease (COPD). Airway dysbiosis occurs in COPD, but whether it contributes to disease progression remains unknown. Here, we show, through a longitudinal analysis of two cohorts involving four UK centers, that baseline airway dysbiosis in COPD patients, characterized by the enrichment of opportunistic pathogenic taxa, associates with a rapid forced expiratory volume in 1 s (FEV1) decline over 2 years. Dysbiosis associates with exacerbation-related FEV1 fall and sudden FEV1 fall at stability, contributing to long-term FEV1 decline. A third cohort in China further validates the microbiota-FEV1-decline association. Human multi-omics and murine studies show that airway Staphylococcus aureus colonization promotes lung function decline through homocysteine, which elicits a neutrophil apoptosis-to-NETosis shift via the AKT1-S100A8/A9 axis. S. aureus depletion via bacteriophages restores lung function in emphysema mice, providing a fresh approach to slow COPD progression by targeting the airway microbiome. [Display omitted] •Baseline airway dysbiosis is associated with rapid lung function decline in COPD•Microbial-metabolite-host interactions differ in COPD rapid lung function decliners•Staphylococcus aureus impairs lung function via the homocysteine-AKT1-S100A8/A9 axis•Bacteriophage-targeting S. aureus restores lung function in emphysema mice Airway dysbiosis is associated with accelerated lung function decline, a hallmark feature in chronic obstructive pulmonary disease (COPD). Staphylococcus aureus impairs lung function via the homocysteine-AKT1-S100A8/A9 axis in emphysema mice, which can be rescued by bacteriophage targeting of this bacterium. These findings imply a translational application to slow COPD progression by targeting the microbiome.