Lung microbiome composition and bronchial epithelial gene expression in patients with COPD versus healthy individuals: a bacterial 16S rRNA gene sequencing and host transcriptomic analysis

Mohammadali Yavari Ramsheh, Koirobi Haldar, Anna Esteve-Codina, Lillie F Purser, Matthew Richardson, Joachim Müller-Quernheim, Timm Greulich, Adam Nowinski, Imre Barta, Mariarita Stendardo, Piera Boschetto, Damian Korzybski, Antje Prasse, David G Parr, Jens M. Hohlfeld, Balazs Dome, Tobias Welte, Simon Heath, Ivo Gut, Julie A MorrisseyLoems Ziegler-Heitbrock, Michael R Barer, Dave Singh, Christopher E Brightling

Research output: Contribution to journalArticlepeer-review


Background Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to determine differences in the airway microbiome from bronchial brushings in COPD and health and to investigate whether these distinguishing bacteria are related to bronchial gene expression. Methods Subjects with mild-to-moderate COPD either receiving (n=202) or not receiving inhaled corticosteroids (n=158) and healthy subjects (n=214) were recruited as part of the EvA consortium from 9 centres (Leicester, Manchester, Coventry, Munich, Marburg, Freiburg, Ferrara, Warszawa, and Budapest) in five European countries (United Kingdom, Germany, Italy, Poland and Hungary) between February 2009 to March 2012 to investigate their lung microbiome composition and bronchial epithelial gene expression as well as detecting potential biomarkers specific to airway disease or emphysema in COPD. Subjects with COPD and healthy individuals underwent clinical characterisation, spirometry, computed tomography (CT) scans (in all COPD subjects and 30 of the healthy controls) and bronchoscopy. All COPD subjects were ex-smokers for at least 12 months, aged <45 or >75 years, at COPD stage IV, with >400 mL improvement of FEV1 (forced expiratory volume in one second) post-bronchodilation, or FEV1 <1.0L were excluded. The same exclusion criteria were applied for the healthy subjects. Microbial profile and gene expression from bronchscopic bronchial brush samples were obtained through 16S rRNA gene sequencing and RNA-Seq respectively. Findings 4 From the 574 bronchial brush samples, 546 were used for further analysis (7 samples excluded as they did not have enough extracted DNA and RNA, and 21 samples were excluded based on the sequencing depth cut off) including 207 healthy subjects and 339 COPD (192 with inhaled glucocorticoids (ICS) and 147 without ICS). The bacterial genera that most strongly distinguished COPD from health were Prevotella (median % [IQR] 34 [14 to 49] versus 48 [31 to 61]), Streptococcus 9 [4 to 16] versus 5 [3 to 1]), and Moraxella (0·05 [0·02 to 0·14] versus 0·02 [0 to 0·07]; p<0·0001). Prevotella abundance was inversely related to COPD severity in terms of symptoms and positively related to the lung function and exercise capacity. From the 546 bronchial brush samples used for microbiome analysis, 446 had assessable RNAseq data including 257 COPD (136 with ICS and 121 without ICS) and 189 healthy control subjects. No significant associations were observed between lung transcriptional signals from bronchial brushings and abundance of bacterial genera in COPD subjects without inhaled corticosteroid treatment and healthy subjects. In COPD subjects using inhaled corticosteroids, gene expression was significantly associated with Prevotella abundance (327 positives, 202 negatives) and Moraxella (192 positives, 35 negatives). Prevotella was positively associated with epithelial genes involved in tight junction promotion and Moraxella with the Interleukin-17 (IL-17) and tumor necrosis factor (TNF) inflammatory pathways. Interpretation With increasing severity of COPD the airway microbiome is associated with decreased abundance of Prevotella and increase Moraxella in concert with down-regulation of genes promoting epithelial defence and up-regulation of pro-inflammatory genes associated with inhaled corticosteroid use. Our work provides further insight in understanding of relationship between microbiome alteration and host inflammatory response which may lead to novel therapeutic strategies for COPD.
Original languageEnglish
JournalThe Lancet
Publication statusPublished - 2021


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