A Refined View of Airway Microbiome in Chronic Obstructive Pulmonary Disease at Species and Strain-levels

Abstract

Little is known about the species and strain-level diversity of the airway microbiome, and its implication in chronic obstructive pulmonary disease (COPD). Here we report the first comprehensive analysis of the COPD airway microbiome at species and strain-levels. The full-length 16S rRNA gene was sequenced from sputum in 98 stable COPD patients and 27 age-matched healthy controls, using the third-generation Pacific Biosciences sequencing platform. Individual species within the same genus exhibited reciprocal relationships with COPD and disease severity. Species dominant in health can be taken over by another species within the same genus in GOLD IV patients. Such turnover was also related to enhanced symptoms and exacerbation frequency. Ralstonia mannitolilytica, an opportunistic pathogen, was significantly increased in COPD frequent exacerbators. There were inflammatory phenotype-specific associations of microbiome at the species-level. One group of four pathogens including Haemophilus influenzae and Moraxella catarrhalis, were specifically associated with sputum mediators for neutrophilic inflammation. Another group of seven species, including Tropheryma whipplei, showed specific associations with mediators for eosinophilic inflammation. Strain-level detection uncovered three non-typeable H. influenzae strains PittEE, PittGG and 86-028NP in the airway microbiome, where PittGG and 86-028NP abundances may inversely predict eosinophilic inflammation. The full-length 16S data augmented the power of functional inference and led to the unique identification of butyrate-producing and nitrate reduction pathways as significantly depleted in COPD. Our analysis uncovered substantial intra-genus heterogeneity in the airway microbiome associated with inflammatory phenotypes and could be of clinical importance, thus enabled a refined view of the airway microbiome in COPD. "Take-home" messageThe species-level analysis using the third-generation sequencing enabled a refined view of the airway microbiome and its relationship with clinical outcome and inflammatory phenotype in COPD.