Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology

Steven L. Taylor, Lex E.X. Leong, Jocelyn M. Choo, Steve Wesselingh, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James, Christine Jenkins, Matthew J. Peters, Melissa Baraket, Guy B. Marks, Peter G. Gibson, Jodie L. Simpson, Geraint B. Rogers

Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly understood. We aimed to characterise airway microbiota in patients with symptomatic stable asthma, and relate composition to airway inflammatory phenotype and other phenotypic characteristics. The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined using alpha and beta diversity measures, and inter-phenotype differences identified using SIMPER, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified using multivariate linear regression. Microbiota composition was determined in 167 participants, classified as eosinophilic (n=84), neutrophilic (n=14), paucigranulocytic (n=60), or mixed neutrophilic-eosinophilic (n=9) phenotypes of asthma. Airway microbiology was significantly less diverse (p=0.022) and more dissimilar (p=0.005) in neutrophilic compared to eosinophilic participants. Sputum neutrophil proportion, but not eosinophil proportion, correlated significantly with these diversity measures (alpha-diversity: Spearman's r=-0.374, p<0.001; beta-diversity: r=0.238, p=0.002). Inter-phenotype differences were characterised by a greater frequency of pathogenic taxa at high relative abundance, and reduced Streptococcus, Gemella and Porphyromonas relative abundance in neutrophilic asthma. Multivariate regression confirmed sputum neutrophil proportion was the strongest predictor of microbiota composition. Neutrophilic asthma is associated with airway microbiology that is significantly different to that in other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition may influence response to antimicrobial and steroid therapies, and risk of lung infection.