Asthma and lower airway disease
The airway microbiome in patients with severe asthma: Associations with disease features and severity

https://doi.org/10.1016/j.jaci.2015.05.044Get rights and content
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Background

Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma. Whether similar relationships exist among patients with severe asthma is unknown.

Objective

We sought to evaluate relationships between the bronchial microbiome and features of severe asthma.

Methods

Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA–based methods. Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects. Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41).

Results

In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index (P < .05, Bray-Curtis distance-based permutational multivariate analysis of variance; PERMANOVA), changes in Asthma Control Questionnaire (ACQ) scores (P < .01), sputum total leukocyte values (P = .06), and bronchial biopsy eosinophil values (per square millimeter, P = .07). Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes). In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5), an indicator of steroid responsiveness, correlated with Actinobacteria. Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria. No taxa were associated with a TH2-related epithelial gene expression signature, but expression of TH17-related genes was associated with Proteobacteria. Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (7.8-fold increase in patients with severe asthma, adjusted P < .001).

Conclusions

Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes. Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use.

Key words

Microbiota
lung
inflammation
16S ribosomal RNA
body mass index
asthma control
steroids
TH2

Abbreviations used

ACQ
Asthma Control Questionnaire
BH
Benjamini-Hochberg
BMI
Body mass index
BOBCAT
Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma
FKBP5
FK506 binding protein
PB
Protected brush
PERMANOVA
Permutational multivariate analysis of variance
PICRUSt
Phylogenetic Investigation of Communities by Reconstruction of Unobserved States
qPCR
Quantitative PCR
16S rRNA
16S Ribosomal RNA

Cited by (0)

Supported by Genentech (to H.B.), the National Institutes of Health/National Heart, Lung, and Blood Institute (HL105572 to Y.J.H.), and the Sandler Family Foundation (to H.B.).

Disclosure of potential conflict of interest: Y. J. Huang has received research support from the National Institutes of Health (NIH). S. Nariya has received research support from the NIH/National Heart, Lung, and Blood Institute (NHLBI). J. M. Harris is employed by Genentech/Roche and receives stock/stock options as part of his compensation. S. V. Lynch has received research support from Genentech, the National Institutes of Allergy and Infectious Diseases, the NHLBI, the National Center for Complementary and Alternative Medicine, Pfizer, the Cystic Fibrosis Foundation, the Sloan Foundation, Janssen, and the Broad Foundation; is a board member for Second Genome; has consultant arrangements with Janssen, Novartis, Boston Consulting Group, and Regeneron; has received payment for lectures from the American Thoracic Society and the American Academy of Allergy, Asthma & Immunology; holds patents US Patent 7,687,474 B2: “Nitroreductase Enzymes,” EP 2393515 A1: Combination antibiotic and antibody therapy for the treatment of pseudomonas aeruginosa infection, WO 2012027302 A2: Systems and methods for detecting antibiotic resistance, and WO 2013155370 A1: Sinusitis diagnostics and treatments; has received royalties from Kalobios; and has received payment for development of educational presentations from Georgia Regents University. D. F. Choy is employed by Genentech, holds Roche stock and options, and is a coinventor of pending patents related to biomarker and therapeutic strategies in asthma through Genentech. J. R. Arron is employed by Genentech and has stock/stock options with Roche Holdings. H. Boushey has had consultant arrangements with Merck, GlaxoSmithKline, Genentech, Kalbios, Pharmaxis, and Johnson & Johnson; has received research support from GlaxoSmithKline and Genentech; has received payment for lectures from the Allergy, Asthma, and Immunology Foundation of Northern California and Breathe California; and has received royalties from the McGraw-Hill Companies.