title: The airway microbiome in patients with severe asthma: Associations with disease features and severity.
abstract: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Mich. Electronic address: yvjhuang@umich.edu.
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California San Francisco, San Francisco, Calif.
authors.forename: Snehal
authors.initials: S
authors.lastname: Nariya
authors.affiliation: Genentech, South San Francisco, Calif.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Harris
authors.affiliation: Division of Gastroenterology, University of California San Francisco, San Francisco, Calif.
authors.forename: Susan V
authors.initials: SV
authors.lastname: Lynch
authors.affiliation: Genentech, South San Francisco, Calif.
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.affiliation: Genentech, South San Francisco, Calif.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.affiliation: Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California San Francisco, San Francisco, Calif.
authors.forename: Homer
authors.initials: H
authors.lastname: Boushey
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D018450:Disease Progression; D064806:Dysbiosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D004804:Eosinophils / Q000276:immunology; D005260:Female; D006801:Humans; D007709:Klebsiella / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008297:Male; D064307:Microbiota; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000276:immunology; D012137:Respiratory System / Q000276:immunology* / Q000382:microbiology; D012720:Severity of Illness Index; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000305:Adrenal Cortex Hormones; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: 16S ribosomal RNA; Microbiota; T(H)2; asthma control; body mass index; inflammation; lung; steroids