title: The effects of airway microbiome on corticosteroid responsiveness in asthma.
abstract: BACKGROUND
  The role of airway microbiome in corticosteroid response in asthma is unknown.
  
  
  OBJECTIVE
  To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.
  
  
  METHODS
  16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.
  
  
  RESULTS
  Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids.
  
  
  CONCLUSIONS
  A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.
authors.affiliation: 1 Department of Pediatrics and.
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
authors.forename: Leisa P
authors.initials: LP
authors.lastname: Jackson
authors.forename: J Kirk
authors.initials: JK
authors.lastname: Harris
authors.forename: Charles E
authors.initials: CE
authors.lastname: Robertson
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.forename: Clifton F
authors.initials: CF
authors.lastname: Hall
authors.forename: James T
authors.initials: JT
authors.lastname: Good
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000382:microbiology; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology*; D016022:Case-Control Studies; D004269:DNA, Bacterial / Q000032:analysis; D004334:Drug Administration Schedule; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D064307:Microbiota; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use*; D012336:RNA, Ribosomal, 16S / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D004269:DNA, Bacterial; D005819:Genetic Markers; D012336:RNA, Ribosomal, 16S; D011241:Prednisone
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