The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma

• Published in: American journal of respiratory and critical care medicine Vol. 188; no. 10; pp. 1193 - 1201
• Main Authors: Goleva, Elena, Jackson, Leisa P., Harris, J. Kirk, Robertson, Charles E., Sutherland, E. Rand, Hall, Clifton F., Good, James T., Gelfand, Erwin W., Martin, Richard J., Leung, Donald Y. M.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15.11.2013
• Subjects: Adrenal Cortex Hormones - therapeutic use; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anti-Asthmatic Agents - therapeutic use; Asthma; Asthma - drug therapy; Asthma - microbiology; Bacteria; Biological and medical sciences; Biomarkers - metabolism; Bronchoalveolar Lavage Fluid - microbiology; Bronchoscopy; Case-Control Studies; Chronic obstructive pulmonary disease, asthma; DNA, Bacterial - analysis; Drug Administration Schedule; Drug Resistance - physiology; Female; Genetic Markers; Humans; Intensive care medicine; Kinases; Macrophages, Alveolar - metabolism; Male; Medical sciences; Microbiota; Middle Aged; Pneumology; Polymerase chain reaction; Prednisone - therapeutic use; Real-Time Polymerase Chain Reaction; RNA, Ribosomal, 16S - analysis; Sequence Analysis, DNA; Steroids; Treatment Outcome; Lung disease; Corticosteroid; Intensive care; corticosteroids; Respiratory disease; Bronchus disease; Obstructive pulmonary disease; microbiome; Resuscitation; Asthma
• DOI: 10.1164/rccm.201304-0775OC
• ISSN: 1073-449X; 1535-4970

The role of airway microbiome in corticosteroid response in asthma is unknown. 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. 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. 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. 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.