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PMID: 24024497 Published · ppublish English Clinical Trial Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The effects of airway microbiome on corticosteroid responsiveness in asthma.

American journal of respiratory and critical care medicine ·Vol. 188 ·No. 10 ·2013-11-15 ·Pages 1193-201

Goleva E, Jackson LP, Harris JK, Robertson CE, Sutherland ER, Hall CF, Good JT, Gelfand EW, Martin RJ, Leung DY

Abstract

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.

MeSH Terms
Adrenal Cortex Hormones/therapeutic use Adult Anti-Asthmatic Agents/therapeutic use Asthma/drug therapy,microbiology Biomarkers/metabolism Bronchoalveolar Lavage Fluid/microbiology Case-Control Studies DNA, Bacterial/analysis Drug Administration Schedule Drug Resistance/physiology Female Genetic Markers Humans Macrophages, Alveolar/metabolism Male Microbiota Middle Aged Prednisone/therapeutic use RNA, Ribosomal, 16S/analysis Real-Time Polymerase Chain Reaction Sequence Analysis, DNA Treatment Outcome
Chemicals
Adrenal Cortex Hormones Anti-Asthmatic Agents Biomarkers DNA, Bacterial Genetic Markers RNA, Ribosomal, 16S Prednisone
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Goleva Elena
1 Department of Pediatrics and.
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
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Article Info
Journal
American journal of respiratory and critical care medicine
Abbr.
Am J Respir Crit Care Med
ISSN
1535-4970
DOI
10.1164/rccm.201304-0775OC
Published
2013-11-15
Pages
1193-201
Language
English
Region
United States
NLM ID
9421642
PMCID
PMC3863730
Subset
IM
Grants
NIAID NIH HHS · 2R56AI070140 · United States
NHLBI NIH HHS · HL37260 · United States
NIAID NIH HHS · R56 AI070140 · United States
NHLBI NIH HHS · R37 HL037260 · United States
NIAID NIH HHS · AI070140 · United States
NIAID NIH HHS · R01 AI070140 · United States
Corrections
CommentIn
PMID: 24236581
External Links
PubMed source DOI: 10.1164/rccm.201304-0775OC PMC Full Text View journal details
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