The effects of airway microbiome on corticosteroid responsiveness in asthma.

RATIONALE The role of airway microbiome in corticosteroid response in asthma is unknown. OBJECTIVES 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. MEASUREMENTS AND MAIN 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.

[1]  W. Bailey,et al.  Medical Section Of The American Lung Association , 2015 .

[2]  J. Harris,et al.  Microbiome of the Lower Airways Alters Corticosteroid Responsiveness in Asthma , 2013 .

[3]  Richard E. Isaacson,et al.  The Lung Microbiome in Moderate and Severe Chronic Obstructive Pulmonary Disease , 2012, PloS one.

[4]  Joel Cooper,et al.  The lung tissue microbiome in chronic obstructive pulmonary disease. , 2012, American journal of respiratory and critical care medicine.

[5]  J. Drazen.  Asthma: the paradox of heterogeneity. , 2012, The Journal of allergy and clinical immunology.

[6]  Julia Oh,et al.  Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis , 2012, Genome research.

[7]  Rakesh K. Kumar,et al.  Emerging roles of pulmonary macrophages in driving the development of severe asthma , 2012, Journal of leukocyte biology.

[8]  A. Arun,et al.  Aquabacterium limnoticum sp. nov., isolated from a freshwater spring. , 2012, International journal of systematic and evolutionary microbiology.

[9]  D. Riches,et al.  Vitamin D Inhibits Monocyte/Macrophage Proinflammatory Cytokine Production by Targeting MAPK Phosphatase-1 , 2012, The Journal of Immunology.

[10]  J. Søndergaard,et al.  Divergent Pro-Inflammatory Profile of Human Dendritic Cells in Response to Commensal and Pathogenic Bacteria Associated with the Airway Microbiota , 2012, PloS one.

[11]  J. Harris,et al.  Asthma Control And Disordered Microbial Communities In The Lower Airways Of Patients With Poorly Controlled Asthma , 2012 .

[12]  D. Riches,et al.  Vitamin D Inhibits Monocyte/macrophage Pro-inflammatory Cytokine Production by Targeting Mitogen-Activated Protein Kinase Phosphatase-1 , 2012 .

[13]  T. Wynn,et al.  Protective and pathogenic functions of macrophage subsets , 2011, Nature Reviews Immunology.

[14]  M. Fenton,et al.  Innate immunity in allergic disease , 2011, Immunological reviews.

[15]  J. Curtis,et al.  Analysis of the Lung Microbiome in the “Healthy” Smoker and in COPD , 2011, PloS one.

[16]  H. Ohta,et al.  Limnobacter litoralis sp. nov., a thiosulfate-oxidizing, heterotrophic bacterium isolated from a volcanic deposit, and emended description of the genus Limnobacter. , 2011, International journal of systematic and evolutionary microbiology.

[17]  Tanja Woyke,et al.  Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. , 2011, The Journal of allergy and clinical immunology.

[18]  D. Littman,et al.  Modulation of immune homeostasis by commensal bacteria. , 2011, Current opinion in microbiology.

[19]  M. Kandefer-Szerszeń,et al.  Low endotoxic activity of lipopolysaccharides isolated from Bradyrhizobium, Mesorhizobium, and Azospirillum strains , 2010, Microbiology and immunology.

[20]  E. R. Sutherland,et al.  Vitamin D levels, lung function, and steroid response in adult asthma. , 2010, American journal of respiratory and critical care medicine.

[21]  O. Holst,et al.  The structure of a novel neutral lipid A from the lipopolysaccharide of Bradyrhizobium elkanii containing three mannose units in the backbone. , 2010, Chemistry.

[22]  H. Tlaskalova-Hogenova.  Faculty Opinions recommendation of Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. , 2010 .

[23]  Lior Pachter,et al.  Disordered Microbial Communities in Asthmatic Airways , 2010, PloS one.

[24]  S. Nordeen,et al.  Estrogen Inhibits Glucocorticoid Action via Protein Phosphatase 5 (PP5)-mediated Glucocorticoid Receptor Dephosphorylation* , 2009, The Journal of Biological Chemistry.

[25]  I. Adcock,et al.  Glucocorticoid resistance in inflammatory diseases , 2009, The Lancet.

[26]  E. R. Sutherland,et al.  Body mass and glucocorticoid response in asthma. , 2008, American journal of respiratory and critical care medicine.

[27]  David W H Riches,et al.  Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. , 2008, The Journal of allergy and clinical immunology.

[28]  D. Artis.  Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut , 2008, Nature Reviews Immunology.

[29]  Ncbi.  National Center for Biotechnology Information , 2008 .

[30]  T. Ogawa,et al.  Soluble CD14 Discriminates Slight Structural Differences between Lipid As That Lead to Distinct Host Cell Activation1 , 2007, The Journal of Immunology.

[31]  Richard J Martin,et al.  Airway remodeling and lack of bronchodilator response in steroid-resistant asthma. , 2007, The Journal of allergy and clinical immunology.

[32]  L. Nelin,et al.  MAPK phosphatases — regulating the immune response , 2007, Nature Reviews Immunology.

[33]  Z. Dzierżewicz,et al.  [The structural diversity of lipid A from gram-negative bacteria]. , 2007, Postepy higieny i medycyny doswiadczalnej.

[34]  Tonya S. King,et al.  The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial. , 2007, Journal of Allergy and Clinical Immunology.

[35]  Richard J Martin,et al.  Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. , 2006, American journal of respiratory and critical care medicine.

[36]  I. Adcock,et al.  Update on glucocorticoid action and resistance. , 2006, The Journal of allergy and clinical immunology.

[37]  J. Douwes,et al.  Interlaboratory evaluation of endotoxin analyses in agricultural dusts--comparison of LAL assay and mass spectrometry. , 2005, Journal of environmental monitoring : JEM.

[38]  S. Akira,et al.  The MyD88-Dependent, but Not the MyD88-Independent, Pathway of TLR4 Signaling Is Important in Clearing Nontypeable Haemophilus influenzae from the Mouse Lung1 , 2005, The Journal of Immunology.

[39]  W. Busse,et al.  Investigative bronchoprovocation and bronchoscopy in airway diseases. , 2005, American journal of respiratory and critical care medicine.

[40]  F. Liew,et al.  Negative regulation of Toll-like receptor-mediated immune responses , 2005, Nature Reviews Immunology.

[41]  D. Leung,et al.  Racial differences in T-lymphocyte response to glucocorticoids. , 2005, Chest.

[42]  Samuel I. Miller,et al.  LPS, TLR4 and infectious disease diversity , 2005, Nature Reviews Microbiology.

[43]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[44]  B. Szponar,et al.  Characterization of Lipopolysaccharides Present in Settled House Dust , 2004, Applied and Environmental Microbiology.

[45]  D. Sexton,et al.  MECHANISMS OF STEROID ACTION AND RESISTANCE IN INFLAMMATION Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma , 2003 .

[46]  T. Ogawa,et al.  Chemical structure and immunobiological activity of lipid A from Prevotella intermedia ATCC 25611 lipopolysaccharide , 2003, FEBS letters.

[47]  John C. Lee,et al.  Restraint of Proinflammatory Cytokine Biosynthesis by Mitogen-Activated Protein Kinase Phosphatase-1 in Lipopolysaccharide-Stimulated Macrophages , 2002, The Journal of Immunology.

[48]  Elliott Bennett-Guerrero,et al.  Structure and function of lipopolysaccharides. , 2002, Microbes and infection.

[49]  Brigit VanGraafeiland,et al.  National Asthma Education and Prevention Program. , 2002, The Nurse practitioner.

[50]  M. Netea,et al.  Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? , 2002, Trends in immunology.

[51]  J. Lafitte,et al.  Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma. , 1999, American journal of respiratory and critical care medicine.

[52]  Lynn Wei,et al.  Oral Montelukast, Inhaled Beclomethasone, and Placebo for Chronic Asthma , 1999, Annals of Internal Medicine.

[53]  R. Pauwels,et al.  GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION , 1996 .

[54]  R. Martin,et al.  Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma , 1995, The Journal of experimental medicine.

[55]  S. Szefler,et al.  Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. , 1994, The Journal of clinical investigation.

[56]  W. Busse,et al.  Steroid-resistant asthma. , 1993, The Journal of allergy and clinical immunology.

[57]  P. Selecky,et al.  Position Paper on Guidelines for Fiberoptic Bronchoscopy in Adults , 1987 .

[58]  Summary and recommendations of a workshop on the investigative use of fiberoptic bronchoscopy and bronchoalveolar lavage in asthmatics. , 1985, The American review of respiratory disease.