Asthma and lower airway disease
Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma

https://doi.org/10.1016/j.jaci.2010.10.048Get rights and content

Background

Improvement in lung function after macrolide antibiotic therapy has been attributed to reduction in bronchial infection by specific bacteria. However, the airway might be populated by a more diverse microbiota, and clinical features of asthma might be associated with characteristics of the airway microbiota present.

Objective

We sought to determine whether relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria.

Methods

In this pilot study bronchial epithelial brushings were collected from 65 adults with suboptimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control and 10 healthy control subjects. A combination of high-density 16S ribosomal RNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements.

Results

Compared with control subjects, 16S ribosomal RNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae, and other bacterial families were highly correlated with the degree of bronchial hyperresponsiveness.

Conclusion: The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with suboptimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis.

Section snippets

Subjects

Bronchial epithelial samples for microbial analysis were obtained from a subset of subjects enrolled in the Macrolides in Asthma (MIA) study23 (NCT00318708, clinicaltrials.gov) conducted by the National Heart, Lung, and Blood Institute–sponsored Asthma Clinical Research Network. Briefly, adults with clinically stable but suboptimally controlled asthma, defined as persistent symptoms on the Asthma Control Questionnaire26 after 4 weeks of standardized treatment with inhaled fluticasone, were

Airway bacterial burden

Bronchial brushings were obtained from 75 subjects: 65 asthmatic patients and 10 healthy control subjects. Subjects’ characteristics are summarized in Table I. All asthmatic patients fulfilled entry criteria for the parent MIA trial,23 and samples for this pilot study were processed as they were received with no additional selection criteria applied. On initial screening, 54 (83%) of 65 asthmatic patients and 8 (80%) of 10 control subjects exhibited a visible 16S rRNA PCR product. However, not

Discussion

To our knowledge, this is the first study to examine whether specific aspects of the airway microbiota are related to relevant clinical or physiologic features of asthma. Our findings suggest that bacterial diversity, variations in community composition, and the relative abundance of specific phylotypes are associated with the degree of bronchial hyperresponsiveness in asthmatic patients administered inhaled corticosteroids (ICSs). This culture-independent study also expands the repertoire of

References (61)

  • J.L. Flanagan et al.

    Loss of bacterial diversity during antibiotic treatment of intubated patients colonized with Pseudomonas aeruginosa

    J Clin Microbiol

    (2007)
  • M. Hilty et al.

    Disordered microbial communities in asthmatic airways

    PLoS One

    (2010)
  • V. Klepac-Ceraj et al.

    Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa

    Environ Microbiol

    (2010)
  • R.G. Ledder et al.

    Molecular analysis of the subgingival microbiota in health and disease

    Appl Environ Microbiol

    (2007)
  • P.J. Turnbaugh et al.

    A core gut microbiome in obese and lean twins

    Nature

    (2009)
  • L. Wen et al.

    Innate immunity and intestinal microbiota in the development of Type 1 diabetes

    Nature

    (2008)
  • E.L. Brodie et al.

    Urban aerosols harbor diverse and dynamic bacterial populations

    Proc Natl Acad Sci U S A

    (2007)
  • L.H. Lin et al.

    Long-term sustainability of a high-energy, low-diversity crustal biome

    Science

    (2006)
  • E.L. Brodie et al.

    Application of a high-density oligonucleotide microarray approach to study bacterial population dynamics during uranium reduction and reoxidation

    Appl Environ Microbiol

    (2006)
  • U.S. Sagaram et al.

    Bacterial diversity analysis of Huanglongbing pathogen-infected citrus, using PhyloChip arrays and 16S rRNA gene clone library sequencing

    Appl Environ Microbiol

    (2009)
  • S. Schonmann et al.

    16S rRNA gene-based phylogenetic microarray for simultaneous identification of members of the genus Burkholderia

    Environ Microbiol

    (2009)
  • M.T. La Duc et al.

    Comprehensive census of bacteria in clean rooms by using DNA microarray and cloning methods

    Appl Environ Microbiol

    (2009)
  • Y.J. Huang et al.

    A persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations

    OMICS

    (2010)
  • M.J. Cox et al.

    Lactobacillus casei abundance is associated with profound shifts in the infant gut microbiome

    PLoS One

    (2010)
  • T.Z. DeSantis et al.

    High-density universal 16S rRNA microarray analysis reveals broader diversity than typical clone library when sampling the environment

    Microb Ecol

    (2007)
  • L. Dethlefsen et al.

    The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing

    PLoS Biol

    (2008)
  • Y.J. Huang et al.

    Detection of diverse bacterial populations in asthmatic airways by 16S rRNA PhyloChip [abstract]

    Am J Respir Crit Care Med

    (2008)
  • S.V. Lynch et al.

    Diverse bacterial communities in the airways of patients with sub-optimally controlled asthma [abstract]

    Am J Respir Crit Care Med

    (2010)
  • E.F. Juniper et al.

    Development and validation of a questionnaire to measure asthma control

    Eur Respir J

    (1999)
  • D.J. Lane

    16S/23S rRNA sequencing

    (1991)

    • Cited by (575)

    • Can Therapeutic Targeting of the Human Microbiome Influence Asthma Management? A Pro/Con Debate

      2024, Journal of Allergy and Clinical Immunology: In Practice

    • Lung microbiota and potential treatment of respiratory diseases

      2023, Microbial Pathogenesis

    • Alterations of nasal microbiome in eosinophilic chronic rhinosinusitis

      2023, Journal of Allergy and Clinical Immunology

    • Genomic attributes of airway commensal bacteria and mucosa

      2024, Communications Biology

    • Lung microbiome: new insights into the pathogenesis of respiratory diseases

      2024, Signal Transduction and Targeted Therapy

    • Microbes little helpers and suppliers for therapeutic asthma approaches

      2024, Respiratory Research
    View all citing articles on Scopus

    Supported by the National Heart, Lung, and Blood Institute (NHLBI; U10 HL 074204) and by the Strategic Asthma Basic Research Center at the University of California, San Francisco, supported by the Sandler Family Foundation. Y.J.H. was funded by National Institutes of Health (NIH)/NHLBI grant T32 HL007185 and by a University of California Tobacco-related Disease Research Program award (17FT-0040). C.E.N. is funded by NSF 0709975 (to C.E.N. and J.M. Melack). S.V.L. is funded by NIH/National Institute of Allergy and Infectious Diseases (NIAID) grant U01 AI075410. E.L.B., T.Z.D., and J.B. are funded under the auspices of the University of California under contract number DOE DE-AC02-05CH11231.

    Disclosure of potential conflict of interest: T. Z. DeSantis is a part-time employee of PhyloTech, Inc. J. Bristow receives research support from the DOE Joint Genome Institute. J. P. Weiner-Kronish is a board member of the Foundation of Anesthesia Education and Research. E. R. Sutherland is an advisor and DSMB member for GlaxoSmithKline, is an advisor for Dey, is a DSMB member for Merck, and receives research support from the National Institutes of Health, Novartis, and Boehringer-Ingelheim. R. J. Martin receives research support from the National Heart, Lung, and Blood Institute of the National Institutes of Health. M. Castro is a consultant for NKT Therapeutics, Schering-Plough, Asthmatx, and Cephalon; is on the Advisory Board for Genentech; is on the speakers’ bureau for Astra-Zeneca, Boehringer-Ingelheim, Pfizer, Merck, and GlaxoSmithKline; has received grant support from Asthmatx, Amgen, Ception, Genentech, MedImmune, Merck, Novartis, the National Institutes of Health, GlaxoSmithKline, and the American Lung Association; and has received royalties from Elsevier. L. C. Denlinger receives research support from the National Institutes of Health (NIH)–National Heart, Lung, and Blood Institute (NHLBI). M. Kraft has received research support from GlaxoSmithKline, Merck, Asthmatx, GE Healthcare, Novartis, and Genentech. S. P. Peters receives grant support from the NIH-NHLBI. S. I. Wasserman has provided legal consultation services/expert witness testimony in cases related to mold toxicity and transfer factor and is president of the American Board of Allergy and Immunology. M. E. Wechsler receives research support from the NHLBI. H. A. Boushey is an ad-hoc consultant for Kalobios, is on the advisory committee for Pharmaxis, is on ad-hoc advisory committees for Glaxo-SmithKline and Merck, and receives research support from GlaxoSmithKline. S. V. Lynch receives research support from the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest.

    ∗

    Investigators of the Asthma Clinical Research Network are listed in Appendix E1 in this article’s Online Repository at www.jacionline.org.

    View full text
    Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.