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Randomized Controlled Trial
. 2017 Jul;140(1):63-75.
doi: 10.1016/j.jaci.2016.08.055. Epub 2016 Nov 10.

Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment

Juliana Durack  1 , Susan V Lynch  1 , Snehal Nariya  2 , Nirav R Bhakta  3 , Avraham Beigelman  4 , Mario Castro  5 , Anne-Marie Dyer  6 , Elliot Israel  7 , Monica Kraft  8 , Richard J Martin  9 , David T Mauger  6 , Sharon R Rosenberg  10 , Tonya Sharp-King  6 , Steven R White  11 , Prescott G Woodruff  3 , Pedro C Avila  10 , Loren C Denlinger  12 , Fernando Holguin  13 , Stephen C Lazarus  3 , Njira Lugogo  14 , Wendy C Moore  15 , Stephen P Peters  15 , Loretta Que  14 , Lewis J Smith  10 , Christine A Sorkness  12 , Michael E Wechsler  9 , Sally E Wenzel  13 , Homer A Boushey  16 , Yvonne J Huang  2 ; National Heart, Lung and Blood Institute's “AsthmaNet”
Affiliations
Randomized Controlled Trial

Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment

Juliana Durack et al. J Allergy Clin Immunol. 2017 Jul.

Abstract

Background: Compositional differences in the bronchial bacterial microbiota have been associated with asthma, but it remains unclear whether the findings are attributable to asthma, to aeroallergen sensitization, or to inhaled corticosteroid treatment.

Objectives: We sought to compare the bronchial bacterial microbiota in adults with steroid-naive atopic asthma, subjects with atopy but no asthma, and nonatopic healthy control subjects and to determine relationships of the bronchial microbiota to phenotypic features of asthma.

Methods: Bacterial communities in protected bronchial brushings from 42 atopic asthmatic subjects, 21 subjects with atopy but no asthma, and 21 healthy control subjects were profiled by using 16S rRNA gene sequencing. Bacterial composition and community-level functions inferred from sequence profiles were analyzed for between-group differences. Associations with clinical and inflammatory variables were examined, including markers of type 2-related inflammation and change in airway hyperresponsiveness after 6 weeks of fluticasone treatment.

Results: The bronchial microbiome differed significantly among the 3 groups. Asthmatic subjects were uniquely enriched in members of the Haemophilus, Neisseria, Fusobacterium, and Porphyromonas species and the Sphingomonodaceae family and depleted in members of the Mogibacteriaceae family and Lactobacillales order. Asthma-associated differences in predicted bacterial functions included involvement of amino acid and short-chain fatty acid metabolism pathways. Subjects with type 2-high asthma harbored significantly lower bronchial bacterial burden. Distinct changes in specific microbiota members were seen after fluticasone treatment. Steroid responsiveness was linked to differences in baseline compositional and functional features of the bacterial microbiome.

Conclusion: Even in subjects with mild steroid-naive asthma, differences in the bronchial microbiome are associated with immunologic and clinical features of the disease. The specific differences identified suggest possible microbiome targets for future approaches to asthma treatment or prevention.

Keywords: 16S ribosomal RNA; Asthma; T(H)2 inflammation; atopy; bacteria; corticosteroids; metabolic pathways; microbiome; short-chain fatty acids; three-gene mean.

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Figures

Figure 1
Figure 1
(A) Principal coordinate analysis (unweighted UniFrac) shows compositional dissimilarity between paired BB and OW samples (LME p<0.0001). (B) Phylogenetic diversity (Faith’s index) in BB and paired OW samples (& Wilcoxon matched-pairs signed rank test). (C) Phylogenetic diversity (Faith’s index) in BB samples for the three subject groups (Welch’s corrected t-test).
Figure 2
Figure 2
Bacterial taxa, significantly enriched or depleted in relative abundance (at least 2 fold; NB regression, q<0.1) in (A) AA (n=28) compared to HC (n=13); (B) ANA (n=15) compared to HC; (C) AA compared to ANA. The OTUs indicated represent the most abundant representatives within the indicated genus.
Figure 3
Figure 3
Mean difference in specific bacterial taxa between groups. Asthma-specific taxa are similarly abundant in AA compared to HC and ANA (NB regression, q<0.1). Atopy-only taxa are similarly abundant in ANA vs. both HC and AA. Taxa positively correlated (rperson≥0.5, q<0.1) with blood eosinophil counts (BEO), serum IgE (IgE) or sputum eosinophil counts (SEO) in AA (*) or ANA (#) subjects.
Figure 4
Figure 4
Mean difference in predicted KEGG orthologs (KOs) between groups. Asthma- specific pathways are similarly abundant in AA compared to HC and ANA. Atopy-only pathways are similarly abundant in ANA compared to HC and AA. Statistical significance was determined using NB regression model corrected for false discovery rate (q<0.1).
Figure 5
Figure 5
(A) AA displayed greater expression of epithelial genes induced by type 2 cytokines compared to non-asthmatic subjects. T2-high AA, with a TGM >1.117 (cut-off value indicated by a dashed line) are colored in maroon red. (B) Significantly lower bacterial burden was observed among T2-high asthma subjects. Statistical significance was determined using Wilcoxon rank sum test.
Figure 6
Figure 6
(A) Mean distance to HC (unweighted UniFrac; Bonferroni-corrected t-test). (B) Taxa significantly enriched or depleted in relative abundance (at least 2 fold; NB regression, q<0.1) in ICS-responders vs. non-responders. (C) Predicted KEGG pathways associated with xenobiotic biodegradation and metabolism in ICS-responders and non-responders. (D) Taxa, differentially expressed (at least 2-fold; ZINB regression, q<0.1) in asthmatics following ICS or placebo treatment.
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