Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2020 Nov;146(5):1016-1026.
doi: 10.1016/j.jaci.2020.03.028. Epub 2020 Apr 13.

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma

Juliana Durack  1 , Laura S Christian  2 , Snehal Nariya  3 , Jeanmarie Gonzalez  2 , Nirav R Bhakta  3 , K Mark Ansel  2 , Avraham Beigelman  4 , Mario Castro  5 , Anne-Marie Dyer  6 , Elliot Israel  7 , Monica Kraft  8 , Richard J Martin  9 , David T Mauger  6 , Stephen P Peters  10 , Sharon R Rosenberg  11 , Christine A Sorkness  12 , Michael E Wechsler  9 , Sally E Wenzel  13 , Steven R White  14 , Susan V Lynch  1 , Homer A Boushey  3 , Yvonne J Huang  15 ; National Heart, Lung, and Blood Institute’s ”AsthmaNet“
Affiliations
Clinical Trial

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma

Juliana Durack et al. J Allergy Clin Immunol. 2020 Nov.

Abstract

Background: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown.

Objective: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma.

Methods: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines.

Results: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders.

Conclusions: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.

Keywords: Microbiome; allergic; asthma; corticosteroids; cytokines; oral; sputum; type 2 inflammation.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest: JD, LSC, SN, JG, AMD have no conflicts of interest related to this work. NRB, KMA, AB, SPP, CAS and SRW report grants from NIH. MC reports grants from NIH, ALA, personal fees from Aviragen, Boehringer-Ingelheim, Boston Scientific, Elsevier, Genentech, GSK, Holaira, and Teva and grants from Boehringer-Ingelheim, Genentech, GSK, Invion, Sanofi-Aventis, Vectura. E.I. reports personal fees from AstraZeneca, Novartis, Philips, Respironics, Regeneron Pharmaceuticals, Research in Real Life (RiRL), TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution, Pharmaceuticals, Vitaeris, Inc, Sanofi, Merck, Entrinsic Health Solutions and GlaxoSmithKline; non-financial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion and TEVA Specialty Pharmaceuticals; grants from Sanofi, Genentech and Boehringer Ingelheim. MK reports grants from NIH; personal fees from Teva Pharmaceuticals, Astra Zeneca, FDA LABA Trials Joint DSMB and Elsevier; grants from Chiesi and Sanofi. RJM reports grants from NIH, personal fees from AstraZeneca, PMD Healthcare and Respiratory Effectiveness Group; from MedImmune and CHiesi FarmaceuticiSpA. DTM reports grants from NIH; non-financial support from GlaxoSmithKIlne, Merck and Boehringer Ingelheim. MEW has received personal fees from Sepracor/Sunovion, Asthmatx/BSCI, Merck, Regeneron, MedImmune, Ambitbio, Vectura, Sanofi, Teva, Mylan, AstraZeneca, Genentech, Meda, Theravance, Novartis, Boehringer Ingelheim, GlaxoSmithKline, Tunitas, and Gliacure. SEW has received grants from Sanofi, Genentech, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim and has received personal fees from AstraZeneca, Aerocrine, GlaxoSmithKline, Actelion, and Boehringer Ingelheim. SVL reports grants from NIH/NIAID, NIH/NICHD, NIH/NIDA, Broad Foundation, Sloan Foundation, Pfizer Inc., Gilead Sciences and Janssen; personal fees from Janssen, Boston Consulting Group, Regeneron, MedImmune, Siolta Therapeutics; has a patent reductive prodrug cancer chemotherapy (Stan449-PRV) issued, a patent Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO 2010091189 A1) with royalties paid to KaloBios Inc., a patent therapeutic microbial consortium for induction of immune tolerance with royalties paid to Siolta Therapeutics, a patent systems and methods for detecting antibiotic resistance (WO 2012027302 A3) issued, a patent nitroreductase enzymes (US 7687474 B2) issued, a patent sinusitis diagnostics and treatments (WO 2013155370 A1) issued, and a patent methods and systems for phylogenetic analysis (US 20120264637 A1) issued; has Co-founded Siolta Therapeutics and is currently a board member, paid consultant for the company, and owns 25% stock. HAB has received grants including travel and lodging compensation from the NIH/NHBI and the NIH/NIAID and has received royalty payments from the McGraw-Hill Companies; he is a consultant for Siolta Therapeutics, Inc of San Francisco, CA. YJH has received grants from the NIH, the Michigan Institute of Health and Clinical Research, and travel compensation for lectures and committee work with the National Academies of Science, American Academy of Allergy, Asthma & Immunology, and the European Academy of Allergy, Asthma, and Clinical Immunology.

Figures

Figure 1:
Figure 1:
Mean difference in relative abundance (mean sequence reads) of specific bacterial taxa present in IS and OW in the two-group comparisons shown (negative binomial regression model q<0.1). Each dot represents a unique OTU within a given bacterial genus. Maroon colored circles highlight taxa most likely to be asthma-associated (i.e. similarly enriched or depleted in AA vs. ANA or HC). Blue colored circles highlight taxa most likely to be atopy-associated (i.e. similarly enriched or depleted in AA and ANA vs. HC).
Figure 2:
Figure 2:
A. Greater expression of airway epithelial genes induced by type 2 (T2) cytokines was observed in AA subjects, particularly in T2-high AAs (n=9) with a TGM of 1.117 or greater (cutoff value indicated by a dashed line; Mann-Whitney test). B. Bacterial burden in IS of T2-high (n=9) and T2-low (n=22) AA subjects (Mann-Whitney test). C. Faith’s Phylogenetic Diversity (PD) in IS samples of T2-high or -low AA subjects (Mann-Whitney test). D. Comparison of bacterial composition (Weighted UniFrac) in IS of T2-high and T2-low AAs to that of non-asthmatic controls (Bonferroni corrected t-test; p>0.1 not shown). E. Mean difference in relative abundance of specific bacterial taxa present in IS of T2-high vs. T2-low AA subjects. Each dot represents a unique OTU within a given bacterial genus (negative binomial regression model q<0.1).
Figure 3:
Figure 3:
Altered bacterial microbiota composition of IS among ‘T2-low’ AA subjects with elevated BAL inflammatory cytokines. A. BAL inflammatory cytokines differentiated T2-low AA subjects into two distinct clusters. Subjects in inflammatory cytokine cluster (ICC) 1 (n=5) exhibited greater airway inflammation compared to ICC2 (n=18). B. Bacterial diversity and evenness was lower in IS samples of T2-low ICC1 AAs vs. ICC2 AAs (Mann-Whitney test). C. Relative abundance of bacterial genera in IS which differentiated ICC1 and ICC2 AA subjects (Mann-Whitney test, FDR adjusted q-values).
Figure 4:
Figure 4:
A. ICS non-responder (ICSNR) subjects showed significantly greater change in paired weighted UniFrac distance in IS, but not OW samples, compared to ICS responders (ICSR; Mann-Whitney test). B. Mean difference in relative abundance of specific bacterial taxa present in IS of ICSR subjects (n=12) and ICSNR (n=8), pre- and post-intervention or in placebo-treated asthmatic subjects (n=10). Each dot represents a unique OTU within a given bacterial genus and whether it is enriched or depleted in the respective pre- or post-intervention sample (negative binomial regression model q<0.1).
See this image and copyright information in PMC

References

    1. Denner DR, Sangwan N, Becker JB, Hogarth DK, Oldham J, Castillo J, et al. Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways. The Journal of allergy and clinical immunology. 2015;137(5):1398–405.e3. - PMC - PubMed
    1. Durack J, Boushey HA, Lynch SV. Airway Microbiota and the Implications of Dysbiosis in Asthma. Current allergy and asthma reports. 2016;16(8):52. - PubMed
    1. Durack J, Lynch SV, Nariya S, Bhakta NR, Beigelman A, Castro M, et al. Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. The Journal of allergy and clinical immunology. 2017;140(1):63–75. - PMC - PubMed
    1. Goleva E, Jackson LP, Kirk Harris J, Robertson CE, Sutherland ER, Hall CF, et al. The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma. Am J Respir Crit Care Med. 2013;188(10):1193–201. - PMC - PubMed
    1. Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, et al. Disordered Microbial Communities in Asthmatic Airways. PLoS One. 2010;5(1):e8578. - PMC - PubMed

Publication types

Associated data