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Microbiome in the pathogenesis of cystic fibrosis and lung transplant-related disease

  • Sushma K. Cribbs
    Correspondence
    Reprint requests: Sushma K. Cribbs, Department of Veterans Affairs Medical Center, Pulmonary Medicine, 1670 Clairmont Rd, Mailstop 151p, Decatur, GA 30033
    Affiliations
    Division of Pulmonary, Allergy, Critical Care and Sleep, Department of Medicine, Emory University School of Medicine, Atlanta, Ga

    Atlanta Veterans Affairs Medical Center, Decatur, Ga
    Search for articles by this author
  • James M. Beck
    Affiliations
    Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado School of Medicine, Aurora, Colo

    Veterans Affairs Eastern Colorado Health Care System, Denver, Colo
    Search for articles by this author
Published:August 03, 2016DOI:https://doi.org/10.1016/j.trsl.2016.07.022
      Significant advances in culture-independent methods have expanded our knowledge about the diversity of the lung microbial environment. Complex microorganisms and microbial communities can now be identified in the distal airways in a variety of respiratory diseases, including cystic fibrosis (CF) and the posttransplantation lung. Although there are significant methodologic concerns about sampling the lung microbiome, several studies have now shown that the microbiome of the lower respiratory tract is distinct from the upper airway. CF is a disease characterized by chronic airway infections that lead to significant morbidity and mortality. Traditional culture–dependent methods have identified a select group of pathogens that cause exacerbations in CF, but studies using bacterial 16S rRNA gene–based microarrays have shown that the CF microbiome is an intricate and dynamic bacterial ecosystem, which influences both host immune health and disease pathogenesis. These microbial communities can shift with external influences, including antibiotic exposure. In addition, there have been a number of studies suggesting a link between the gut microbiome and respiratory health in CF. Compared with CF, there is significantly less knowledge about the microbiome of the transplanted lung. Risk factors for bronchiolitis obliterans syndrome, one of the leading causes of death, include microbial infections. Lung transplant patients have a unique lung microbiome that is different than the pretransplanted microbiome and changes with time. Understanding the host-pathogen interactions in these diseases may suggest targeted therapies and improve long-term survival in these patients.

      Abbreviations:

      CF (cystic fibrosis), BOS (bronchiolitis obliterans syndrome), rRNA (ribosomal small subunit RNA), HIV (human immunodeficiency virus-1), COPD (chronic obstructive pulmonary disease), CFTR (CF transmembrane conductance regulator), BAL (bronchoalveolar lavage), OP (oropharyngeal), IS (induced sputum), ES (expectorated sputum), GI (gastrointestinal), OW (oral wash)
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      References

        • National Institutes of Health
        Human Microbiome Project.
        The NIH Common Fund. Division of Program Coordination, Planning, and Strategic Initiatives, Bethesda, Maryland, 2016 (Available at:) (Accessed July 26, 2016)
        • Proctor L.M.
        The Human Microbiome Project in 2011 and beyond.
        Cell Host Microbe. 2011; 10: 287-291
        • Morris A.
        • Beck J.M.
        • Schloss P.D.
        • et al.
        Comparison of the respiratory microbiome in healthy nonsmokers and smokers.
        Am J Respir Crit Care Med. 2013; 187: 1067-1075
        • Hayashi H.
        • Sakamoto M.
        • Benno Y.
        Phylogenetic analysis of the human gut microbiota using 16S rDNA clone libraries and strictly anaerobic culture-based methods.
        Microbiol Immunol. 2002; 46: 535-548
        • Sibley C.D.
        • Grinwis M.E.
        • Field T.R.
        • et al.
        Culture enriched molecular profiling of the cystic fibrosis airway microbiome.
        PLoS One. 2011; 6: e22702
        • Lynch S.V.
        • Bruce K.D.
        The cystic fibrosis airway microbiome.
        Cold Spring Harb Perspect Med. 2013; 3: a009738
        • Surette M.G.
        The cystic fibrosis lung microbiome.
        Ann Am Thorac Soc. 2014; 11: S61-S65
        • Whelan F.J.
        • Surette M.G.
        Clinical insights into pulmonary exacerbations in cystic fibrosis from the microbiome. What Are We Missing?.
        Ann Am Thorac Soc. 2015; 12: S207-S211
        • Huse S.M.
        • Ye Y.
        • Zhou Y.
        • Fodor A.A.
        A core human microbiome as viewed through 16S rRNA sequence clusters.
        PLoS One. 2012; 7: e34242
        • Dickson R.P.
        • Erb-Downward J.R.
        • Huffnagle G.B.
        Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis.
        Lancet Respir Med. 2014; 2: 238-246
        • Willner D.
        • Haynes M.R.
        • Furlan M.
        • et al.
        Spatial distribution of microbial communities in the cystic fibrosis lung.
        ISME J. 2012; 6: 471-474
        • Erb-Downward J.R.
        • Thompson D.L.
        • Han M.K.
        • et al.
        Analysis of the lung microbiome in the “healthy” smoker and in COPD.
        PLoS One. 2011; 6: e16384
        • Harris J.K.
        • De Groote M.A.
        • Sagel S.D.
        • et al.
        Molecular identification of bacteria in bronchoalveolar lavage fluid from children with cystic fibrosis.
        Proc Natl Acad Sci U S A. 2007; 104: 20529-20533
        • Charlson E.S.
        • Bittinger K.
        • Haas A.R.
        • et al.
        Topographical continuity of bacterial populations in the healthy human respiratory tract.
        Am J Respir Crit Care Med. 2011; 184: 957-963
        • Rogers G.B.
        • Carroll M.P.
        • Serisier D.J.
        • et al.
        Use of 16S rRNA gene profiling by terminal restriction fragment length polymorphism analysis to compare bacterial communities in sputum and mouthwash samples from patients with cystic fibrosis.
        J Clin Microbiol. 2006; 44: 2601-2604
        • Goddard A.F.
        • Staudinger B.J.
        • Dowd S.E.
        • et al.
        Direct sampling of cystic fibrosis lungs indicates that DNA-based analyses of upper-airway specimens can misrepresent lung microbiota.
        Proc Natl Acad Sci U S A. 2012; 109: 13769-13774
        • Zemanick E.T.
        • Wagner B.D.
        • Robertson C.E.
        • et al.
        Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods.
        Ann Am Thorac Soc. 2015; 12: 221-229
        • Hogan D.A.
        • Willger S.D.
        • Dolben E.L.
        • et al.
        Analysis of lung microbiota in bronchoalveolar lavage, protected brush and sputum samples from subjects with mild-to-moderate cystic fibrosis lung disease.
        PLoS One. 2016; 11: e0149998
        • Rowntree R.K.
        • Harris A.
        The phenotypic consequences of CFTR mutations.
        Ann Hum Genet. 2003; 67: 471-485
        • O'Sullivan B.P.
        • Freedman S.D.
        Cystic fibrosis.
        Lancet. 2009; 373: 1891-1904
        • Rowe S.M.
        • Miller S.
        • Sorscher E.J.
        Cystic fibrosis.
        N Engl J Med. 2005; 352: 1992-2001
        • Gibson R.L.
        • Burns J.L.
        • Ramsey B.W.
        Pathophysiology and management of pulmonary infections in cystic fibrosis.
        Am J Respir Crit Care Med. 2003; 168: 918-951
        • Lyczak J.B.
        • Cannon C.L.
        • Pier G.B.
        Lung infections associated with cystic fibrosis.
        Clin Microbiol Rev. 2002; 15: 194-222
        • Govan J.R.
        • Deretic V.
        Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia.
        Microbiol Rev. 1996; 60: 539-574
        • Burkett A.
        • Vandemheen K.L.
        • Giesbrecht-Lewis T.
        • et al.
        Persistency of Pseudomonas aeruginosa in sputum cultures and clinical outcomes in adult patients with cystic fibrosis.
        Eur J Clin Microbiol Infect Dis. 2012; 31: 1603-1610
        • Razvi S.
        • Quittell L.
        • Sewall A.
        • Quinton H.
        • Marshall B.
        • Saiman L.
        Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005.
        Chest. 2009; 136: 1554-1560
        • Lipuma J.J.
        The changing microbial epidemiology in cystic fibrosis.
        Clin Microbiol Rev. 2010; 23: 299-323
        • Dasenbrook E.C.
        • Checkley W.
        • Merlo C.A.
        • Konstan M.W.
        • Lechtzin N.
        • Boyle M.P.
        Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis.
        JAMA. 2010; 303: 2386-2392
        • Chmiel J.F.
        • Aksamit T.R.
        • Chotirmall S.H.
        • et al.
        Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi.
        Ann Am Thorac Soc. 2014; 11: 1298-1306
        • Tunney M.M.
        • Klem E.R.
        • Fodor A.A.
        • et al.
        Use of culture and molecular analysis to determine the effect of antibiotic treatment on microbial community diversity and abundance during exacerbation in patients with cystic fibrosis.
        Thorax. 2011; 66: 579-584
        • Ghorbani P.
        • Santhakumar P.
        • Hu Q.
        • et al.
        Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth.
        Eur Respir J. 2015; 46: 1033-1045
        • O'Neill K.
        • Bradley J.M.
        • Johnston E.
        • et al.
        Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis.
        PLoS One. 2015; 10: e0126980
        • Duan K.
        • Dammel C.
        • Stein J.
        • Rabin H.
        • Surette M.G.
        Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication.
        Mol Microbiol. 2003; 50: 1477-1491
        • Zemanick E.T.
        • Wagner B.D.
        • Harris J.K.
        • Wagener J.S.
        • Accurso F.J.
        • Sagel S.D.
        Pulmonary exacerbations in cystic fibrosis with negative bacterial cultures.
        Pediatr Pulmonol. 2010; 45: 569-577
        • Cox M.J.
        • Allgaier M.
        • Taylor B.
        • et al.
        Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients.
        PLoS One. 2010; 5: e11044
        • Guss A.M.
        • Roeselers G.
        • Newton I.L.
        • et al.
        Phylogenetic and metabolic diversity of bacteria associated with cystic fibrosis.
        ISME J. 2011; 5: 20-29
        • van der Gast C.J.
        • Walker A.W.
        • Stressmann F.A.
        • et al.
        Partitioning core and satellite taxa from within cystic fibrosis lung bacterial communities.
        ISME J. 2011; 5: 780-791
        • Douglas T.A.
        • Brennan S.
        • Gard S.
        • et al.
        Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis.
        Eur Respir J. 2009; 33: 305-311
        • Ramsey K.A.
        • Ranganathan S.
        • Park J.
        • et al.
        Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis.
        Am J Respir Crit Care Med. 2014; 190: 1111-1116
        • Gangell C.
        • Gard S.
        • Douglas T.
        • et al.
        Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis.
        Clin Infect Dis. 2011; 53: 425-432
        • Sly P.D.
        • Gangell C.L.
        • Chen L.
        • et al.
        Risk factors for bronchiectasis in children with cystic fibrosis.
        N Engl J Med. 2013; 368: 1963-1970
        • Linnane B.M.
        • Hall G.L.
        • Nolan G.
        • et al.
        Lung function in infants with cystic fibrosis diagnosed by newborn screening.
        Am J Respir Crit Care Med. 2008; 178: 1238-1244
        • Sibley C.D.
        • Rabin H.
        • Surette M.G.
        Cystic fibrosis: a polymicrobial infectious disease.
        Future Microbiol. 2006; 1: 53-61
        • Armstrong D.S.
        • Grimwood K.
        • Carlin J.B.
        • et al.
        Lower airway inflammation in infants and young children with cystic fibrosis.
        Am J Respir Crit Care Med. 1997; 156: 1197-1204
        • Sly P.D.
        • Brennan S.
        • Gangell C.
        • et al.
        Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening.
        Am J Respir Crit Care Med. 2009; 180: 146-152
        • Stressmann F.A.
        • Rogers G.B.
        • van der Gast C.J.
        • et al.
        Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience.
        Thorax. 2012; 67: 867-873
        • Zhao J.
        • Schloss P.D.
        • Kalikin L.M.
        • et al.
        Decade-long bacterial community dynamics in cystic fibrosis airways.
        Proc Natl Acad Sci U S A. 2012; 109: 5809-5814
        • Klepac-Ceraj V.
        • Lemon K.P.
        • Martin T.R.
        • et al.
        Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa.
        Environ Microbiol. 2010; 12: 1293-1303
        • Fodor A.A.
        • Klem E.R.
        • Gilpin D.F.
        • et al.
        The adult cystic fibrosis airway microbiota is stable over time and infection type, and highly resilient to antibiotic treatment of exacerbations.
        PLoS One. 2012; 7: e45001
        • Zhao J.
        • Murray S.
        • Lipuma J.J.
        Modeling the impact of antibiotic exposure on human microbiota.
        Sci Rep. 2014; 4: 4345
        • Hoen A.G.
        • Li J.
        • Moulton L.A.
        • et al.
        Associations between gut microbial colonization in early life and respiratory outcomes in cystic fibrosis.
        J Pediatr. 2015; 167: 138-147
        • Madan J.C.
        • Koestler D.C.
        • Stanton B.A.
        • et al.
        Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures.
        MBio. 2012; 3
        • Rogers G.B.
        • Carroll M.P.
        • Hoffman L.R.
        • Walker A.W.
        • Fine D.A.
        • Bruce K.D.
        Comparing the microbiota of the cystic fibrosis lung and human gut.
        Gut Microbes. 2010; 1: 85-93
        • Kahl B.C.
        Impact of Staphylococcus aureus on the pathogenesis of chronic cystic fibrosis lung disease.
        Int J Med Microbiol. 2010; 300: 514-519
        • Prevaes S.M.
        • de Winter-de Groot K.M.
        • Janssens H.M.
        • et al.
        Development of the nasopharyngeal microbiota in infants with cystic fibrosis.
        Am J Respir Crit Care Med. 2016; 193: 504-515
        • Regev-Yochay G.
        • Dagan R.
        • Raz M.
        • et al.
        Association between carriage of Streptococcus pneumoniae and Staphylococcus aureus in children.
        JAMA. 2004; 292: 716-720
        • Jain K.
        • Wainwright C.
        • Smyth A.R.
        Bronchoscopy-guided antimicrobial therapy for cystic fibrosis.
        Cochrane Database Syst Rev. 2013; 12: CD009530
        • Rosenfeld M.
        • Emerson J.
        • Accurso F.
        • et al.
        Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis.
        Pediatr Pulmonol. 1999; 28: 321-328
        • Brown P.S.
        • Pope C.E.
        • Marsh R.L.
        • et al.
        Directly sampling the lung of a young child with cystic fibrosis reveals diverse microbiota.
        Ann Am Thorac Soc. 2014; 11: 1049-1055
        • Hampton T.H.
        • Green D.M.
        • Cutting G.R.
        • et al.
        The microbiome in pediatric cystic fibrosis patients: the role of shared environment suggests a window of intervention.
        Microbiome. 2014; 2: 14
      1. Cystic Fibrosis Foundation Patient Registry 2013 Annual Data Report. Available at: https://www.cff.org/2013_CFF_Patient_Registry_Annual_Data_Report.pdf. Accessed March 7, 2016. 2016. Ref Type: Generic.

        • Quon B.S.
        • Aitken M.L.
        Cystic fibrosis: what to expect now in the early adult years.
        Paediatr Respir Rev. 2012; 13: 206-214
        • Dunbar J.
        • Ticknor L.O.
        • Kuske C.R.
        Assessment of microbial diversity in four southwestern United States soils by 16S rRNA gene terminal restriction fragment analysis.
        Appl Environ Microbiol. 2000; 66: 2943-2950
        • Rogers G.B.
        • Hart C.A.
        • Mason J.R.
        • Hughes M.
        • Walshaw M.J.
        • Bruce K.D.
        Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling.
        J Clin Microbiol. 2003; 41: 3548-3558
        • Rogers G.B.
        • Carroll M.P.
        • Serisier D.J.
        • Hockey P.M.
        • Jones G.
        • Bruce K.D.
        Characterization of bacterial community diversity in cystic fibrosis lung infections by use of 16s ribosomal DNA terminal restriction fragment length polymorphism profiling.
        J Clin Microbiol. 2004; 42: 5176-5183
        • Carmody L.A.
        • Zhao J.
        • Kalikin L.M.
        • et al.
        The daily dynamics of cystic fibrosis airway microbiota during clinical stability and at exacerbation.
        Microbiome. 2015; 3: 12
        • Coburn B.
        • Wang P.W.
        • Diaz C.J.
        • et al.
        Lung microbiota across age and disease stage in cystic fibrosis.
        Sci Rep. 2015; 5: 10241
        • Zemanick E.T.
        • Harris J.K.
        • Wagner B.D.
        • et al.
        Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.
        PLoS One. 2013; 8: e62917
        • Field T.R.
        • Sibley C.D.
        • Parkins M.D.
        • Rabin H.R.
        • Surette M.G.
        The genus Prevotella in cystic fibrosis airways.
        Anaerobe. 2010; 16: 337-344
        • Tunney M.M.
        • Field T.R.
        • Moriarty T.F.
        • et al.
        Detection of anaerobic bacteria in high numbers in sputum from patients with cystic fibrosis.
        Am J Respir Crit Care Med. 2008; 177: 995-1001
        • Worlitzsch D.
        • Rintelen C.
        • Bohm K.
        • et al.
        Antibiotic-resistant obligate anaerobes during exacerbations of cystic fibrosis patients.
        Clin Microbiol Infect. 2009; 15: 454-460
        • Hassett D.J.
        • Sutton M.D.
        • Schurr M.J.
        • Herr A.B.
        • Caldwell C.C.
        • Matu J.O.
        Pseudomonas aeruginosa hypoxic or anaerobic biofilm infections within cystic fibrosis airways.
        Trends Microbiol. 2009; 17: 130-138
        • Zemanick E.T.
        • Wagner B.D.
        • Sagel S.D.
        • Stevens M.J.
        • Accurso F.J.
        • Harris J.K.
        Reliability of quantitative real-time PCR for bacterial detection in cystic fibrosis airway specimens.
        PLoS One. 2010; 5: e15101
        • Stokell J.R.
        • Gharaibeh R.Z.
        • Hamp T.J.
        • Zapata M.J.
        • Fodor A.A.
        • Steck T.R.
        Analysis of changes in diversity and abundance of the microbial community in a cystic fibrosis patient over a multiyear period.
        J Clin Microbiol. 2015; 53: 237-247
        • Mowat E.
        • Paterson S.
        • Fothergill J.L.
        • et al.
        Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis chronic infections.
        Am J Respir Crit Care Med. 2011; 183: 1674-1679
        • Workentine M.L.
        • Sibley C.D.
        • Glezerson B.
        • et al.
        Phenotypic heterogeneity of Pseudomonas aeruginosa populations in a cystic fibrosis patient.
        PLoS One. 2013; 8: e60225
        • Goffard A.
        • Lambert V.
        • Salleron J.
        • et al.
        Virus and cystic fibrosis: rhinoviruses are associated with exacerbations in adult patients.
        J Clin Virol. 2014; 60: 147-153
        • Willger S.D.
        • Grim S.L.
        • Dolben E.L.
        • et al.
        Characterization and quantification of the fungal microbiome in serial samples from individuals with cystic fibrosis.
        Microbiome. 2014; 2: 40
        • Rogers G.B.
        • Marsh P.
        • Stressmann A.F.
        • et al.
        The exclusion of dead bacterial cells is essential for accurate molecular analysis of clinical samples.
        Clin Microbiol Infect. 2010; 16: 1656-1658
        • Zhao J.
        • Carmody L.A.
        • Kalikin L.M.
        • et al.
        Impact of enhanced Staphylococcus DNA extraction on microbial community measures in cystic fibrosis sputum.
        PLoS One. 2012; 7: e33127
        • Flume P.A.
        • Mogayzel Jr., P.J.
        • Robinson K.A.
        • et al.
        Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.
        Am J Respir Crit Care Med. 2009; 180: 802-808
        • de B.K.
        • Vandemheen K.L.
        • Tullis E.
        • et al.
        Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis.
        Thorax. 2011; 66: 680-685
        • Waters V.
        • Stanojevic S.
        • Atenafu E.G.
        • et al.
        Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis.
        Eur Respir J. 2012; 40: 61-66
        • Lam J.C.
        • Somayaji R.
        • Surette M.G.
        • Rabin H.R.
        • Parkins M.D.
        Reduction in Pseudomonas aeruginosa sputum density during a cystic fibrosis pulmonary exacerbation does not predict clinical response.
        BMC Infect Dis. 2015; 15: 145
        • Sibley C.D.
        • Parkins M.D.
        • Rabin H.R.
        • Surette M.G.
        The relevance of the polymicrobial nature of airway infection in the acute and chronic management of patients with cystic fibrosis.
        Curr Opin Investig Drugs. 2009; 10: 787-794
        • Hoffman L.R.
        • Deziel E.
        • D'Argenio D.A.
        • et al.
        Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa.
        Proc Natl Acad Sci U S A. 2006; 103: 19890-19895
        • Schwab U.
        • Abdullah L.H.
        • Perlmutt O.S.
        • et al.
        Localization of Burkholderia cepacia complex bacteria in cystic fibrosis lungs and interactions with Pseudomonas aeruginosa in hypoxic mucus.
        Infect Immun. 2014; 82: 4729-4745
        • Tomlin K.L.
        • Coll O.P.
        • Ceri H.
        Interspecies biofilms of Pseudomonas aeruginosa and Burkholderia cepacia.
        Can J Microbiol. 2001; 47: 949-954
        • Burmolle M.
        • Thomsen T.R.
        • Fazli M.
        • et al.
        Biofilms in chronic infections - a matter of opportunity - monospecies biofilms in multispecies infections.
        FEMS Immunol Med Microbiol. 2010; 59: 324-336
        • Magalhaes A.P.
        • Azevedo N.F.
        • Pereira M.O.
        • Lopes S.P.
        The cystic fibrosis microbiome in an ecological perspective and its impact in antibiotic therapy.
        Appl Microbiol Biotechnol. 2016; 100: 1163-1181
        • Price K.E.
        • Hampton T.H.
        • Gifford A.H.
        • et al.
        Unique microbial communities persist in individual cystic fibrosis patients throughout a clinical exacerbation.
        Microbiome. 2013; 1: 27
        • Carmody L.A.
        • Zhao J.
        • Schloss P.D.
        • et al.
        Changes in cystic fibrosis airway microbiota at pulmonary exacerbation.
        Ann Am Thorac Soc. 2013; 10: 179-187
        • Walker A.W.
        • Sanderson J.D.
        • Churcher C.
        • et al.
        High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease.
        BMC Microbiol. 2011; 11: 7
        • Biesbroek G.
        • Tsivtsivadze E.
        • Sanders E.A.
        • et al.
        Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.
        Am J Respir Crit Care Med. 2014; 190: 1283-1292
        • Bargon J.
        • Dauletbaev N.
        • Kohler B.
        • Wolf M.
        • Posselt H.G.
        • Wagner T.O.
        Prophylactic antibiotic therapy is associated with an increased prevalence of Aspergillus colonization in adult cystic fibrosis patients.
        Respir Med. 1999; 93: 835-838
        • Baxter C.G.
        • Rautemaa R.
        • Jones A.M.
        • et al.
        Intravenous antibiotics reduce the presence of Aspergillus in adult cystic fibrosis sputum.
        Thorax. 2013; 68: 652-657
        • Palmer C.
        • Bik E.M.
        • DiGiulio D.B.
        • Relman D.A.
        • Brown P.O.
        Development of the human infant intestinal microbiota.
        PLoS Biol. 2007; 5: e177
        • Gill S.R.
        • Pop M.
        • Deboy R.T.
        • et al.
        Metagenomic analysis of the human distal gut microbiome.
        Science. 2006; 312: 1355-1359
        • Ley R.E.
        • Hamady M.
        • Lozupone C.
        • et al.
        Evolution of mammals and their gut microbes.
        Science. 2008; 320: 1647-1651
        • Yatsunenko T.
        • Rey F.E.
        • Manary M.J.
        • et al.
        Human gut microbiome viewed across age and geography.
        Nature. 2012; 486: 222-227
        • Ivanov I.I.
        • Atarashi K.
        • Manel N.
        • et al.
        Induction of intestinal Th17 cells by segmented filamentous bacteria.
        Cell. 2009; 139: 485-498
        • De F.C.
        • Cavalieri D.
        • Di P.M.
        • et al.
        Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
        Proc Natl Acad Sci U S A. 2010; 107: 14691-14696
        • Turnbaugh P.J.
        • Backhed F.
        • Fulton L.
        • Gordon J.I.
        Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.
        Cell Host Microbe. 2008; 3: 213-223
        • De Lisle R.C.
        • Borowitz D.
        The cystic fibrosis intestine.
        Cold Spring Harb Perspect Med. 2013; 3: a009753
        • Gelfond D.
        • Borowitz D.
        Gastrointestinal complications of cystic fibrosis.
        Clin Gastroenterol Hepatol. 2013; 11: 333-342
        • Lynch S.V.
        • Goldfarb K.C.
        • Wild Y.K.
        • Kong W.
        • De Lisle R.C.
        • Brodie E.L.
        Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota.
        Gut Microbes. 2013; 4: 41-47
        • Schippa S.
        • Iebba V.
        • Santangelo F.
        • et al.
        Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients.
        PLoS One. 2013; 8: e61176
        • Hoffman L.R.
        • Pope C.E.
        • Hayden H.S.
        • et al.
        Escherichia coli dysbiosis correlates with gastrointestinal dysfunction in children with cystic fibrosis.
        Clin Infect Dis. 2014; 58: 396-399
        • Duytschaever G.
        • Huys G.
        • Bekaert M.
        • Boulanger L.
        • De B.K.
        • Vandamme P.
        Cross-sectional and longitudinal comparisons of the predominant fecal microbiota compositions of a group of pediatric patients with cystic fibrosis and their healthy siblings.
        Appl Environ Microbiol. 2011; 77: 8015-8024
        • Backhed F.
        • Roswall J.
        • Peng Y.
        • et al.
        Dynamics and stabilization of the human gut microbiome during the first year of life.
        Cell Host Microbe. 2015; 17: 690-703
        • Orens J.B.
        • Garrity Jr., E.R.
        General overview of lung transplantation and review of organ allocation.
        Proc Am Thorac Soc. 2009; 6: 13-19
        • Yusen R.D.
        • Christie J.D.
        • Edwards L.B.
        • et al.
        The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report–2013; focus theme: age.
        J Heart Lung Transplant. 2013; 32: 965-978
        • Christie J.D.
        • Edwards L.B.
        • Kucheryavaya A.Y.
        • et al.
        The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012.
        J Heart Lung Transplant. 2012; 31: 1073-1086
        • Verleden G.M.
        Chronic allograft rejection (obliterative bronchiolitis).
        Semin Respir Crit Care Med. 2001; 22: 551-558
        • Jaramillo A.
        • Fernandez F.G.
        • Kuo E.Y.
        • Trulock E.P.
        • Patterson G.A.
        • Mohanakumar T.
        Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation.
        Pediatr Transplant. 2005; 9: 84-93
        • Estenne M.
        • Hertz M.I.
        Bronchiolitis obliterans after human lung transplantation.
        Am J Respir Crit Care Med. 2002; 166: 440-444
        • Verleden G.M.
        • Dupont L.J.
        • Van Raemdonck D.E.
        Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal?.
        Eur Respir J. 2005; 25: 221-224
        • Willner D.L.
        • Hugenholtz P.
        • Yerkovich S.T.
        • et al.
        Reestablishment of recipient-associated microbiota in the lung allograft is linked to reduced risk of bronchiolitis obliterans syndrome.
        Am J Respir Crit Care Med. 2013; 187: 640-647
        • Glanville A.R.
        • Aboyoun C.L.
        • Havryk A.
        • Plit M.
        • Rainer S.
        • Malouf M.A.
        Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation.
        Am J Respir Crit Care Med. 2008; 177: 1033-1040
        • Hopkins P.M.
        • Aboyoun C.L.
        • Chhajed P.N.
        • et al.
        Association of minimal rejection in lung transplant recipients with obliterative bronchiolitis.
        Am J Respir Crit Care Med. 2004; 170: 1022-1026
        • Husain A.N.
        • Siddiqui M.T.
        • Holmes E.W.
        • et al.
        Analysis of risk factors for the development of bronchiolitis obliterans syndrome.
        Am J Respir Crit Care Med. 1999; 159: 829-833
        • Botha P.
        • Archer L.
        • Anderson R.L.
        • et al.
        Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome.
        Transplantation. 2008; 85: 771-774
        • Khalifah A.P.
        • Hachem R.R.
        • Chakinala M.M.
        • et al.
        Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death.
        Am J Respir Crit Care Med. 2004; 170: 181-187
        • Kotsimbos T.C.
        • Snell G.I.
        • Levvey B.
        • et al.
        Chlamydia pneumoniae serology in donors and recipients and the risk of bronchiolitis obliterans syndrome after lung transplantation.
        Transplantation. 2005; 79: 269-275
        • Weigt S.S.
        • Elashoff R.M.
        • Huang C.
        • et al.
        Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.
        Am J Transplant. 2009; 9: 1903-1911
        • Gerhardt S.G.
        • McDyer J.F.
        • Girgis R.E.
        • Conte J.V.
        • Yang S.C.
        • Orens J.B.
        Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study.
        Am J Respir Crit Care Med. 2003; 168: 121-125
        • Jain R.
        • Hachem R.R.
        • Morrell M.R.
        • et al.
        Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome.
        J Heart Lung Transplant. 2010; 29: 531-537
        • Vos R.
        • Vanaudenaerde B.M.
        • Verleden S.E.
        • et al.
        A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.
        Eur Respir J. 2011; 37: 164-172
        • Nakajima T.
        • Palchevsky V.
        • Perkins D.L.
        • Belperio J.A.
        • Finn P.W.
        Lung transplantation: infection, inflammation, and the microbiome.
        Semin Immunopathol. 2011; 33: 135-156
        • Atkins B.Z.
        • Trachtenberg M.S.
        • Prince-Petersen R.
        • et al.
        Assessing oropharyngeal dysphagia after lung transplantation: altered swallowing mechanisms and increased morbidity.
        J Heart Lung Transplant. 2007; 26: 1144-1148
        • Robertson A.G.
        • Griffin S.M.
        • Murphy D.M.
        • et al.
        Targeting allograft injury and inflammation in the management of post-lung transplant bronchiolitis obliterans syndrome.
        Am J Transplant. 2009; 9: 1272-1278
        • Speich R.
        • van der Bij W.
        Epidemiology and management of infections after lung transplantation.
        Clin Infect Dis. 2001; 33: S58-S65
        • Duncan M.D.
        • Wilkes D.S.
        Transplant-related immunosuppression: a review of immunosuppression and pulmonary infections.
        Proc Am Thorac Soc. 2005; 2: 449-455
        • Kotloff R.M.
        • Thabut G.
        Lung transplantation.
        Am J Respir Crit Care Med. 2011; 184: 159-171
        • Aguilar-Guisado M.
        • Givalda J.
        • Ussetti P.
        • et al.
        Pneumonia after lung transplantation in the RESITRA Cohort: a multicenter prospective study.
        Am J Transplant. 2007; 7: 1989-1996
        • Palacio F.
        • Reyes L.F.
        • Levine D.J.
        • et al.
        Understanding the concept of health care-associated pneumonia in lung transplant recipients.
        Chest. 2015; 148: 516-522
        • Palmer S.M.
        • Burch L.H.
        • Trindade A.J.
        • et al.
        Innate immunity influences long-term outcomes after human lung transplant.
        Am J Respir Crit Care Med. 2005; 171: 780-785
        • Riera J.
        • Caralt B.
        • Lopez I.
        • et al.
        Ventilator-associated respiratory infection following lung transplantation.
        Eur Respir J. 2015; 45: 726-737
        • Sharples L.D.
        • McNeil K.
        • Stewart S.
        • Wallwork J.
        Risk factors for bronchiolitis obliterans: a systematic review of recent publications.
        J Heart Lung Transplant. 2002; 21: 271-281
        • Valentine V.G.
        • Bonvillain R.W.
        • Gupta M.R.
        • et al.
        Infections in lung allograft recipients: ganciclovir era.
        J Heart Lung Transplant. 2008; 27: 528-535
        • Round J.L.
        • Mazmanian S.K.
        The gut microbiota shapes intestinal immune responses during health and disease.
        Nat Rev Immunol. 2009; 9: 313-323
        • Dickson R.P.
        • Erb-Downward J.R.
        • Freeman C.M.
        • et al.
        Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations.
        PLoS One. 2014; 9: e97214
        • Borewicz K.
        • Pragman A.A.
        • Kim H.B.
        • Hertz M.
        • Wendt C.
        • Isaacson R.E.
        Longitudinal analysis of the lung microbiome in lung transplantation.
        FEMS Microbiol Lett. 2013; 339: 57-65
        • Charlson E.S.
        • Diamond J.M.
        • Bittinger K.
        • et al.
        Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant.
        Am J Respir Crit Care Med. 2012; 186: 536-545
        • Lozupone C.
        • Knight R.
        UniFrac: a new phylogenetic method for comparing microbial communities.
        Appl Environ Microbiol. 2005; 71: 8228-8235
        • D'Ovidio F.
        • Mura M.
        • Tsang M.
        • et al.
        Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation.
        J Thorac Cardiovasc Surg. 2005; 129: 1144-1152
        • Herve P.
        • Silbert D.
        • Cerrina J.
        • Simonneau G.
        • Dartevelle P.
        Impairment of bronchial mucociliary clearance in long-term survivors of heart/lung and double-lung transplantation. The Paris-Sud Lung Transplant Group.
        Chest. 1993; 103: 59-63
        • Gottlieb J.
        • Mattner F.
        • Weissbrodt H.
        • et al.
        Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis.
        Respir Med. 2009; 103: 743-749
        • Gupta M.R.
        • Valentine V.G.
        • Walker Jr., J.E.
        • et al.
        Clinical spectrum of gram-positive infections in lung transplantation.
        Transpl Infect Dis. 2009; 11: 424-431
        • Nunley D.R.
        • Grgurich W.
        • Iacono A.T.
        • et al.
        Allograft colonization and infections with pseudomonas in cystic fibrosis lung transplant recipients.
        Chest. 1998; 113: 1235-1243
        • Vos R.
        • Vanaudenaerde B.M.
        • Geudens N.
        • Dupont L.J.
        • Van Raemdonck D.E.
        • Verleden G.M.
        Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation?.
        Eur Respir J. 2008; 31: 1037-1045
        • Walter S.
        • Gudowius P.
        • Bosshammer J.
        • et al.
        Epidemiology of chronic Pseudomonas aeruginosa infections in the airways of lung transplant recipients with cystic fibrosis.
        Thorax. 1997; 52: 318-321
        • Chaparro C.
        • Maurer J.
        • Gutierrez C.
        • et al.
        Infection with Burkholderia cepacia in cystic fibrosis: outcome following lung transplantation.
        Am J Respir Crit Care Med. 2001; 163: 43-48
        • Meachery G.
        • De S.A.
        • Nicholson A.
        • et al.
        Outcomes of lung transplantation for cystic fibrosis in a large UK cohort.
        Thorax. 2008; 63: 725-731
        • Zeglen S.
        • Wojarski J.
        • Wozniak-Grygiel E.
        • et al.
        Frequency of Pseudomonas aeruginosa colonizations/infections in lung transplant recipients.
        Transplant Proc. 2009; 41: 3222-3224
        • Bonvillain R.W.
        • Valentine V.G.
        • Lombard G.
        • LaPlace S.
        • Dhillon G.
        • Wang G.
        Post-operative infections in cystic fibrosis and non-cystic fibrosis patients after lung transplantation.
        J Heart Lung Transplant. 2007; 26: 890-897
        • Fink J.
        • Mathaba L.T.
        • Stewart G.A.
        • et al.
        Moraxella catarrhalis stimulates the release of proinflammatory cytokines and prostaglandin E from human respiratory epithelial cells and monocyte-derived macrophages.
        FEMS Immunol Med Microbiol. 2006; 46: 198-208
        • Larsen J.M.
        • Musavian H.S.
        • Butt T.M.
        • Ingvorsen C.
        • Thysen A.H.
        • Brix S.
        Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology.
        Immunology. 2015; 144: 333-342
        • Segal L.N.
        • Alekseyenko A.V.
        • Clemente J.C.
        • et al.
        Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation.
        Microbiome. 2013; 1: 19
        • Sze M.A.
        • Utokaparch S.
        • Elliott W.M.
        • Hogg J.C.
        • Hegele R.G.
        Loss of GD1-positive lactobacillus correlates with inflammation in human lungs with COPD.
        BMJ Open. 2015; 5: e006677
        • Shankar J.
        • Nguyen M.H.
        • Crespo M.M.
        • et al.
        Looking beyond respiratory cultures: microbiome-cytokine signatures of bacterial pneumonia and tracheobronchitis in lung transplant recipients.
        Am J Transplant. 2016; 16: 1766-1778
        • Patella M.
        • Anile M.
        • Del P.P.
        • et al.
        Role of cytokine profile in the differential diagnosis between acute lung rejection and pulmonary infections after lung transplantationdagger.
        Eur J Cardiothorac Surg. 2015; 47: 1031-1036
        • Cribbs S.K.
        • Uppal K.
        • Li S.
        • et al.
        Correlation of the lung microbiota with metabolic profiles in bronchoalveolar lavage fluid in HIV infection.
        Microbiome. 2016; 4: 3