IMMUNE NETWORK

  • 제21권3호
  • /
  • Pages.19.1-19.18
  • /
  • 2021
  • /
  • 1598-2629(pISSN)
  • /
  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
권호 표지
DOI QR코드

DOI QR Code

The Role of Upper Airway Microbiome in the Development of Adult Asthma

  • Purevsuren Losol (Department of Internal Medicine, Seoul National University Bundang Hospital) ;
  • Jun-Pyo Choi (Department of Internal Medicine, Seoul National University Bundang Hospital) ;
  • Sae-Hoon Kim (Department of Internal Medicine, Seoul National University Bundang Hospital) ;
  • Yoon-Seok Chang (Department of Internal Medicine, Seoul National University Bundang Hospital)
  • 투고 : 2021.04.19
  • 심사 : 2021.06.24
  • 발행 : 2021.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Clinical and molecular phenotypes of asthma are complex. The main phenotypes of adult asthma are characterized by eosinophil and/or neutrophil cell dominant airway inflammation that represent distinct clinical features. Upper and lower airways constitute a unique system and their interaction shows functional complementarity. Although human upper airway contains various indigenous commensals and opportunistic pathogenic microbiome, imbalance of this interactions lead to pathogen overgrowth and increased inflammation and airway remodeling. Competition for epithelial cell attachment, different susceptibilities to host defense molecules and antimicrobial peptides, and the production of proinflammatory cytokine and pattern recognition receptors possibly determine the pattern of this inflammation. Exposure to environmental factors, including infection, air pollution, smoking is commonly associated with asthma comorbidity, severity, exacerbation and resistance to anti-microbial and steroid treatment, and these effects may also be modulated by host and microbial genetics. Administration of probiotic, antibiotic and corticosteroid treatment for asthma may modify the composition of resident microbiota and clinical features. This review summarizes the effect of some environmental factors on the upper respiratory microbiome, the interaction between host-microbiome, and potential impact of asthma treatment on the composition of the upper airway microbiome.

키워드

과제정보

This work was supported by Brain Pool Program through the National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (grant No. 2019H1D3A2A02102333). We appreciate Ms. Sunhee An from Gyeonggi-do Atopy Asthma Education Information Center for illustrations.

참고문헌

  1. Global Asthma Network. The Global Asthma Report. Auckland: Global Asthma Network; 2018. 
  2. Kang SY, Song WJ, Cho SH, Chang YS. Time trends of the prevalence of allergic diseases in Korea: a systematic literature review. Asia Pac Allergy 2018;8:e8.
  3. Pakkasela J, Ilmarinen P, Honkamaki J, Tuomisto LE, Andersen H, Piirila P, Hisinger-Molkanen H, Sovijarvi A, Backman H, Lundback B, et al. Age-specific incidence of allergic and non-allergic asthma. BMC Pulm Med 2020;20:9.
  4. Song WJ, Chang YS. Respiratory allergies in the elderly: findings from the Korean Longitudinal Study on Health and Aging phase I study (2005-2006). Asia Pac Allergy 2017;7:185-192. https://doi.org/10.5415/apallergy.2017.7.4.185
  5. Holgate ST. A look at the pathogenesis of asthma: the need for a change in direction. Discov Med 2010;9:439-447.
  6. Kim KW, Ober C. Lessons learned from GWAS of asthma. Allergy Asthma Immunol Res 2019;11:170-187. https://doi.org/10.4168/aair.2019.11.2.170
  7. Thomsen SF. Genetics of asthma: an introduction for the clinician. Eur Clin Respir J 2015;2:24643.
  8. Murrison LB, Brandt EB, Myers JB, Hershey GK. Environmental exposures and mechanisms in allergy and asthma development. J Clin Invest 2019;129:1504-1515. https://doi.org/10.1172/JCI124612
  9. Man WH, de Steenhuijsen Piters WA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol 2017;15:259-270.  https://doi.org/10.1038/nrmicro.2017.14
  10. Giavina-Bianchi P, Aun MV, Takejima P, Kalil J, Agondi RC. United airway disease: current perspectives. J Asthma Allergy 2016;9:93-100. https://doi.org/10.2147/JAA.S81541
  11. Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, Bushman FD, Collman RG. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011;184:957-963. https://doi.org/10.1164/rccm.201104-0655OC
  12. Abdel-Aziz MI, Vijverberg SJH, Neerincx AH, Kraneveld AD, Maitland-van der Zee AH. The crosstalk between microbiome and asthma: exploring associations and challenges. Clin Exp Allergy 2019;49:1067-1086. https://doi.org/10.1111/cea.13444
  13. Song WJ, Chang YS, Lim MK, Yun EH, Kim SH, Kang HR, Park HW, Tomassen P, Choi MH, Min KU, et al. Staphylococcal enterotoxin sensitization in a community-based population: a potential role in adult-onset asthma. Clin Exp Allergy 2014;44:553-562. https://doi.org/10.1111/cea.12239
  14. Song WJ, Sintobin I, Sohn KH, Kang MG, Park HK, Jo EJ, Lee SE, Yang MS, Kim SH, Park HK, et al. Staphylococcal enterotoxin IgE sensitization in late-onset severe eosinophilic asthma in the elderly. Clin Exp Allergy 2016;46:411-421. https://doi.org/10.1111/cea.12652
  15. Song WJ, Jo EJ, Lee JW, Kang HR, Cho SH, Min KU, Chang YS. Staphylococcal enterotoxin specific IgE and asthma: a systematic review and meta-analysis. Asia Pac Allergy 2013;3:120-126. https://doi.org/10.5415/apallergy.2013.3.2.120
  16. NIH HMP Working Group, Peterson J, Garges S, Giovanni M, McInnes P, Wang L, Schloss JA, Bonazzi V, McEwen JE, Wetterstrand KA, et al. The NIH Human Microbiome Project. Genome Res 2009;19:2317-2323. https://doi.org/10.1101/gr.096651.109
  17. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016;14:e1002533.
  18. Allaband C, McDonald D, Vazquez-Baeza Y, Minich JJ, Tripathi A, Brenner DA, Loomba R, Smarr L, Sandborn WJ, Schnabl B, et al. Microbiome 101: studying, analyzing, and interpreting gut microbiome data for clinicians. Clin Gastroenterol Hepatol 2019;17:218-230. https://doi.org/10.1016/j.cgh.2018.09.017
  19. Carr TF, Zeki AA, Kraft M. Eosinophilic and noneosinophilic asthma. Am J Respir Crit Care Med 2018;197:22-37. https://doi.org/10.1164/rccm.201611-2232PP
  20. Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat Med 2013;19:977-979. https://doi.org/10.1038/nm.3300
  21. Maes T, Joos GF, Brusselle GG. Targeting interleukin-4 in asthma: lost in translation? Am J Respir Cell Mol Biol 2012;47:261-270. https://doi.org/10.1165/rcmb.2012-0080TR
  22. van Veen IH, Ten Brinke A, Gauw SA, Sterk PJ, Rabe KF, Bel EH. Consistency of sputum eosinophilia in difficult-to-treat asthma: a 5-year follow-up study. J Allergy Clin Immunol 2009;124:615-617. https://doi.org/10.1016/j.jaci.2009.06.029
  23. Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells--how did we miss them? Nat Rev Immunol 2013;13:75-87. https://doi.org/10.1038/nri3349
  24. Pelly VS, Kannan Y, Coomes SM, Entwistle LJ, Ruckerl D, Seddon B, MacDonald AS, McKenzie A, Wilson MS. IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol 2016;9:1407-1417. https://doi.org/10.1038/mi.2016.4
  25. Winkler C, Hochdorfer T, Israelsson E, Hasselberg A, Cavallin A, Thorn K, Muthas D, Shojaee S, Luer K, Muller M, et al. Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients. J Allergy Clin Immunol 2019;144:61-69.e7. https://doi.org/10.1016/j.jaci.2019.01.027
  26. Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: moving toward precision medicine. J Allergy Clin Immunol 2019;144:1-12. https://doi.org/10.1016/j.jaci.2019.05.031
  27. Peters SP. Asthma phenotypes: nonallergic (intrinsic) asthma. J Allergy Clin Immunol Pract 2014;2:650-652.  https://doi.org/10.1016/j.jaip.2014.09.006
  28. Baos S, Calzada D, Cremades-Jimeno L, Sastre J, Picado C, Quiralte J, Florido F, Lahoz C, Cardaba B. Nonallergic asthma and its severity: biomarkers for its discrimination in peripheral samples. Front Immunol 2018;9:1416.
  29. Liu L, Zhang X, Liu Y, Zhang L, Zheng J, Wang J, Hansbro PM, Wang L, Wang G, Hsu AC. Chitinase-like protein YKL-40 correlates with inflammatory phenotypes, anti-asthma responsiveness and future exacerbations. Respir Res 2019;20:95.
  30. Chen JH, Qin L, Shi YY, Feng JT, Zheng YL, Wan YF, Xu CQ, Yang XM, Hu CP. IL-17 protein levels in both induced sputum and plasma are increased in stable but not acute asthma individuals with obesity. Respir Med 2016;121:48-58. https://doi.org/10.1016/j.rmed.2016.10.018
  31. Ntontsi P, Loukides S, Bakakos P, Kostikas K, Papatheodorou G, Papathanassiou E, Hillas G, Koulouris N, Papiris S, Papaioannou AI. Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: comparison with different sputum phenotypes. Allergy 2017;72:1761-1767. https://doi.org/10.1111/all.13184
  32. Demarche S, Schleich F, Henket M, Paulus V, Van Hees T, Louis R. Detailed analysis of sputum and systemic inflammation in asthma phenotypes: are paucigranulocytic asthmatics really non-inflammatory? BMC Pulm Med 2016;16:46.
  33. Irvin C, Zafar I, Good J, Rollins D, Christianson C, Gorska MM, Martin RJ, Alam R. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol 2014;134:1175-1186.e7. https://doi.org/10.1016/j.jaci.2014.05.038
  34. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008;177:148-155. https://doi.org/10.1164/rccm.200707-1134OC
  35. Ratner AJ, Lysenko ES, Paul MN, Weiser JN. Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces. Proc Natl Acad Sci U S A 2005;102:3429-3434. https://doi.org/10.1073/pnas.0500599102
  36. Bachert C, Humbert M, Hanania NA, Zhang N, Holgate S, Buhl R, Broker BM. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge. Eur Respir J 2020;55:1901592.
  37. Huang YJ, Nariya S, Harris JM, Lynch SV, Choy DF, Arron JR, Boushey H. The airway microbiome in patients with severe asthma: associations with disease features and severity. J Allergy Clin Immunol 2015;136:874-884. https://doi.org/10.1016/j.jaci.2015.05.044
  38. Groneberg DA, Peiser C, Dinh QT, Matthias J, Eynott PR, Heppt W, Carlstedt I, Witt C, Fischer A, Chung KF. Distribution of respiratory mucin proteins in human nasal mucosa. Laryngoscope 2003;113:520-524. https://doi.org/10.1097/00005537-200303000-00023
  39. Ali MS, Pearson JP. Upper airway mucin gene expression: a review. Laryngoscope 2007;117:932-938. https://doi.org/10.1097/MLG.0b013e3180383651
  40. Takeyama K, Fahy JV, Nadel JA. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med 2001;163:511-516. https://doi.org/10.1164/ajrccm.163.2.2001038
  41. Mao YJ, Chen HH, Wang B, Liu X, Xiong GY. Increased expression of MUC5AC and MUC5B promoting bacterial biofilm formation in chronic rhinosinusitis patients. Auris Nasus Larynx 2015;42:294-298. https://doi.org/10.1016/j.anl.2014.12.004
  42. Dohrman A, Miyata S, Gallup M, Li JD, Chapelin C, Coste A, Escudier E, Nadel J, Basbaum C. Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. Biochim Biophys Acta 1998;1406:251-259. https://doi.org/10.1016/S0925-4439(98)00010-6
  43. Shuter J, Hatcher VB, Lowy FD. Staphylococcus aureus binding to human nasal mucin. Infect Immun 1996;64:310-318. https://doi.org/10.1128/iai.64.1.310-318.1996
  44. Cohn L, Whittaker L, Niu N, Homer RJ. Cytokine regulation of mucus production in a model of allergic asthma. Novartis Found Symp 2002;248:201-213. https://doi.org/10.1002/0470860790.ch13
  45. Hiemstra PS, McCray PB Jr, Bals R. The innate immune function of airway epithelial cells in inflammatory lung disease. Eur Respir J 2015;45:1150-1162. https://doi.org/10.1183/09031936.00141514
  46. Niyonsaba F, Someya A, Hirata M, Ogawa H, Nagaoka I. Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells. Eur J Immunol 2001;31:1066-1075. https://doi.org/10.1002/1521-4141(200104)31:4<1066::AID-IMMU1066>3.0.CO;2-#
  47. Mahdavinia M, Keshavarzian A, Tobin MC, Landay AL, Schleimer RP. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin Exp Allergy 2016;46:21-41. https://doi.org/10.1111/cea.12666
  48. Vareille M, Kieninger E, Edwards MR, Regamey N. The airway epithelium: soldier in the fight against respiratory viruses. Clin Microbiol Rev 2011;24:210-229. https://doi.org/10.1128/CMR.00014-10
  49. Zakeri A, Russo M. Dual role of Toll-like receptors in human and experimental asthma models. Front Immunol 2018;9:1027.
  50. Dong Z, Xiong L, Zhang W, Gibson PG, Wang T, Lu Y, Wang G, Li H, Wang F. Holding the inflammatory system in check: TLRs and their targeted therapy in asthma. Mediators Inflamm 2016;2016:2180417.
  51. Losol P, Kim SH, Ahn S, Lee S, Choi JP, Kim YH, Hong SJ, Kim BS, Chang YS. Genetic variants in the TLR-related pathway and smoking exposure alter the upper airway microbiota in adult asthmatic patients. Allergy 2021. doi: 10.1111/all.14970.
  52. Askarian F, Wagner T, Johannessen M, Nizet V. Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol Rev 2018;42:656-671. https://doi.org/10.1093/femsre/fuy025
  53. Ritchie ND, Ijaz UZ, Evans TJ. IL-17 signalling restructures the nasal microbiome and drives dynamic changes following Streptococcus pneumoniae colonization. BMC Genomics 2017;18:807.
  54. Baba S, Kagoya R, Kondo K, Suzukawa M, Ohta K, Yamasoba T. T-cell phenotypes in chronic rhinosinusitis with nasal polyps in Japanese patients. Allergy Asthma Clin Immunol 2015;11:33.
  55. Jackson DJ, Makrinioti H, Rana BM, Shamji BW, Trujillo-Torralbo MB, Footitt J, Del-Rosario J, Telcian AG, Nikonova A, Zhu J, et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med 2014;190:1373-1382. https://doi.org/10.1164/rccm.201406-1039OC
  56. Walford HH, Lund SJ, Baum RE, White AA, Bergeron CM, Husseman J, Bethel KJ, Scott DR, Khorram N, Miller M, et al. Increased ILC2s in the eosinophilic nasal polyp endotype are associated with corticosteroid responsiveness. Clin Immunol 2014;155:126-135. https://doi.org/10.1016/j.clim.2014.09.007
  57. de Steenhuijsen Piters WA, Sanders EA, Bogaert D. The role of the local microbial ecosystem in respiratory health and disease. Philos Trans R Soc Lond B Biol Sci 2015;370:20140294.
  58. Chen CH, Wang Y, Nakatsuji T, Liu YT, Zouboulis C, Gallo R, Zhang L, Hsieh MF, Huang CM. An innate bactericidal oleic acid effective against skin infection of methicillin-resistant Staphylococcus aureus: a therapy concordant with evolutionary medicine. J Microbiol Biotechnol 2011;21:391-399. https://doi.org/10.4014/jmb.1011.11014
  59. Harriott MM, Noverr MC. Candida albicans and Staphylococcus aureus form polymicrobial biofilms: effects on antimicrobial resistance. Antimicrob Agents Chemother 2009;53:3914-3922. https://doi.org/10.1128/AAC.00657-09
  60. Bellinghausen C, Gulraiz F, Heinzmann AC, Dentener MA, Savelkoul PH, Wouters EF, Rohde GG, Stassen FR. Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection. Respir Res 2016;17:68.
  61. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012;486:207-214. https://doi.org/10.1038/nature11234
  62. Zhou Y, Mihindukulasuriya KA, Gao H, La Rosa PS, Wylie KM, Martin JC, Kota K, Shannon WD, Mitreva M, Sodergren E, et al. Exploration of bacterial community classes in major human habitats. Genome Biol 2014;15:R66. 
  63. Biswas K, Hoggard M, Jain R, Taylor MW, Douglas RG. The nasal microbiota in health and disease: variation within and between subjects. Front Microbiol 2015;9:134.
  64. Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J 2013;41:716-726. https://doi.org/10.1183/09031936.00073312
  65. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001;15:1110-1112. https://doi.org/10.1096/fsb2fj000432fje
  66. Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun 2010;34:J258-J265. https://doi.org/10.1016/j.jaut.2009.12.003
  67. Sapkota AR, Berger S, Vogel TM. Human pathogens abundant in the bacterial metagenome of cigarettes. Environ Health Perspect 2010;118:351-356. https://doi.org/10.1289/ehp.0901201
  68. De Boeck I, Wittouck S, Wuyts S, Oerlemans EF, van den Broek MF, Vandenheuvel D, Vanderveken O, Lebeer S. Comparing the healthy nose and nasopharynx microbiota reveals continuity as well as niche-specificity. Front Microbiol 2017;8:2372.
  69. Qin T, Zhang F, Zhou H, Ren H, Du Y, Liang S, Wang F, Cheng L, Xie X, Jin A, et al. High-level PM2.5/PM10 exposure is associated with alterations in the human pharyngeal microbiota composition. Front Microbiol 2019;10:54.
  70. Charlson ES, Chen J, Custers-Allen R, Bittinger K, Li H, Sinha R, Hwang J, Bushman FD, Collman RG. Disordered microbial communities in the upper respiratory tract of cigarette smokers. PLoS One 2010;5:e15216.
  71. Munck C, Helby J, Westergaard CG, Porsbjerg C, Backer V, Hansen LH. Smoking cessation and the microbiome in induced sputum samples from cigarette smoking asthma patients. PLoS One 2016;11:e0158622.
  72. Huang C, Shi G. Smoking and microbiome in oral, airway, gut and some systemic diseases. J Transl Med 2019;17:225.
  73. Guarnieri M, Balmes JR. Outdoor air pollution and asthma. Lancet 2014;383:1581-1592. https://doi.org/10.1016/S0140-6736(14)60617-6
  74. De Grove KC, Provoost S, Brusselle GG, Joos GF, Maes T. Insights in particulate matter-induced allergic airway inflammation: focus on the epithelium. Clin Exp Allergy 2018;48:773-786. https://doi.org/10.1111/cea.13178
  75. Liu H, Zhang X, Zhang H, Yao X, Zhou M, Wang J, He Z, Zhang H, Lou L, Mao W, et al. Effect of air pollution on the total bacteria and pathogenic bacteria in different sizes of particulate matter. Environ Pollut 2018;233:483-493. https://doi.org/10.1016/j.envpol.2017.10.070
  76. Mostafavi N, Jeong A, Vlaanderen J, Imboden M, Vineis P, Jarvis D, Kogevinas M, Probst-Hensch N, Vermeulen R. The mediating effect of immune markers on the association between ambient air pollution and adult-onset asthma. Sci Rep 2019;9:8818.
  77. Whelan R, Kim C, Chen M, Leiter J, Grunstein MM, Hakonarson H. Role and regulation of interleukin-1 molecules in pro-asthmatic sensitised airway smooth muscle. Eur Respir J 2004;24:559-567. https://doi.org/10.1183/09031936.04.00133803
  78. Godwin MS, Reeder KM, Garth JM, Blackburn JP, Jones M, Yu Z, Matalon S, Hastie AT, Meyers DA, Steele C. IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation. JCI Insight 2019;4:e129055.
  79. Igartua C, Davenport ER, Gilad Y, Nicolae DL, Pinto J, Ober C. Host genetic variation in mucosal immunity pathways influences the upper airway microbiome. Microbiome 2017;5:16.
  80. Lee JJ, Kim SH, Lee MJ, Kim BK, Song WJ, Park HW, Cho SH, Hong SJ, Chang YS, Kim BS. Different upper airway microbiome and their functional genes associated with asthma in young adults and elderly individuals. Allergy 2019;74:709-719.  https://doi.org/10.1111/all.13608
  81. Gan W, Yang F, Tang Y, Zhou D, Qing D, Hu J, Liu S, Liu F, Meng J. The difference in nasal bacterial microbiome diversity between chronic rhinosinusitis patients with polyps and a control population. Int Forum Allergy Rhinol 2019;9:582-592. https://doi.org/10.1002/alr.22297
  82. Chalermwatanachai T, Vilchez-Vargas R, Holtappels G, Lacoere T, Jauregui R, Kerckhof FM, Pieper DH, Van de Wiele T, Vaneechoutte M, Van Zele T, et al. Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota. Sci Rep 2018;8:7926.
  83. Losol P, Kim SH, Hwang EK, Shin YS, Park HS. IL-5 promoter polymorphism enhances IgE responses to staphylococcal superantigens in adult asthmatics. Allergy Asthma Immunol Res 2013;5:106-109. https://doi.org/10.4168/aair.2013.5.2.106
  84. Ramakrishnan VR, Hauser LJ, Feazel LM, Ir D, Robertson CE, Frank DN. Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. J Allergy Clin Immunol 2015;136:334-342.e1. https://doi.org/10.1016/j.jaci.2015.02.008
  85. Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, Davies J, Ervine A, Poulter L, Pachter L, et al. Disordered microbial communities in asthmatic airways. PLoS One 2010;5:e8578.
  86. Fazlollahi M, Lee TD, Andrade J, Oguntuyo K, Chun Y, Grishina G, Grishin A, Bunyavanich S. The nasal microbiome in asthma. J Allergy Clin Immunol 2018;142:834-843.e2. https://doi.org/10.1016/j.jaci.2018.02.020
  87. Yang HJ, LoSavio PS, Engen PA, Naqib A, Mehta A, Kota R, Khan RJ, Tobin MC, Green SJ, Schleimer RP, et al. Association of nasal microbiome and asthma control in patients with chronic rhinosinusitis. Clin Exp Allergy 2018;48:1744-1747. https://doi.org/10.1111/cea.13255
  88. Zhang Q, Cox M, Liang Z, Brinkmann F, Cardenas PA, Duff R, Bhavsar P, Cookson W, Moffatt M, Chung KF. Airway microbiota in severe asthma and relationship to asthma severity and phenotypes. PLoS One 2016;11:e0152724.
  89. Denner DR, Sangwan N, Becker JB, Hogarth DK, Oldham J, Castillo J, Sperling AI, Solway J, Naureckas ET, Gilbert JA, et al. Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways. J Allergy Clin Immunol 2016;137:1398-1405.e3. https://doi.org/10.1016/j.jaci.2015.10.017
  90. Biesbroek G, Tsivtsivadze E, Sanders EA, Montijn R, Veenhoven RH, Keijser BJ, Bogaert D. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am J Respir Crit Care Med 2014;190:1283-1292. https://doi.org/10.1164/rccm.201407-1240OC
  91. Ta LDH, Yap GC, Tay CJX, Lim ASM, Huang CH, Chu CW, De Sessions PF, Shek LP, Goh A, Van Bever HPS, et al. Establishment of the nasal microbiota in the first 18 months of life: correlation with early-onset rhinitis and wheezing. J Allergy Clin Immunol 2018;142:86-95. https://doi.org/10.1016/j.jaci.2018.01.032
  92. Miraglia Del Giudice M, Indolfi C, Capasso M, Maiello N, Decimo F, Ciprandi G. Bifidobacterium mixture (B longum BB536, B infantis M-63, B breve M-16V) treatment in children with seasonal allergic rhinitis and intermittent asthma. Ital J Pediatr 2017;43:25.
  93. Martens K, Pugin B, De Boeck I, Spacova I, Steelant B, Seys SF, Lebeer S, Hellings PW. Probiotics for the airways: potential to improve epithelial and immune homeostasis. Allergy 2018;73:1954-1963. https://doi.org/10.1111/all.13495
  94. Ishida Y, Nakamura F, Kanzato H, Sawada D, Hirata H, Nishimura A, Kajimoto O, Fujiwara S. Clinical effects of Lactobacillus acidophilus strain L-92 on perennial allergic rhinitis: a double-blind, placebo-controlled study. J Dairy Sci 2005;88:527-533. https://doi.org/10.3168/jds.S0022-0302(05)72714-4
  95. Xu LZ, Yang LT, Qiu SQ, Yang G, Luo XQ, Miao BP, Geng XR, Liu ZQ, Liu J, Wen Z, et al. Combination of specific allergen and probiotics induces specific regulatory B cells and enhances specific immunotherapy effect on allergic rhinitis. Oncotarget 2016;7:54360-54369. https://doi.org/10.18632/oncotarget.10946
  96. Singh A, Hacini-Rachinel F, Gosoniu ML, Bourdeau T, Holvoet S, Doucet-Ladeveze R, Beaumont M, Mercenier A, Nutten S. Immune-modulatory effect of probiotic Bifidobacterium lactis NCC2818 in individuals suffering from seasonal allergic rhinitis to grass pollen: an exploratory, randomized, placebo-controlled clinical trial. Eur J Clin Nutr 2013;67:161-167. https://doi.org/10.1038/ejcn.2012.197
  97. Dennis-Wall JC, Culpepper T, Nieves C Jr, Rowe CC, Burns AM, Rusch CT, Federico A, Ukhanova M, Waugh S, Mai V, et al. Probiotics (Lactobacillus gasseri KS-13, Bifidobacterium bifidum G9-1, and Bifidobacterium longum MM-2) improve rhinoconjunctivitis-specific quality of life in individuals with seasonal allergies: a double-blind, placebo-controlled, randomized trial. Am J Clin Nutr 2017;105:758-767. https://doi.org/10.3945/ajcn.116.140012
  98. Martensson A, Greiff L, Lamei SS, Lindstedt M, Olofsson TC, Vasquez A, Cervin A. Effects of a honeybee lactic acid bacterial microbiome on human nasal symptoms, commensals, and biomarkers. Int Forum Allergy Rhinol 2016;6:956-963. https://doi.org/10.1002/alr.21762
  99. Perez-Cobas AE, Gosalbes MJ, Friedrichs A, Knecht H, Artacho A, Eismann K, Otto W, Rojo D, Bargiela R, von Bergen M, et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut 2013;62:1591-1601. https://doi.org/10.1136/gutjnl-2012-303184
  100. Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope 1997;107:1661-1666. https://doi.org/10.1097/00005537-199712000-00016
  101. Desaki M, Takizawa H, Ohtoshi T, Kasama T, Kobayashi K, Sunazuka T, Omura S, Yamamoto K, Ito K. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun 2000;267:124-128. https://doi.org/10.1006/bbrc.1999.1917
  102. Ferrer M, Mendez-Garcia C, Rojo D, Barbas C, Moya A. Antibiotic use and microbiome function. Biochem Pharmacol 2017;134:114-126. https://doi.org/10.1016/j.bcp.2016.09.007
  103. de Oliveira IS, Borges Crosara PF, Cassali GD, Dos Reis DC, Rodrigues DS, Nunes FB, Guimaraes RE. Azithromycin for the treatment of eosinophilic nasal polyposis: clinical and histologic analysis. Allergy Rhinol (Providence) 2016;7:55-61. https://doi.org/10.2500/ar.2016.7.0160
  104. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet 2017;390:659-668. https://doi.org/10.1016/S0140-6736(17)31281-3
  105. Johnston SL, Szigeti M, Cross M, Brightling C, Chaudhuri R, Harrison T, Mansur A, Robison L, Sattar Z, Jackson D, et al. Azithromycin for acute exacerbations of asthma: the AZALEA randomized clinical trial. JAMA Intern Med 2016;176:1630-1637. https://doi.org/10.1001/jamainternmed.2016.5664
  106. Feazel LM, Robertson CE, Ramakrishnan VR, Frank DN. Microbiome complexity and Staphylococcus aureus in chronic rhinosinusitis. Laryngoscope 2012;122:467-472. https://doi.org/10.1002/lary.22398
  107. Liu CM, Soldanova K, Nordstrom L, Dwan MG, Moss OL, Contente-Cuomo TL, Keim P, Price LB, Lane AP. Medical therapy reduces microbiota diversity and evenness in surgically recalcitrant chronic rhinosinusitis. Int Forum Allergy Rhinol 2013;3:775-781. https://doi.org/10.1002/alr.21195
  108. Yao J, Carter RA, Vuagniaux G, Barbier M, Rosch JW, Rock CO. A pathogen-selective antibiotic minimizes disturbance to the microbiome. Antimicrob Agents Chemother 2016;60:4264-4273. https://doi.org/10.1128/AAC.00535-16
  109. Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta-analysis. Allergy 2013;68:569-579. https://doi.org/10.1111/all.12124
  110. Ramakrishnan VR, Holt J, Nelson LF, Ir D, Robertson CE, Frank DN. Determinants of the nasal microbiome: pilot study of effects of intranasal medication use. Allergy Rhinol (Providence) 2018;9:2152656718789519.
  111. Chung KF. Airway microbial dysbiosis in asthmatic patients: a target for prevention and treatment? J Allergy Clin Immunol 2017;139:1071-1081. https://doi.org/10.1016/j.jaci.2017.02.004