Abstract
The human respiratory tract, usually considered sterile, is currently being investigated for human-associated microbial communities. According to Dickson's conceptual model, the lung microbiota (LMt) is a dynamic ecosystem, whose composition, in healthy lungs, is likely to reflect microbial migration, reproduction, and elimination. However, which microbial genera constitutes a “healthy microbiome” per se remains hotly debated. It is now widely accepted that a bi-directional gut-lung axis connects the intestinal with the pulmonary microbiota and that the diet could have a role in modulating both microbiotas as in health as in pathological status. The LMt is altered in numerous respiratory disorders such as obstructive airway diseases, interstitial lung diseases, infections, and lung cancer. Some authors hypothesize that the use of specific bacterial strains, termed “probiotics,” with positive effects on the host immunity and/or against pathogens, could have beneficial effects in the treatment of intestinal disorders and pulmonary diseases. In this manuscript, we have reviewed the literature available on the LMt to delineate and discuss the potential relationship between composition alterations of LMt and lung diseases. Finally, we have reported some meaningful clinical studies that used integrated probiotics’ treatments to contrast some lung-correlated disorders.
This is a preview of subscription content, access via your institution.




References
Lederberg BJ, McCray AT (2001) ’Ome sweet’ omics—a genealogical treasury of words. Sci 15:8. https://doi.org/10.1110/ps.9.11.2181
Marchesi JR, Ravel J (2015) The vocabulary of microbiome research: a proposal. Microbiome 3:31. https://doi.org/10.1186/s40168-015-0094-5
Yatsunenko T, Rey FE, Manary MJ et al (2012) Human gut microbiome viewed across age and geography. Nature 486:222–227. https://doi.org/10.1038/nature11053
Kumar M, Babaei P, Ji B, Nielsen J (2016) Human gut microbiota and healthy aging: recent developments and future prospective. Nutr Health Age 4:3–16. https://doi.org/10.3233/NHA-150002
Laterza L, Rizzatti G, Gaetani E et al (2016) The gut microbiota and immune system relationship in human graft-versus-host disease. Mediterr J Hematol Infect Dis 8:e2016025–e2016025. https://doi.org/10.4084/MJHID.2016.025
Ames NJ, Ranucci A, Moriyama B, Wallen GR (2017) The human microbiome and understanding the 16S rRNA gene in translational nursing science. Nurs Res 66:184–197. https://doi.org/10.1097/NNR.0000000000000212
Faner R, Sibila O, Agustí A et al (2017) The microbiome in respiratory medicine: current challenges and future perspectives. Eur Respir J 49:1–12. https://doi.org/10.1183/13993003.02086-2016
Budden KF, Shukla SD, Rehman SF et al (2019) Functional effects of the microbiota in chronic respiratory disease. Lancet Respir Med 2600:1–14. https://doi.org/10.1016/S2213-2600(18)30510-1
Ahmed B, Cox MJ, Cuthbertson L (2019) Growing up with your airway microbiota: a risky business. Thorax 74:525 LP-526. https://doi.org/10.1136/thoraxjnl-2019-213162
Niccolai E, Boem F, Russo E, Amedei A (2019) The gut–brain axis in the neuropsychological disease model of obesity: a classical movie revised by the emerging director “microbiome”. Nutrients 11:156. https://doi.org/10.3390/nu11010156
Amedei A, Boem F (2018) I’ve gut a feeling: microbiota impacting the conceptual and experimental perspectives of personalized medicine. Int J Mol Sci 19:3756. https://doi.org/10.3390/ijms19123756
Russo E, Bacci G, Chiellini C et al (2018) Preliminary comparison of oral and intestinal human microbiota in patients with colorectal cancer: a pilot study. Front Microbiol 8:2699. https://doi.org/10.3389/fmicb.2017.02699
Beck JM, Young VB, Huffnagle GB (2012) The microbiome of the lung. Transl Res 160:258–266. https://doi.org/10.1016/j.trsl.2012.02.005
Cui L, Morris A, Huang L et al (2014) The microbiome and the lung. Ann. Am. Thorac, Soc
Dickson RP, Erb-Downward JR, Prescott HC et al (2015) Intraalveolar catecholamines and the human lung microbiome. Am J Respir Crit Care Med 192:257–259. https://doi.org/10.1164/rccm.201502-0326LE
Charlson ES, Bittinger K, Haas AR et al (2011) Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 184:957–963. https://doi.org/10.1164/rccm.201104-0655OC
Lemon KP, Klepac-Ceraj V, Schiffer HK et al (2010) Comparative analyses of the bacterial microbiota of the human nostril and oropharynx. MBio 1:e00129–e210. https://doi.org/10.1128/mBio.00129-10
Segal LN, Alekseyenko AV, Clemente JC et al (2013) Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 1:19. https://doi.org/10.1186/2049-2618-1-19
Mathieu E, Escribano-Vazquez U, Descamps D et al (2018) Paradigms of lung microbiota functions in health and disease, particularly, in asthma. Front Physiol 9:1–11. https://doi.org/10.3389/fphys.2018.01168
Bassis CM, Erb-Downward JR, Dickson RP et al (2015) Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. MBio 6
Dickson RP, Erb-Downward JR, Huffnagle GB (2015) Homeostasis and its disruption in the lung microbiome. Am J Physiol Lung Cell Mol Physiol. https://doi.org/10.1152/ajplung.00279.2015
Kasubuchi M, Hasegawa S, Hiramatsu T et al (2015) Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation. Nutrients 7:2839–2849. https://doi.org/10.3390/nu7042839
Günther A, Siebert C, Schmidt R et al (1996) Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med 153:176–184. https://doi.org/10.1164/ajrccm.153.1.8542113
Zhang X, Essmann M, Burt ET, Larsen B (2000) Estrogen effects on Candida albicans: a potential virulence-regulating mechanism. J Infect Dis 181:1441–1446
Zaborina O, Lepine F, Xiao G et al (2007) Dynorphin activates quorum sensing quinolone signaling in Pseudomonas aeruginosa. PLoS Pathog 3:e35–e35. https://doi.org/10.1371/journal.ppat.0030035
Arumugam M, Raes J, Pelletier E et al (2011) Enterotypes of the human gut microbiome. Nature 473:174–180. https://doi.org/10.1038/nature09944
Papa E, Docktor M, Smillie C et al (2012) Non-invasive mapping of the gastrointestinal microbiota identifies children with inflammatory bowel disease. PLoS ONE 7:e39242
Turnbaugh PJ, Ridaura VK, Faith JJ, et al (2009) The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice. Sci Transl Med 1:6ra14 LP-6ra14
Rinninella E, Raoul P, Cintoni M et al (2019) What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 7:14. https://doi.org/10.3390/microorganisms7010014
Bull MJ, Plummer NT (2014) Part 1: the human gut microbiome in health and disease. Integr Med (Encinitas) 13:17–22
Dang AT, Marsland BJ (2019) Microbes, metabolites, and the gut–lung axis. Mucosal Immunol 12:843–850. https://doi.org/10.1038/s41385-019-0160-6
Wypych TP, Wickramasinghe LC, Marsland BJ (2019) The influence of the microbiome on respiratory health. Nat Immunol. https://doi.org/10.1038/s41590-019-0451-9
Kalliomäki M, Kirjavainen P, Eerola E et al (2001) Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 107:129–134. https://doi.org/10.1067/mai.2001.111237
Ichinohe T, Pang IK, Kumamoto Y, et al (2011) Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci 108:5354 LP-5359
Qian G, Jiang W, Zou B et al (2018) LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma. J Exp Med 215:2397–2412. https://doi.org/10.1084/jem.20172225
Coopersmith C, Stromberg P, Davis G et al (2003) Sepsis from Pseudomonas aeruginosa pneumonia decreases intestinal proliferation and induces gut epithelial cell cycle arrest. Crit Care Med 31:1630–1637. https://doi.org/10.1097/01.CCM.0000055385.29232.11
Burke DG, Fouhy F, Harrison MJ et al (2017) The altered gut microbiota in adults with cystic fibrosis. BMC Microbiol 17:58. https://doi.org/10.1186/s12866-017-0968-8
S Anand SS Mande 2018 Diet front microbiol microbiota and gut-lung connection 10.3389/fmicb.2018.02147
Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3:858–876. https://doi.org/10.3390/nu3100858
Samuelson DR, Welsh DA, Shellito JE (2015) Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol 6:1085. https://doi.org/10.3389/fmicb.2015.01085
McGhee JR, Fujihashi K (2012) Inside the mucosal immune system. PLOS Biol 10:e1001397
Zhang R, Chen L, Cao L et al (2018) Effects of smoking on the lower respiratory tract microbiome in mice. Respir Res 19:253. https://doi.org/10.1186/s12931-018-0959-9
Erb-Downward JR, Thompson DL, Han MK et al (2011) Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS ONE 6:e16384–e16384. https://doi.org/10.1371/journal.pone.0016384
Panzer AR, Lynch SV, Langelier C et al (2017) Lung microbiota is related to smoking status and to development of acute respiratory distress syndrome in critically ill trauma patients. Am J Respir Crit Care Med 197:621–631. https://doi.org/10.1164/rccm.201702-0441OC
Global Initiative for Chronic Obstructive Lung Disease (2019) GOLD Report 2019. 1–155
Di Stefano A, Ricciardolo FLM, Caramori G, et al (2017) Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression. Eur Respir J 49:
Langille MGI, Zaneveld J, Caporaso JG et al (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31:814–821. https://doi.org/10.1038/nbt.2676
Hilty M, Burke C, Pedro H et al (2010) Disordered microbial communities in asthmatic airways. PLoS ONE 5:e8578–e8578. https://doi.org/10.1371/journal.pone.0008578
Sze MA, Dimitriu PA, Hayashi S et al (2012) The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 185:1073–1080. https://doi.org/10.1164/rccm.201111-2075OC
Sze MA, Dimitriu PA, Suzuki M et al (2015) Host response to the lung microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 192:438–445. https://doi.org/10.1164/rccm.201502-0223OC
Wang L, Hao K, Yang T, Wang C (2017) Role of the lung microbiome in the pathogenesis of chronic obstructive pulmonary disease. Chin Med J (Engl) 130(17):2107–2111. https://doi.org/10.4103/0366-6999.211452
Leitao Filho FS, Alotaibi NM, Ngan D et al (2018) Sputum microbiome is associated with 1-year mortality following COPD hospitalizations. Am J Respir Crit Care Med. https://doi.org/10.1164/rccm.201806-1135OC
Mayhew D, Devos N, Lambert C et al (2018) Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations. Thorax 73:422–430. https://doi.org/10.1136/thoraxjnl-2017-210408
Sullivan A, Hunt E, MacSharry J, Murphy DM (2016) The microbiome and the pathophysiology of asthma. Respir Res 17:163. https://doi.org/10.1186/s12931-016-0479-4
Stiemsma LT, Turvey SE (2017) Asthma and the microbiome: defining the critical window in early life. Allergy Asthma Clin Immunol 13:3. https://doi.org/10.1186/s13223-016-0173-6
Fujimura KE, Sitarik AR, Havstad S et al (2016) Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med 22:1187
Stokholm J, Blaser MJ, Thorsen J et al (2018) Maturation of the gut microbiome and risk of asthma in childhood. Nat Commun 9:141. https://doi.org/10.1038/s41467-017-02573-2
Olszak T, An D, Zeissig S, et al (2012) Microbial exposure during early life has persistent effects on natural killer t cell function. Science 80(336):489 LP-493
Dales RE, Zwanenburg H, Burnett R, Franklin CA (1991) Respiratory health effects of home dampness and molds among canadian children. Am J Epidemiol 134:196–203
Arrieta M-C, Stiemsma LT, Dimitriu PA, et al (2015) Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med 7:307ra152 LP-307ra152
Raghu G, Collard HR, Egan JJ et al (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183:788–824. https://doi.org/10.1164/rccm.2009-040GL
Han MK, Zhou Y, Murray S et al (2014) Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. Lancet Respir Med 2:548–556. https://doi.org/10.1016/S2213-2600(14)70069-4
Salisbury ML, Han MK, Dickson RP, Molyneaux PL (2017) Microbiome in interstitial lung disease: from pathogenesis to treatment target. Curr Opin Pulm Med 23:404–410. https://doi.org/10.1097/MCP.0000000000000399
Molyneaux PL, Cox MJ, Willis-Owen SAG et al (2014) The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 190:906–913. https://doi.org/10.1164/rccm.201403-0541OC
Molyneaux PL, Maher TM (2013) The role of infection in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir Rev 22:376 LP-381
Dickson RP, Erb-Downward JR, Freeman CM et al (2015) Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 12:821–830. https://doi.org/10.1513/AnnalsATS.201501-029OC
Zakharkina T, Martin-Loeches I, Matamoros S, et al (2017) The dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia. Thorax 72:803 LP-810. https://doi.org/10.1136/thoraxjnl-2016-209158
Flierl MA, Rittirsch D, Nadeau BA et al (2007) Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449:721
Dickson RP, Erb-Downward JR, Prescott HC et al (2014) Analysis of culture-dependent versus culture-independent techniques for identification of bacteria in clinically obtained bronchoalveolar lavage fluid. J Clin Microbiol 52:3605–3613. https://doi.org/10.1128/JCM.01028-14
Cho WCS, Kwan CK, Yau S et al (2011) The role of inflammation in the pathogenesis of lung cancer. Expert Opin Ther Targets 15:1127–1137. https://doi.org/10.1517/14728222.2011.599801
Mejri I, Ourari B, Cherif H, et al (2016) Pulmonary tuberculosis and lung cancer: A complex interaction. Eur Respir J 48
Lee SH, Sung JY, Yong D et al (2016) Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions. Lung Cancer 102:89–95. https://doi.org/10.1016/j.lungcan.2016.10.016
Yan X, Yang M, Liu J et al (2015) Discovery and validation of potential bacterial biomarkers for lung cancer. Am J Cancer Res 5:3111–3122
Toh ZQ, Anzela A, Tang M, Licciardi P (2012) Probiotic therapy as a novel approach for allergic disease. Front Pharmacol 3:171
Mortaz E, Adcock IM, Ricciardolo FLM, et al (2015) in vitro administration of L. rhamnosus and B. breve suppresses the pro-inflammatory mediators induced by exposure of macrophages to cigarette smoke. These findings may indicate importance of probiotics in treatment of cigarette smoke induced diseases lik. PLoS One 10:e0136455
Zuccotti G, Meneghin F, Aceti A et al (2015) Probiotics for prevention of atopic diseases in infants: systematic review and meta-analysis. Allergy 70:1356–1371. https://doi.org/10.1111/all.12700
Lerner A, Shoenfeld Y, Matthias T (2019) Probiotics: if it does not help it does not do any harm. Really? Microorganisms 7:104. https://doi.org/10.3390/microorganisms7040104
Cummings JH, Macfarlane GT, Englyst HN (2001) Prebiotic digestion and fermentation. Am J Clin Nutr 73:415s–420s. https://doi.org/10.1093/ajcn/73.2.415s
Garcia-Larsen V, Del Giacco SR, Moreira A et al (2016) Asthma and dietary intake: an overview of systematic reviews. Allergy 71:433–442. https://doi.org/10.1111/all.12800
Shi LH, Balakrishnan K, Thiagarajah K, et al (2016) Beneficial Properties of Probiotics. Trop life Sci Res 27:73–90. https://doi.org/10.21315/tlsr2016.27.2.6
Sivan A, Corrales L, Hubert N et al (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084–1089. https://doi.org/10.1126/science.aac4255
Daillère R, Vétizou M, Waldschmitt N et al (2016) Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45:931–943. https://doi.org/10.1016/j.immuni.2016.09.009
Huang YJ, Sethi S, Murphy T et al (2014) Airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease. J Clin Microbiol 52:2813–2823. https://doi.org/10.1128/JCM.00035-14
Becker AB, Abrams EM (2017) Asthma guidelines : the Global Initiative for Asthma in relation to national guidelines. 99–103. https://doi.org/10.1097/ACI.0000000000000346
Denner DR, Sangwan N, Becker JB et al (2016) Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways. J Allergy Clin Immunol 137:1398–1405.e3. https://doi.org/10.1016/j.jaci.2015.10.017
Funding
The study was unfunded.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest related to the present manuscript.
Statement of human and animal rights
This article does not contain any studies with animals performed by any of the authors.
Informed consent
All participants provided informed consent prior to their participation.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Fabbrizzi, A., Amedei, A., Lavorini, F. et al. The lung microbiome: clinical and therapeutic implications. Intern Emerg Med 14, 1241–1250 (2019). https://doi.org/10.1007/s11739-019-02208-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11739-019-02208-y
Keywords
- Lung microbiota
- Microbiota
- Microbiome
- Gut–lung axis
- Dysbiosis
- Probiotics