Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The influence of the microbiome on respiratory health

Abstract

The revolution in microbiota research over the past decade has provided invaluable knowledge about the function of the microbial species that inhabit the human body. It has become widely accepted that these microorganisms, collectively called ‘the microbiota’, engage in networks of interactions with each other and with the host that aim to benefit both the microbial members and the mammalian members of this unique ecosystem. The lungs, previously thought to be sterile, are now known to harbor a unique microbiota and, additionally, to be influenced by microbial signals from distal body sites, such as the intestine. Here we review the role of the lung and gut microbiotas in respiratory health and disease and highlight the main pathways of communication that underlie the gut–lung axis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Lung microbiota in healthy versus diseased settings.
Fig. 2: Major routes of communications within the gut–lung axis.
Fig. 3: Manipulating the microbiome to combat respiratory disease.
Fig. 4: The impact of intranasal or oral exposure to select microbes on respiratory health in animal models.

References

  1. 1.

    Dickson, R. P., Erb-Downward, J. R., Martinez, F. J. & Huffnagle, G. B. The microbiome and the respiratory tract. Annu. Rev. Physiol. 78, 481–504 (2016).

    CAS  PubMed  Google Scholar 

  2. 2.

    Pattaroni, C. et al. Early-life formation of the microbial and immunological environment of the human airways. Cell Host Microbe 24, 857–865.e854 (2018).

    CAS  PubMed  Google Scholar 

  3. 3.

    Grønseth, R. et al. Protected sampling is preferable in bronchoscopic studies of the airway microbiome. ERJ Open Res 3, 00019–2017 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Bassis, C. M. et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. MBio 6, e00037 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Dickson, R. P. et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann. Am. Thorac. Soc. 12, 821–830 (2015).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Segal, L. N. et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 1, 19 (2013).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Hilty, M. et al. Disordered microbial communities in asthmatic airways. PLoS One 5, e8578 (2010).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Yu, G. et al. Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features. Genome Biol. 17, 163 (2016).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Erb-Downward, J. R. et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 6, e16384 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Morris, A. et al. Comparison of the respiratory microbiome in healthy nonsmokers and smokers. Am. J. Respir. Crit. Care Med. 187, 1067–1075 (2013).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Segal, L. N. et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat. Microbiol. 1, 16031 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Huffnagle, G. B., Dickson, R. P. & Lukacs, N. W. The respiratory tract microbiome and lung inflammation: a two-way street. Mucosal Immunol. 10, 299–306 (2017).

    CAS  PubMed  Google Scholar 

  13. 13.

    Mathieu, E. et al. Paradigms of lung microbiota functions in health and disease, particularly, in asthma. Front. Physiol. 9, 1168 (2018).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Guarner, F. & Malagelada, J. R. Gut flora in health and disease. Lancet 361, 512–519 (2003).

    Google Scholar 

  15. 15.

    Gallacher, D. J. & Kotecha, S. Respiratory microbiome of new-born infants. Front Pediatr. 4, 10 (2016).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Venkataraman, A. et al. Application of a neutral community model to assess structuring of the human lung microbiome. MBio 6, e02284–14 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Huxley, E. J., Viroslav, J., Gray, W. R. & Pierce, A. K. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am. J. Med. 64, 564–568 (1978).

    CAS  PubMed  Google Scholar 

  18. 18.

    Carreiro, J.E. An Osteopathic Approach to Children (Churchill Livingstone, 2009).

  19. 19.

    Gleeson, K., Eggli, D. F. & Maxwell, S. L. Quantitative aspiration during sleep in normal subjects. Chest 111, 1266–1272 (1997).

    CAS  PubMed  Google Scholar 

  20. 20.

    Lohmann, P. et al. The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia. Pediatr. Res. 76, 294–301 (2014).

    CAS  PubMed  Google Scholar 

  21. 21.

    Gollwitzer, E. S. & Marsland, B. J. Impact of early-life exposures on immune maturation and susceptibility to disease. Trends Immunol. 36, 684–696 (2015).

    CAS  PubMed  Google Scholar 

  22. 22.

    Muhlebach, M. S. et al. Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children. PLoS Pathog. 14, e1006798 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Molyneaux, P. L. et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 190, 906–913 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Tunney, M. M. et al. Lung microbiota and bacterial abundance in patients with bronchiectasis when clinically stable and during exacerbation. Am. J. Respir. Crit. Care Med. 187, 1118–1126 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Byun, M. K., Chang, J., Kim, H. J. & Jeong, S. H. Differences of lung microbiome in patients with clinically stable and exacerbated bronchiectasis. PLoS One 12, e0183553 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lee, S. H. et al. Characterization of microbiota in bronchiectasis patients with different disease severities. J. Clin. Med. 7, E429 (2018).

    PubMed  Google Scholar 

  27. 27.

    Ubags, N. D. J. & Marsland, B. J. Mechanistic insight into the function of the microbiome in lung diseases. Eur. Respir. J. 50, 1602467 (2017).

    PubMed  Google Scholar 

  28. 28.

    Huang, Y. J. & LiPuma, J. J. The microbiome in cystic fibrosis. Clin. Chest Med. 37, 59–67 (2016).

    CAS  PubMed  Google Scholar 

  29. 29.

    Hewitt, R. J. & Molyneaux, P. L. The respiratory microbiome in idiopathic pulmonary fibrosis. Ann. Transl. Med. 5, 250 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Fastrès, A. et al. The lung microbiome in idiopathic pulmonary fibrosis: a promising approach for targeted therapies. Int. J. Mol. Sci. 18, E2735 (2017).

    PubMed  Google Scholar 

  31. 31.

    Matsuoka, K. & Kanai, T. The gut microbiota and inflammatory bowel disease. Semin. Immunopathol. 37, 47–55 (2015).

    CAS  PubMed  Google Scholar 

  32. 32.

    Songür, N. et al. Pulmonary function tests and high-resolution CT in the detection of pulmonary involvement in inflammatory bowel disease. J. Clin. Gastroenterol. 37, 292–298 (2003).

    PubMed  Google Scholar 

  33. 33.

    Douglas, J. G. et al. Respiratory impairment in inflammatory bowel disease: does it vary with disease activity? Respir. Med. 83, 389–394 (1989).

    CAS  PubMed  Google Scholar 

  34. 34.

    Ceyhan, B. B., Karakurt, S., Cevik, H. & Sungur, M. Bronchial hyperreactivity and allergic status in inflammatory bowel disease. Respiration 70, 60–66 (2003).

    PubMed  Google Scholar 

  35. 35.

    Camus, P. & Colby, T. V. Bronchiectasis associated with inflammatory bowel disease. Eur. Respir. Mon. 52, 163–177 (2011).

    Google Scholar 

  36. 36.

    Dilantika, C. et al. Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness. BMC Infect. Dis. 10, 3 (2010).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Wang, J. et al. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J. Exp. Med. 211, 2397–2410 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Samuelson, D. R. et al. Analysis of the intestinal microbial community and inferred functional capacities during the host response to Pneumocystis pneumonia. Exp. Lung Res. 42, 425–439 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sze, M. A. et al. Changes in the bacterial microbiota in gut, blood, and lungs following acute LPS instillation into mice lungs. PLoS One 9, e111228 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Durack, J. et al. Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. J. Allergy Clin. Immunol. 140, 63–75 (2017).

    CAS  PubMed  Google Scholar 

  41. 41.

    Yang, X., Li, H., Ma, Q., Zhang, Q. & Wang, C. Neutrophilic asthma is associated with increased airway bacterial burden and disordered community composition. BioMed Res. Int. 2018, 9230234 (2018).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Huang, Y. J. et al. The airway microbiome in patients with severe asthma: associations with disease features and severity. J. Allergy Clin. Immunol. 136, 874–884 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Green, B. J. et al. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One 9, e100645 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Simpson, J. L. et al. Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma. Eur. Respir. J. 47, 792–800 (2016).

    PubMed  Google Scholar 

  45. 45.

    Sverrild, A. et al. Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome. J. Allergy Clin. Immunol. 140, 407–417.e411 (2017).

    PubMed  Google Scholar 

  46. 46.

    Mouraux, S. et al. Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung. J. Allergy Clin. Immunol. 141, 718–729.e717 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Bernasconi, E. et al. Airway microbiota determines innate cell inflammatory or tissue remodeling profiles in lung transplantation. Am. J. Respir. Crit. Care Med. 194, 1252–1263 (2016).

    CAS  PubMed  Google Scholar 

  48. 48.

    Zhang, Q. et al. Airway microbiota in severe asthma and relationship to asthma severity and phenotypes. PLoS One 11, e0152724 (2016).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Li, N. et al. Sputum microbiota in severe asthma patients: relationship to eosinophilic inflammation. Respir. Med. 131, 192–198 (2017).

    CAS  PubMed  Google Scholar 

  50. 50.

    Robinson, P. F. M. et al. Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze. J. Allergy Clin. Immunol. 143, 1607–1610.e1603 (2019).

    PubMed  Google Scholar 

  51. 51.

    Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).

    CAS  PubMed  Google Scholar 

  52. 52.

    Qian, G. et al. LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma. J. Exp. Med. 215, 2397–2412 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Matsumoto, M. et al. Impact of intestinal microbiota on intestinal luminal metabolome. Sci. Rep. 2, 233 (2012).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    CAS  PubMed  Google Scholar 

  55. 55.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  Google Scholar 

  57. 57.

    Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    CAS  PubMed  Google Scholar 

  58. 58.

    Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 (2015).

    CAS  PubMed  Google Scholar 

  59. 59.

    den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).

    Google Scholar 

  60. 60.

    Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

    CAS  PubMed  Google Scholar 

  61. 61.

    Cait, A. et al. Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids. Mucosal Immunol. 11, 785–795 (2018).

    CAS  PubMed  Google Scholar 

  62. 62.

    Thorburn, A. N. et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat. Commun. 6, 7320 (2015).

    CAS  PubMed  Google Scholar 

  63. 63.

    Trompette, A. et al. Dietary fiber confers protection against flu by shaping Ly6c patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity 48, 992–1005.e1008 (2018).

    CAS  PubMed  Google Scholar 

  64. 64.

    Steed, A. L. et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357, 498–502 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    CAS  PubMed  Google Scholar 

  66. 66.

    Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

    CAS  PubMed  Google Scholar 

  67. 67.

    Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Kibe, R. et al. Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci. Rep. 4, 4548 (2014).

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Geiger, R. et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842.e813 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 89 (2019).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Morita, N. et al. GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites. Nature 566, 110–114 (2019).

    CAS  PubMed  Google Scholar 

  72. 72.

    Jia, W., Xie, G. & Jia, W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat. Rev. Gastroenterol. Hepatol. 15, 111–128 (2018).

    CAS  PubMed  Google Scholar 

  73. 73.

    Zmora, N. et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 174, 1388–1405.e1321 (2018).

    CAS  PubMed  Google Scholar 

  74. 74.

    Huang, Y. et al. S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science 359, 114–119 (2018).

    CAS  PubMed  Google Scholar 

  75. 75.

    Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Gray, J. et al. Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection. Sci. Transl. Med. 9, eaaf9412 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Bradley, C. P. et al. Segmented filamentous bacteria provoke lung autoimmunity by inducing gut–lung axis Th17 cells expressing dual TCRs. Cell Host Microbe 22, 697–704.e694 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Korolkova, O. Y., Myers, J. N., Pellom, S. T., Wang, L. & M’Koma, A. E. Characterization of serum cytokine profile in predominantly colonic inflammatory bowel disease to delineate ulcerative and Crohn’s colitides. Clin. Med. Insights Gastroenterol. 8, 29–44 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    He, Y. et al. Gut–lung axis: The microbial contributions and clinical implications. Crit. Rev. Microbiol. 43, 81–95 (2017).

    CAS  PubMed  Google Scholar 

  80. 80.

    Young, R. P., Hopkins, R. J. & Marsland, B. The gut-liver-lung axis. modulation of the innate immune response and its possible role in chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 54, 161–169 (2016).

    CAS  PubMed  Google Scholar 

  81. 81.

    Plantinga, T. S. et al. Human genetic susceptibility to Candida infections. Med. Mycol. 50, 785–794 (2012).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Tso, G. H. W. et al. Experimental evolution of a fungal pathogen into a gut symbiont. Science 362, 589–595 (2018).

    CAS  PubMed  Google Scholar 

  83. 83.

    Fyhrquist, N. et al. Acinetobacter species in the skin microbiota protect against allergic sensitization and inflammation. J. Allergy Clin. Immunol. 134, 1301–1309.e1311 (2014).

    CAS  PubMed  Google Scholar 

  84. 84.

    Debarry, J. et al. Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties. J. Allergy Clin. Immunol. 119, 1514–1521 (2007).

    PubMed  Google Scholar 

  85. 85.

    Conrad, M. L. et al. Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J. Exp. Med. 206, 2869–2877 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Hagner, S. et al. Farm-derived Gram-positive bacterium Staphylococcus sciuri W620 prevents asthma phenotype in HDM- and OVA-exposed mice. Allergy 68, 322–329 (2013).

    CAS  PubMed  Google Scholar 

  87. 87.

    Nembrini, C. et al. Bacterial-induced protection against allergic inflammation through a multicomponent immunoregulatory mechanism. Thorax 66, 755–763 (2011).

    PubMed  Google Scholar 

  88. 88.

    Vogel, K. et al. Animal shed Bacillus licheniformis spores possess allergy-protective as well as inflammatory properties. J. Allergy Clin. Immunol. 122, 307–312 (2008).

    PubMed  Google Scholar 

  89. 89.

    Arnold, I. C. et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J. Clin. Invest. 121, 3088–3093 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Oertli, M. et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J. Clin. Invest. 122, 1082–1096 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Oertli, M. et al. Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc. Natl Acad. Sci. USA 110, 3047–3052 (2013).

    CAS  PubMed  Google Scholar 

  92. 92.

    Koch, K. N. et al. Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma. J. Clin. Invest. 125, 3297–3302 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Kyburz, A. et al. Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells. J. Allergy Clin. Immunol. 143, 1496–1512.e111 (2018).

    PubMed  Google Scholar 

  94. 94.

    Eberl, G. Immunity by equilibrium. Nat. Rev. Immunol. 16, 524–532 (2016).

    CAS  PubMed  Google Scholar 

  95. 95.

    Brown, R. L., Sequeira, R. P. & Clarke, T. B. The microbiota protects against respiratory infection via GM-CSF signaling. Nat. Commun. 8, 1512 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Kanmani, P. et al. Respiratory commensal bacteria Corynebacterium pseudodiphtheriticum improves resistance of infant mice to respiratory syncytial virus and Streptococcus pneumoniae superinfection. Front. Microbiol. 8, 1613 (2017).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Gauguet, S. et al. Intestinal microbiota of mice influences resistance to Staphylococcus aureus pneumonia. Infect. Immun. 83, 4003–4014 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Chua, H. H. et al. Intestinal dysbiosis featuring abundance of Ruminococcus gnavus associates with allergic diseases in infants. Gastroenterology 154, 154–167 (2018).

    PubMed  Google Scholar 

  99. 99.

    Noverr, M. C., Falkowski, N. R., McDonald, R. A., McKenzie, A. N. & Huffnagle, G. B. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect. Immun. 73, 30–38 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Noverr, M. C., Noggle, R. M., Toews, G. B. & Huffnagle, G. B. Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect. Immun. 72, 4996–5003 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Li, X. et al. Response to fungal dysbiosis by gut-resident CX3CR1+ mononuclear phagocytes aggravates allergic airway disease. Cell Host Microbe 24, 847–856 e844 (2018).

    CAS  PubMed  Google Scholar 

  102. 102.

    Wheeler, M. L. et al. Immunological consequences of intestinal fungal dysbiosis. Cell Host Microbe 19, 865–873 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Skalski, J. H. et al. Expansion of commensal fungus Wallemia mellicola in the gastrointestinal mycobiota enhances the severity of allergic airway disease in mice. PLoS Pathog. 14, e1007260 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Rondanelli, M. et al. Using probiotics in clinical practice: where are we now? A review of existing meta-analyses. Gut Microbes 8, 521–543 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Malikowski, T., Khanna, S. & Pardi, D. S. Fecal microbiota transplantation for gastrointestinal disorders. Curr. Opin. Gastroenterol. 33, 8–13 (2017).

    CAS  PubMed  Google Scholar 

  106. 106.

    Schuijt, T. J. et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 65, 575–583 (2016).

    CAS  PubMed  Google Scholar 

  107. 107.

    Maizels, R. M., Smits, H. H. & McSorley, H. J. Modulation of host immunity by helminths: the expanding repertoire of parasite effector molecules. Immunity 49, 801–818 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Zaiss, M. M. et al. The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity 43, 998–1010 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Xu, M. et al. Altered gut microbiota composition in subjects infected with Clonorchis sinensis. Front. Microbiol. 9, 2292 (2018).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Groves, H. T. et al. Respiratory disease following viral lung infection alters the murine gut microbiota. Front. Immunol. 9, 182 (2018).

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Erb Downward, J. R., Falkowski, N. R., Mason, K. L., Muraglia, R. & Huffnagle, G. B. Modulation of post-antibiotic bacterial community reassembly and host response by Candida albicans. Sci. Rep. 3, 2191 (2013).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Mason, K. L. et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect. Immun. 80, 3371–3380 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Jartti, T. & Gern, J. E. Role of viral infections in the development and exacerbation of asthma in children. J. Allergy Clin. Immunol. 140, 895–906 (2017).

    PubMed  Google Scholar 

  114. 114.

    Jiang, T. T. et al. Commensal fungi recapitulate the protective benefits of intestinal bacteria. Cell Host Microbe 22, 809–816.e804 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Ursell, L. K., Metcalf, J. L., Parfrey, L. W. & Knight, R. Defining the human microbiome. Nutr. Rev. 70, S38–S44 (2012).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Gordon, H. A. & Pesti, L. The gnotobiotic animal as a tool in the study of host microbial relationships. Bacteriol. Rev. 35, 390–429 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Mackowiak, P. A. Recycling metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front. Public Health 1, 52 (2013).

    PubMed  PubMed Central  Google Scholar 

  118. 118.

    Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006).

    CAS  PubMed  Google Scholar 

  119. 119.

    Koropatkin, N. M., Cameron, E. A. & Martens, E. C. How glycan metabolism shapes the human gut microbiota. Nat. Rev. Microbiol. 10, 323–335 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Macpherson, A. J., Geuking, M. B. & McCoy, K. D. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 115, 153–162 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Cerutti, A. & Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity 28, 740–750 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Pabst, O. New concepts in the generation and functions of IgA. Nat. Rev. Immunol. 12, 821–832 (2012).

    CAS  PubMed  Google Scholar 

  123. 123.

    Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358, eaan6619 (2017).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541–553 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Lindner, C. et al. Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J. Exp. Med. 209, 365–377 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Lindner, C. et al. Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota. Nat. Immunol. 16, 880–888 (2015).

    CAS  PubMed  Google Scholar 

  128. 128.

    Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).

    CAS  PubMed  Google Scholar 

  129. 129.

    Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

    CAS  PubMed  Google Scholar 

  130. 130.

    Kellermayer, R. et al. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice. FASEB J. 25, 1449–1460 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Carvalho, F. A. et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139–152 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Frantz, A. L. et al. Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. Mucosal Immunol. 5, 501–512 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Ubeda, C. et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209, 1445–1456 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Mamantopoulos, M. et al. Nlrp6- and ASC-dependent inflammasomes do not shape the commensal gut microbiota composition. Immunity 47, 339–348.e334 (2017).

    CAS  PubMed  Google Scholar 

  136. 136.

    Scholz, F., Badgley, B. D., Sadowsky, M. J. & Kaplan, D. H. Immune mediated shaping of microflora community composition depends on barrier site. PLoS One 9, e84019 (2014).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Sheflin, A. M., Melby, C. L., Carbonero, F. & Weir, T. L. Linking dietary patterns with gut microbial composition and function. Gut Microbes 8, 113–129 (2017).

    CAS  PubMed  Google Scholar 

  138. 138.

    Wypych, T. P. & Marsland, B. J. Diet hypotheses in light of the microbiota revolution: new perspectives. Nutrients 9, E537 (2017).

    PubMed  Google Scholar 

  139. 139.

    Hanski, I. et al. Environmental biodiversity, human microbiota, and allergy are interrelated. Proc. Natl Acad. Sci. USA 109, 8334–8339 (2012).

    CAS  PubMed  Google Scholar 

  140. 140.

    Azad, M. B. et al. Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity. Allergy Asthma Clin. Immunol. 9, 15 (2013).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Song, S. J. et al. Cohabiting family members share microbiota with one another and with their dogs. eLife 2, e00458 (2013).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Tun, H. M. et al. Exposure to household furry pets influences the gut microbiota of infant at 3–4 months following various birth scenarios. Microbiome 5, 40 (2017).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Bartley, J. M., Zhou, X., Kuchel, G. A., Weinstock, G. M. & Haynes, L. Impact of age, caloric restriction, and influenza infection on mouse gut microbiome: an exploratory study of the role of age-related microbiome changes on influenza responses. Front. Immunol. 8, 1164 (2017).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Yildiz, S., Mazel-Sanchez, B., Kandasamy, M., Manicassamy, B. & Schmolke, M. Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis. Microbiome 6, 9 (2018).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Hoffmann, C. et al. Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing. Infect. Immun. 77, 4668–4678 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Bretin, A. et al. AIEC infection triggers modification of gut microbiota composition in genetically predisposed mice, contributing to intestinal inflammation. Sci. Rep. 8, 12301 (2018).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Itthitaetrakool, U. et al. Chronic Opisthorchis viverrini infection changes the liver microbiome and promotes Helicobacter growth. PLoS One 11, e0165798 (2016).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Kuhn, K. A. & Stappenbeck, T. S. Peripheral education of the immune system by the colonic microbiota. Semin. Immunol. 25, 364–369 (2013).

    CAS  PubMed  Google Scholar 

  149. 149.

    Gensollen, T., Iyer, S. S., Kasper, D. L. & Blumberg, R. S. How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Torow, N. & Hornef, M. W. The neonatal window of opportunity: setting the stage for life-long host-microbial interaction and immune homeostasis. J. Immunol. 198, 557–563 (2017).

    CAS  PubMed  Google Scholar 

  151. 151.

    Becattini, S., Taur, Y. & Pamer, E. G. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol. Med. 22, 458–478 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Wypych, T. P. & Marsland, B. J. Antibiotics as instigators of microbial dysbiosis: implications for asthma and allergy. Trends Immunol. 39, 697–711 (2018).

    CAS  PubMed  Google Scholar 

  153. 153.

    Langdon, A., Crook, N. & Dantas, G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 8, 39 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Hori, T., Kiyoshima, J., Shida, K. & Yasui, H. Augmentation of cellular immunity and reduction of influenza virus titer in aged mice fed Lactobacillus casei strain Shirota. Clin. Diagn. Lab. Immunol. 9, 105–108 (2002).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Yasui, H., Shida, K., Matsuzaki, T. & Yokokura, T. Immunomodulatory function of lactic acid bacteria. Antonie van Leeuwenhoek 76, 383–389 (1999).

    CAS  PubMed  Google Scholar 

  156. 156.

    Jung, Y. J. et al. Heat-killed Lactobacillus casei confers broad protection against influenza A virus primary infection and develops heterosubtypic immunity against future secondary infection. Sci. Rep. 7, 17360 (2017).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Kawase, M., He, F., Kubota, A., Harata, G. & Hiramatsu, M. Oral administration of lactobacilli from human intestinal tract protects mice against influenza virus infection. Lett. Appl. Microbiol. 51, 6–10 (2010).

    CAS  PubMed  Google Scholar 

  158. 158.

    Zelaya, H., Villena, J., Lopez, A. G., Alvarez, S. & Agüero, G. Modulation of the inflammation-coagulation interaction during pneumococcal pneumonia by immunobiotic Lactobacillus rhamnosus CRL1505: role of Toll-like receptor 2. Microbiol. Immunol. 58, 416–426 (2014).

    CAS  PubMed  Google Scholar 

  159. 159.

    Kawase, M. et al. Heat-killed Lactobacillus gasseri TMC0356 protects mice against influenza virus infection by stimulating gut and respiratory immune responses. FEMS Immunol. Med. Microbiol. 64, 280–288 (2012).

    CAS  PubMed  Google Scholar 

  160. 160.

    Nakayama, Y. et al. Oral administration of Lactobacillus gasseri SBT2055 is effective for preventing influenza in mice. Sci. Rep. 4, 4638 (2014).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Kobayashi, N. et al. Oral administration of heat-killed Lactobacillus pentosus strain b240 augments protection against influenza virus infection in mice. Int. Immunopharmacol. 11, 199–203 (2011).

    CAS  PubMed  Google Scholar 

  162. 162.

    Maeda, N. et al. Oral administration of heat-killed Lactobacillus plantarum L-137 enhances protection against influenza virus infection by stimulation of type I interferon production in mice. Int. Immunopharmacol. 9, 1122–1125 (2009).

    CAS  PubMed  Google Scholar 

  163. 163.

    Takeda, S. et al. Efficacy of oral administration of heat-killed probiotics from Mongolian dairy products against influenza infection in mice: alleviation of influenza infection by its immunomodulatory activity through intestinal immunity. Int. Immunopharmacol. 11, 1976–1983 (2011).

    CAS  PubMed  Google Scholar 

  164. 164.

    Park, M. K. et al. Lactobacillus plantarum DK119 as a probiotic confers protection against influenza virus by modulating innate immunity. PLoS One 8, e75368 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Kikuchi, Y. et al. Oral administration of Lactobacillus plantarum strain AYA enhances IgA secretion and provides survival protection against influenza virus infection in mice. PLoS One 9, e86416 (2014).

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    Waki, N. et al. Oral administration of Lactobacillus brevis KB290 to mice alleviates clinical symptoms following influenza virus infection. Lett. Appl. Microbiol. 58, 87–93 (2014).

    CAS  PubMed  Google Scholar 

  167. 167.

    Fujimura, K. E. et al. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. Proc. Natl Acad. Sci. USA 111, 805–810 (2014).

    CAS  PubMed  Google Scholar 

  168. 168.

    Villena, J. et al. Lactobacillus casei improves resistance to pneumococcal respiratory infection in malnourished mice. J. Nutr. 135, 1462–1469 (2005).

    CAS  PubMed  Google Scholar 

  169. 169.

    Racedo, S. et al. Lactobacillus casei administration reduces lung injuries in a Streptococcus pneumoniae infection in mice. Microbes Infect. 8, 2359–2366 (2006).

    PubMed  Google Scholar 

  170. 170.

    Salva, S., Villena, J. & Alvarez, S. Immunomodulatory activity of Lactobacillus rhamnosus strains isolated from goat milk: impact on intestinal and respiratory infections. Int. J. Food Microbiol. 141, 82–89 (2010).

    CAS  PubMed  Google Scholar 

  171. 171.

    Alvarez, S., Herrero, C., Bru, E. & Perdigon, G. Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice. J. Food Prot. 64, 1768–1774 (2001).

    CAS  PubMed  Google Scholar 

  172. 172.

    Khailova, L., Petrie, B., Baird, C. H., Dominguez Rieg, J. A. & Wischmeyer, P. E. Lactobacillus rhamnosus GG and Bifidobacterium longum attenuate lung injury and inflammatory response in experimental sepsis. PLoS One 9, e97861 (2014).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    Zelaya, H. et al. Nasal priming with immunobiotic Lactobacillus rhamnosus modulates inflammation-coagulation interactions and reduces influenza virus-associated pulmonary damage. Inflamm. Res. 64, 589–602 (2015).

    CAS  PubMed  Google Scholar 

  174. 174.

    Kruisselbrink, A., Heijne Den Bak-Glashouwer, M. J., Havenith, C. E., Thole, J. E. & Janssen, R. Recombinant Lactobacillus plantarum inhibits house dust mite-specific T-cell responses. Clin. Exp. Immunol. 126, 2–8 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Forsythe, P., Inman, M. D. & Bienenstock, J. Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am. J. Respir. Crit. Care Med. 175, 561–569 (2007).

    PubMed  Google Scholar 

  176. 176.

    Feleszko, W. et al. Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma. Clin. Exp. Allergy 37, 498–505 (2007).

    CAS  PubMed  Google Scholar 

  177. 177.

    Blümer, N. et al. Perinatal maternal application of Lactobacillus rhamnosus GG suppresses allergic airway inflammation in mouse offspring. Clin. Exp. Allergy 37, 348–357 (2007).

    PubMed  Google Scholar 

  178. 178.

    Karimi, K., Inman, M. D., Bienenstock, J. & Forsythe, P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 179, 186–193 (2009).

    CAS  PubMed  Google Scholar 

  179. 179.

    Wang, X. et al. Oral administration of Lactobacillus paracasei L9 attenuates PM2.5-induced enhancement of airway hyperresponsiveness and allergic airway response in murine model of asthma. PLoS One 12, e0171721 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    Kawahara, T. et al. Consecutive oral administration of Bifidobacterium longum MM-2 improves the defense system against influenza virus infection by enhancing natural killer cell activity in a murine model. Microbiol. Immunol. 59, 1–12 (2015).

    CAS  PubMed  Google Scholar 

  181. 181.

    Vieira, A. T. et al. Control of Klebsiella pneumoniae pulmonary infection and immunomodulation by oral treatment with the commensal probiotic Bifidobacterium longum 5(1A). Microbes Infect. 18, 180–189 (2016).

    PubMed  Google Scholar 

  182. 182.

    Hougee, S. et al. Oral treatment with probiotics reduces allergic symptoms in ovalbumin-sensitized mice: a bacterial strain comparative study. Int. Arch. Allergy Immunol. 151, 107–117 (2010).

    CAS  PubMed  Google Scholar 

  183. 183.

    MacSharry, J. et al. Immunomodulatory effects of feeding with Bifidobacterium longum on allergen-induced lung inflammation in the mouse. Pulm. Pharmacol. Ther. 25, 325–334 (2012).

    CAS  PubMed  Google Scholar 

  184. 184.

    Mendes, E. et al. Prophylactic supplementation of Bifidobacterium longum 51A protects mice from ovariectomy-induced exacerbated allergic airway inflammation and airway hyperresponsiveness. Front. Microbiol. 8, 1732 (2017).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    Sagar, S. et al. Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma. Respir. Res. 15, 46 (2014).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

T.P.W. is supported by a Postdoc Mobility Fellowship from the Swiss National Science Foundation. B.J.M. is an NHMRC Senior Research Fellow and a VESKI Innovation Fellow.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Tomasz P. Wypych or Benjamin J. Marsland.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information: Jamie D.K. Wilson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wypych, T.P., Wickramasinghe, L.C. & Marsland, B.J. The influence of the microbiome on respiratory health. Nat Immunol 20, 1279–1290 (2019). https://doi.org/10.1038/s41590-019-0451-9

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing