The influence of the microbiome on respiratory health

Article metrics


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 optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


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.


  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).

  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).

  3. 3.

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

  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).

  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).

  6. 6.

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

  7. 7.

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

  8. 8.

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

  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).

  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).

  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).

  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).

  13. 13.

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

  14. 14.

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

  15. 15.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  26. 26.

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

  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).

  28. 28.

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

  29. 29.

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

  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).

  31. 31.

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

  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).

  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).

  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).

  35. 35.

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

  36. 36.

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

  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).

  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).

  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).

  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).

  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).

  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).

  43. 43.

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

  44. 44.

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

  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).

  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).

  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).

  48. 48.

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

  49. 49.

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

  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).

  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).

  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).

  53. 53.

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

  54. 54.

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

  55. 55.

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

  56. 56.

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

  57. 57.

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

  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).

  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).

  60. 60.

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

  61. 61.

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

  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).

  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).

  64. 64.

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

  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).

  66. 66.

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

  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).

  68. 68.

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

  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).

  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).

  71. 71.

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

  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).

  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).

  74. 74.

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

  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).

  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).

  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).

  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).

  79. 79.

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

  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).

  81. 81.

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

  82. 82.

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

  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).

  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).

  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).

  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).

  87. 87.

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

  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).

  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).

  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).

  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).

  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).

  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).

  94. 94.

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

  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).

  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).

  97. 97.

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

  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).

  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).

  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).

  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).

  102. 102.

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

  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).

  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).

  105. 105.

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

  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).

  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).

  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).

  109. 109.

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

  110. 110.

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

  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).

  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).

  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).

  114. 114.

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

  115. 115.

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

  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).

  117. 117.

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

  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).

  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).

  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).

  121. 121.

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

  122. 122.

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

  123. 123.

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

  124. 124.

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

  125. 125.

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

  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).

  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).

  128. 128.

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

  129. 129.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  138. 138.

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

  139. 139.

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

  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).

  141. 141.

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

  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).

  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).

  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).

  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).

  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).

  147. 147.

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

  148. 148.

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

  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).

  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).

  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).

  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).

  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).

  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).

  155. 155.

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

  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).

  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).

  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).

  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).

  160. 160.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  168. 168.

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

Download references


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

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