Microbiota-Mediated Immunomodulation and Asthma: Current and Future Perspectives

Opinion statement

Estimated to burden over 300 million people and their families around the world, asthma is now considered one of the most common forms of non-communicable disease worldwide (Masoli et al. Allergy Eur J Allergy Clin Immunol 59:469–78, 2004 1). The epidemic rise in prevalence this disease has seen over recent decades (Platts-Mills J Allergy Clin Immunol 136:3–13, 2015 2) suggests that environmental factors are the primary drivers of this phenomenon. In particular, the importance of early life microbial exposure and the composition of the early life gut and lung microbiota are emerging as key determinants of asthma outcomes later in life. Borne out of epidemiological data showing associations between the composition of the early life gut microbiota and later development of asthma, interest in harnessing the human microbiome as a therapeutic tool to prevent the development of asthma is rising. As research elucidating the mechanisms, specific microbial species, and microbial products mediating this link continues, it is becoming clear that, like the disease itself, the relationships between microbes and their hosts are highly complex and heterogeneous across populations. As a result, probiotic trials aimed at the primary prevention of asthma have been largely unsuccessful thus far. Future work aiming to apply our understanding of the role of the microbiota in health and disease to the prevention of atopic asthma will likely need to take a population-specific approach and has the potential to dramatically change the face of current asthma treatment practices.

This is a preview of subscription content, log in to check access.

Fig. 1

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy Eur J Allergy Clin Immunol. 2004;59:469–78.

    Article  Google Scholar 

  2. 2.

    Platts-Mills TAE. The allergy epidemics: 1870-2010. J. Allergy Clin. Immunol. 2015;136:3–13.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    WHO. Global status report on noncommunicable diseases 2014. World Health. 2014;176.

  4. 4.

    Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800.

    Article  Google Scholar 

  5. 5.

    Busse WW, Lemansk RFJR. Asthma. N Engl J Med. 2001;344:350–62.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Hirota N, Martin JG. Mechanisms of airway remodeling. Chest. 2013;144:1026–32.

    PubMed  Article  Google Scholar 

  7. 7.

    Lynch SV, Wood RA, Boushey H, Bacharier LB, Bloomberg GR, Kattan M, et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J. Allergy Clin. Immunol. 2014;134:593–601.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun. 2006;7:95–100.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Beigelman A, Bacharier LB. Early-life respiratory infections and asthma development. Curr Opin Allergy Clin Immunol. 2016;16:172–8.

    PubMed  Article  Google Scholar 

  10. 10.

    Lin T-Y, Poon AH, Hamid Q. Asthma phenotypes and endotypes. Curr Opin Pulm Med. 2013;19:18–23.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16:45–56.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Mckinley L, Alcorn JF, Peterson A, Dupont B, Kapadia S, Logar A, et al. Th17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008;6:4089–97.

    Article  Google Scholar 

  13. 13.

    Nakagome K, Nagata M. Pathogenesis of airway inflammation in bronchial asthma. Auris Nasus Larynx. 2011;38:555–63.

    PubMed  Article  Google Scholar 

  14. 14.

    Mallol J, Crane J, von Mutius E, Odhiambo J, Keil U, Stewart A. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three: a global synthesis. Allergol Immunopathol (Madr). 2013;41:73–85.

    CAS  Article  Google Scholar 

  15. 15.

    Pearce N, Aït-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E, et al. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2007;62:758–66.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Noverr MC, Huffnagle GB. The “microflora hypothesis” of allergic diseases. Clin Exp Allergy. 2005;35:1511–20.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Kondrashova A, Seiskari T, Ilonen J, Knip M, Hyöty H. The “hygiene hypothesis” and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS. 2013;121:478–93.

    PubMed  Article  Google Scholar 

  19. 19.

    Brown EM, Arrieta M-C, Finlay BB. A fresh look at the hygiene hypothesis: how intestinal microbial exposure drives immune effector responses in atopic disease. Semin Immunol. 2013;25:378–87.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Wold AE. The hygiene hypothesis revised : is the frequency of allergy d ue to changes in the intestinal flora? Allergy. 1998;53:20–5.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Björkstén B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J. Allergy Clin. Immunol. 2001;108:516–20.

    PubMed  Article  Google Scholar 

  22. 22.

    Kalliomäki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J. Allergy Clin. Immunol. 2001;107:129–34.

    PubMed  Article  Google Scholar 

  23. 23•.

    Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy. 2014;44:842–50. Using 16s rDNA 454 pyrosequencing, these authors demonstrate using data from a long-term follow-up study in a Swedish birth cohort that children who develop asthma by age seven harbor a less diverse microbiota at one week and one month of age as compared to healthy children. These differences do not persist into the first year of life

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Bisgaard H, Li N, Bonnelykke K, Chawes BLK, Skov T, Paludan-Müller G, et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J. Allergy Clin. Immunol. 2011;128:646–52.

    PubMed  Article  Google Scholar 

  25. 25.

    Sjögren YM, Jenmalm MC, Böttcher MF, Björkstén B, Sverremark-Ekström E. Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy. 2009;39:518–26.

    PubMed  Article  Google Scholar 

  26. 26.

    Björkstén B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy. 1999;29:342–6.

    PubMed  Article  Google Scholar 

  27. 27.

    Van Nimwegen FA, Penders J, Stobberingh EE, Postma DS, Koppelman GH, Kerkhof M, et al. Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. J. Allergy Clin. Immunol. 2011;128:948–55.

    PubMed  Article  Google Scholar 

  28. 28.

    Tollånes MC, Moster D, Daltveit AK, Irgens LM. Cesarean section and risk of severe childhood asthma: a population-based cohort study. J Pediatr. 2008;153:112–6.

    PubMed  Article  Google Scholar 

  29. 29.

    Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118:511–21.

    PubMed  Article  Google Scholar 

  30. 30•.

    Fall, T, Lundholm, C, Örtqvist, AK, Fall, K, Fang, F, Hedhammar, Å, et al. Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma. JAMA Pediatr. 2015;169. In the biggest nationwide cohort study to date, these authors found that dog ownership and farm animal exposure during the first year of life are associated with protection against asthma at age six. The study enrolment of over one million subjects, stringent asthma outcome criteria, comprehensive assessment and correction for potential confounds, and long-term follow up period all contribute to the validity of these findings.

  31. 31.

    Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med. 2009;343:538–43.

    Article  Google Scholar 

  32. 32.

    Murk W, Risnes KR, Bracken MB. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics. 2011;127:1125–38.

    PubMed  Article  Google Scholar 

  33. 33•.

    Meropol SB, Edwards A. Development of the infant intestinal microbiome: a bird’s eye view of a complex process. Birth Defects Res Part C - Embryo Today Rev. 2015;105:228–39. Up-to-date review of the process of colonization of the infant gut by the gut microbiota, the factors influencing this process, and studies showing associations between microbial dysbiosis and the development of pathologies of the immune system, metabolism, and brain

    CAS  Article  Google Scholar 

  34. 34.

    Stensballe LG, Simonsen J, Jensen SM, Bønnelykke K, Bisgaard H. Use of antibiotics during pregnancy increases the risk of asthma in early childhood. J Pediatr. 2013;162:832–8.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529:212–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Ege MJ, Bieli C, Frei R, van Strien RT, Riedler J, Üblagger E, et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J. Allergy Clin. Immunol. 2006;117:817–23.

    PubMed  Article  Google Scholar 

  37. 37•.

    Gollwitzer ES, Marsland BJ. Impact of early-life exposures on immune maturation and susceptibility to disease. Trends Immunol. 2015;36:684–96 .Timely review covering the nature of and mechanisms by which early life environmental factors influence the development of the immune system during a critical period of maturation, including an in-depth discussion of the role of the microbiota in this process

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107:11971–5.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Eggesbø M, Moen B, Peddada S, Baird D, Rugtveit J, Midtvedt T, et al. Development of gut microbiota in infants not exposed to medical interventions. APMIS. 2011;119:17–35.

    PubMed  Article  Google Scholar 

  40. 40.

    Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2009;457:222–7.

    Google Scholar 

  41. 41.

    Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337–40.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Renz H, Brandtzaeg P, Hornef M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol. 2011;12:9–23.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Prescott SL, Macaubas C, Holt BJ, Troy B, Loh R, Sly PD, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol. 1998;160.

  44. 44.

    Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergen-specific T-cell memory in atopic and normal children. Lancet. 1999;353:196–200.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol. 1997;159:1739–45.

    CAS  PubMed  Google Scholar 

  46. 46.

    Herbst T, Sichelstiel A, Schär C, Yadava K, Bürki K, Cahenzli J, et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med. 2011;184:198–205.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012;336:489–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012;13:440–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49••.

    Russell SL, Gold MJ, Willing BP, Thorson L, Mcnagny KM, Finlay BB. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes. 2013;4:158–64. In an addendum to their previous work, these authors use a murine model of asthma to show that the exacerbated allergic asthma phenotype observed in mice treated perinatally with vancomycin occurs only if antibiotic exposure occurs between birth and three weeks of age, and is associated with increased circulating IgE levels and reduced colonic CD4+CD25+Foxp3+ Tregs. Prenatal antibiotic exposure alone was not sufficient to increase allergic asthma susceptibility compared to controls

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Penders J, Thijs C, van den Brandt PA, Kummeling I, Snijders B, Stelma F, et al. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA birth cohort study. Gut. 2007;56:661–7.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Ege MJ, Mayer M, Normand A-C, Genuneit J, Cookson WOCM, Braun-Fahrlander C, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011;364:701–9.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016;7:1–8.

    Article  CAS  Google Scholar 

  53. 53.

    Kummeling I, Stelma FF, Dagnelie PC, Snijders BEP, Penders J, Huber M, et al. Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics. 2007;119.

  54. 54.

    Risnes KR, Belanger K, Murk W, Bracken MB. Antibiotic exposure by 6 months and asthma and aAllergy at 6 Years: findings in a cohort of 1,401 US children. Am J Epidemiol. 2010;173:310–8.

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55••.

    Fujimura KE, Demoor T, Rauch M, Faruqi AA, Jang S, Johnson CC, et al. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. Proc Natl Acad Sci U S A. 2014;111:805–10. Using two different murine models of asthma, these authors show that early life exposure to house dust from a home containing a dog is associated with protection against the development of Th2-type asthma pathology and with increased levels of fecal microbes from the genera Clostridia and Bacilli as compared to mice exposed to dust from a non-dog house. Representing one of the most highly enriched groups, these authors further show that oral administration of L. johnsonii to wild-type animals alone is sufficient to protect against both asthmatic airway inflammation and infection by respiratory syncytial virus

    CAS  PubMed  Article  Google Scholar 

  56. 56••.

    Arrieta MC, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7:307ra152. In the first study to show a causal link between early life microbial dysbiosis and the later development of asthma, these authors found that children at high risk of developing asthma exhibit reduced levels of bacteria from the genera Lachnospira, Veillonella, Faecalibacterium, and Rothia (FLVR) in their feces as well as differences in fecal and urine metabolite concentrations at three months of age relative to healthy children. They further show in a murine model of asthma that the addition of FLVR organisms to an inoculum of feces from a three month old child at high risk of developing asthma given to germ-free mice reduces airway inflammation observed in their progeny as compared to the progeny of mice inoculated with the non-supplemented feces

  57. 57••.

    Schuijs MJ, Willart MA, Vergote K, Gras D, Deswarte K, Ege MJ, et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science. 2015;349:1106–10. This is the first study to show a mechanistic link between farm dust exposure and protection against allergic asthma. These authors used a murine model of asthma to show that mice chronically exposed intranasally to low-dose endotoxin or farm dust are protected against the airway inflammation observed in control animals. This effect was found to be mediated by reduced expression of the A20 protein in lung epithelial tissue leading to diminished DC infiltration to the lungs and reduced DC-induced Th2 cell maturation following allergen sensitization and challenge. Further confirming the clinical relevance of their findings, the authors also showed that humans with a mutation in the gene encoding A20 are at increased risk of developing asthma, especially when they are raised in a farming environment

    CAS  PubMed  Article  Google Scholar 

  58. 58••.

    Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ, et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun. 2015;6:7320. In a potentially landmark study, these authors show that mice fed a high-fiber diet harbor a gut microbiota that is compositionally distinct from that of mice fed a control or no-fiber diet. This microbiota was associated with higher levels of fecal acetate and protection against allergic airway inflammation in a murine model of asthma. Moreover, mice born to mothers who consumed a high-fiber diet or acetate were protected against airway inflammation in the same model. This effect was maintained even if mice were delivered by caesarean section and thought to be mediated by an increase in the numbers and activation of Treg cells resulting from epigenetically-induced changes in gene expression in the lungs of these mice

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J, et al. Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J. Allergy Clin. Immunol. 2011;128:618–25.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Conrad ML, Ferstl R, Teich R, Brand S, Blümer N, Yildirim AO, et al. Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med. 2009;206:2869–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Braga M, Schiavone C, Di Gioacchino G, De Angelis I, Cavallucci E, Lazzarin F, et al. Environment and T regulatory cells in allergy. Sci. Total Environ. Elsevier B.V.; 2012;423:193–201.

  62. 62.

    Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, et al. Extrathymically generated regulatory T cells control mucosal Th2 inflammation. Nature. 2012;482:395–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J Clin Invest. 2011;121:3088–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med. 2012;18:538–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Chu KH, Chiang BL. Regulatory T cells induced by mucosal B cells alleviate allergic airway hypersensitivity. Am J Respir Cell Mol Biol. 2012;46:651–9.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Russell SL, Finlay BB. The impact of gut microbes in allergic diseases. Curr Opin Gastroenterol. 2012;28:563–9.

    PubMed  Article  Google Scholar 

  68. 68.

    Steinmeyer S, Lee K, Jayaraman A, Alaniz RC. Microbiota metabolite regulation of host immune homeostasis: a mechanistic missing link. Curr Allergy Asthma Rep. 2015;15:24.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–50.

    CAS  PubMed  Article  Google Scholar 

  70. 70•.

    Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73. One of the first studies to show that bacteria-derived SCFAs are important in the regulation of colonic Foxp3+IL-10–producing Treg cell activity and proliferation. The authors used the SCFA propionate to further show that these SCFA-mediated effects depend on normal Ffar2 expression

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, DeRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17:662–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Vuillermin PJ, Ponsonby AL, Saffery R, Tang ML, Ellis JA, Sly P, et al. Microbial exposure, interferon gamma gene demethylation in naïve T-cells, and the risk of allergic disease. Allergy Eur J Allergy Clin Immunol. 2009;64:348–53.

    CAS  Article  Google Scholar 

  74. 74.

    Suarez-Alvarez B, Rodriguez RM, Fraga MF, López-Larrea C. DNA methylation: a promising landscape for immune system-related diseases. Trends Genet. 2012;28:506–14.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Schaub B, Liu J, Höppler S, Schleich I, Huehn J, Olek S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol. 2009;123:774–82.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Gerhold K, Avagyan A, Seib C, Frei R, Steinle J, Ahrens B, et al. Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J. Allergy Clin. Immunol. 2006;118:666–73.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357:1487–95.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Korppi M. Bacterial infections and pediatric asthma. Immunol Allergy Clin N Am. 2010;30:565–74.

    Article  Google Scholar 

  79. 79•.

    Earl CS, An S, Ryan RP. The changing face of asthma and its relation with microbes. Trends Microbiol. 2015;23:408–18. Recent review focusing primarily on the influences of airway microorganisms on the development of specific subtypes of asthma. The authors also include a nice summary table of the findings of studies since 2011 looking at the effects of pre- and probiotics as well as other supplements on asthma and asthma-related symptoms

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Green BJ, Wiriyachaiporn S, Grainge C, Rogers GB, Kehagia V, Lau R, et al. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One. 2014;9:4–10.

    Google Scholar 

  81. 81.

    Tomosada Y, Chiba E, Zelaya H, Takahashi T, Tsukida K, Kitazawa H, et al. Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. BMC Immunol. 2013;14:40.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Kloepfer KM, Lee WM, Pappas TE, Kang TJ, Vrtis RF, Evans MD, et al. Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations. J. Allergy Clin. Immunol. 2014;133:1301–7.

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83•.

    Holt PG. The mechanism or mechanisms driving atopic asthma initiation: the infant respiratory microbiome moves to center stage. J Allergy Clin Immunol. 2015;136:15–22. Detailed review of the role of early life viral respiratory tract infections in the development of the pathological features of asthma, and how this relationship is further complicated by the influences of pathogenic bacteria in the airway and the airway microbiome

    PubMed  Article  Google Scholar 

  84. 84.

    Forsythe P. Probiotics and lung diseases. Chest. 2011;139:901–8.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Gill N, Wlodarska M, Finlay BB. The future of mucosal immunology: studying an integrated system-wide organ. Nat Immunol. 2010;11:558–60.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 2004;12:562–8.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Arrieta M-C, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The intestinal microbiome in early life: health and disease. Front Immunol. 2014;5:1–18.

    CAS  Article  Google Scholar 

  88. 88.

    Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med. 2014;20:642–7.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, et al. Disordered microbial communities in asthmatic airways. PLoS One. 2010;5.

  90. 90.

    Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J. Allergy Clin. Immunol. 2011;127:372–81.

    PubMed  Article  Google Scholar 

  91. 91.

    Park H, Shin JW, Park S-G, Kim W. Microbial communities in the upper respiratory tract of patients with asthma and chronic obstructive pulmonary disease. PLoS One. 2014;9.

  92. 92.

    Marri PR, Stern DA, Wright AL, Billheimer D, Martinez FD. Asthma-associated differences in microbial composition of induced sputum. J Allergy Clin Immunol. 2013;131:346–52.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015;17:704–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Wilson MT, Hamilos DL. The nasal and sinus microbiome in health and disease. Curr Allergy Asthma Rep. 2014;14:485.

    PubMed  Article  CAS  Google Scholar 

  95. 95••.

    Fujimura KE, Lynch SV. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe. 2015;17:592–602. Extensive and detailed review of the literature to date implicating the gut and lung microbiota in the development of asthma and other allergic diseases. The authors discuss the mechanisms involved, as well as the factors capable of influencing these relationships

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Asher I, Pearce N. Global burden of asthma among children. Int J Tuberc Lung Dis. 2014;18:1269–78.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Jackson KD, Howie LD, Akinbami LJ. Trends in allergic conditions among children : United States, 1997–2011. NCHS Br. 2013;1–8.

  98. 98.

    Royce D. Knowledge translation opportunities in allergic disease and asthma. Allergy, asthma. Clin Immunol. 2010;6:A2.

    Google Scholar 

  99. 99.

    Lougheed DM, Lemiere C, Dell SD, Ducharme FM, FitzGerald MJ, Leigh R, et al. Canadian Thoracic Society Asthma Management Continuum - 2010 Consensus Summary for children six years of age and over, and adults. Can Respir J. 2010;17:15–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Lougheed MD, Garvey N, Chapman KR, Cicutto L, Dales R, Day AG, et al. The Ontario asthma regional variation study: emergency department visit rates and the relation to hospitalization rates. Chest. 2006;129:909–17.

    PubMed  Article  Google Scholar 

  101. 101.

    Sanders ME. Probiotics: definition, sources, selection, and uses. Clin Infect Dis. 2008;46:S58–61.

    PubMed  Article  Google Scholar 

  102. 102.

    Osborn D, Sinn J. Prebiotics in infants for prevention of allergy ( Review ). Cochrane Database Syst Rev. 2013;CD006474.

  103. 103.

    Forsythe P, Inman MD, Bienenstock J. Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am J Respir Crit Care Med. 2007;175:561–9.

    PubMed  Article  Google Scholar 

  104. 104.

    Lyons A, O’Mahony D, O’Brien F, MacSharry J, Sheil B, Ceddia M, et al. Bacterial strain-specific induction of Foxp3+ T regulatory cells is protective in murine allergy models. Clin Exp Allergy. 2010;40:811–9.

    CAS  PubMed  Google Scholar 

  105. 105.

    Blumer N, Sel S, Virna S, Patrascan C, Zimmermann S, Herz U, et al. Perinatal maternal application of Lactobacillus rhamnosus GG supresses allergic airway inflammation in mouse offsrping. Clin Exp Allergy. 2007;37:348–57.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Forsberg A, Abrahamsson TR, Björkstén B, Jenmalm MC. Pre- and post-natal Lactobacillus reuteri supplementation decreases allergen responsiveness in infancy. Clin Exp Allergy. 2013;43:434–42.

    CAS  PubMed  Article  Google Scholar 

  107. 107••.

    Cuello-Garcia, CA, Brożek, JL, Fiocchi, A, Pawankar, R, Yepes-Nuñez, JJ, Terracciano, L, et al. Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials. J. Allergy Clin. Immunol. 2015;1–10.Recent most comprehensive systematic review and meta-analysis of randomized controlled trials investigating the efficacy of probiotics in the prevention of allergic diseases published to date. The authors found that while the use of probiotics in pregnancy and/or infancy was associated with protection against infant eczema, no protective effects were found for the use of current probiotics against the development of asthma.

  108. 108.

    Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): probiotics. World Allergy Organ J. 2015;8:4.

    PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Prescott SL, Bjorksten B. Probiotics for the prevention or treatment of allergic diseases. J Allergy Clin Immunol. 2007;120:255–62.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Jenmalm MC, Duchén K. Timing of allergy-preventive and immunomodulatory dietary interventions - are prenatal, perinatal or postnatal strategies optimal? Clin Exp Allergy. 2013;43:273–8.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Stiehm M, Peters K, Wiesmüller KH, Bufe A, Peters M. A novel synthetic lipopeptide is allergy-protective by the induction of LPS-tolerance. Clin Exp Allergy. 2013;43:785–97.

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Moncayo AL, Vaca M, Oviedo G, Erazo S, Quinzo I, Fiaccone RL, et al. Risk factors for atopic and non-atopic asthma in a rural area of Ecuador. Thorax. 2010;65:409–16.

    PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Hevia A, Milani C, López P, Donado CD, Cuervo A, González S, et al. Allergic patients with long-term asthma display low levels of Bifidobacterium adolescentis. PLoS One. 2016;11.

Download references


The authors would like to thank Dr. Lisa Reynolds, Kylynda Bauer, and Dr. Marie-Claire Arrieta for their critical review of the manuscript and thoughtful insights.

Author information



Corresponding author

Correspondence to B. Brett Finlay PhD.

Ethics declarations

Conflict of Interest

Rozlyn C.T. Boutin declares that she has no conflict of interest.

Dr. B. Brett Finlay declares that he has no conflict of interest.

Rozlyn C.T. Boutin was supported by a Vancouver Coastal Health-CIHR-UBC MD/PhD Studentship Award during the writing of this review.

Dr. Finlay is the UBC Peter Wall Distinguished Professor and CIFAR Senior Fellow. The Finlay Lab is supported by operating grants from the Canadian Institute for Health Research (CIHR), AllerGen, and CIFAR-HMB.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Allergic Asthma

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Boutin, R.C.T., Finlay, B.B. Microbiota-Mediated Immunomodulation and Asthma: Current and Future Perspectives. Curr Treat Options Allergy 3, 292–309 (2016). https://doi.org/10.1007/s40521-016-0087-z

Download citation


  • Asthma
  • Microbiota
  • Allergy
  • Perinatal immune development
  • Atopy