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.

  • Review Article
  • Published:

Early life microbial exposures and allergy risks: opportunities for prevention

Nature Reviews Immunology volume 21, pages 177–191 (2021)Cite this article

Subjects

Abstract

Allergies, including asthma, food allergy and atopic dermatitis, are increasing in prevalence, particularly in westernized countries. Although a detailed mechanistic explanation for this increase is lacking, recent evidence indicates that, in addition to genetic predisposition, lifestyle changes owing to modernization have an important role. Such changes include increased rates of birth by caesarean delivery, increased early use of antibiotics, a westernized diet and the associated development of obesity, and changes in indoor and outdoor lifestyle and activity patterns. Most of these factors directly and indirectly impact the formation of a diverse microbiota, which includes bacterial, viral and fungal components; the microbiota has a leading role in shaping (early) immune responses. This default programme is markedly disturbed under the influence of environmental and lifestyle risk factors. Here, we review the most important allergy risk factors associated with changes in our exposure to the microbial world and the application of this knowledge to allergy prevention strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Caesarean delivery is an important risk factor for the development of chronic immune and metabolic disease.
Fig. 2: Prenatal and postnatal risk factors for the development of allergy and asthma.
Fig. 3: Reciprocal negative regulation of type I and III interferons and TH2-type responses in patients with asthma.
Fig. 4: The concept of inflammatory resilience.

Similar content being viewed by others

References

  1. Hill, D. A. & Spergel, J. M. The atopic march: critical evidence and clinical relevance. Ann. Allergy Asthma Immunol. 120, 131–137 (2018).

    PubMed  PubMed Central  Google Scholar 

  2. Belgrave, D. C. M. et al. Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies. PLoS Med. 11, e1001748 (2014).

    PubMed  PubMed Central  Google Scholar 

  3. Saunes, M. et al. Early eczema and the risk of childhood asthma: a prospective, population-based study. BMC Pediatr. 12, 168 (2012).

    PubMed  PubMed Central  Google Scholar 

  4. Kobyletzki, L. B. von et al. Eczema in early childhood is strongly associated with the development of asthma and rhinitis in a prospective cohort. BMC Dermatol. 12, 11 (2012).

    Google Scholar 

  5. Alduraywish, S. A. et al. The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies. Allergy 71, 77–89 (2016).

    CAS  PubMed  Google Scholar 

  6. Brough, H. A. et al. Peanut allergy. Effect of environmental peanut exposure in children with filaggrin loss-of-function mutations. J. Allergy Clin. Immunol. 134, 867–875.e1 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Bønnelykke, K. et al. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nat. Genet. 45, 902–906 (2013).

    PubMed  PubMed Central  Google Scholar 

  8. Torgerson, T. R. et al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology 132, 1705–1717 (2007).

    CAS  PubMed  Google Scholar 

  9. Ober, C. & Yao, T.-C. The genetics of asthma and allergic disease: a 21st century perspective. Immunol. Rev. 242, 10–30 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Dasgupta, S., Erturk-Hasdemir, D., Ochoa-Reparaz, J., Reinecker, H.-C. & Kasper, D. L. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 15, 413–423 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

    CAS  PubMed  Google Scholar 

  13. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    CAS  PubMed  Google Scholar 

  14. Chng, K. R. et al. Whole metagenome profiling reveals skin microbiome-dependent susceptibility to atopic dermatitis flare. Nat. Microbiol. 1, 16106 (2016).

    CAS  PubMed  Google Scholar 

  15. Meylan, P. et al. Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy. J. Invest. Dermatol. 137, 2497–2504 (2017).

    CAS  PubMed  Google Scholar 

  16. Tauber, M. et al. Staphylococcus aureus density on lesional and nonlesional skin is strongly associated with disease severity in atopic dermatitis. J. Allergy Clin. Immunol. 137, 1272–1274.e3 (2016).

    PubMed  Google Scholar 

  17. McKenzie, C., Tan, J., Macia, L. & Mackay, C. R. The nutrition-gut microbiome-physiology axis and allergic diseases. Immunol. Rev. 278, 277–295 (2017).

    CAS  PubMed  Google Scholar 

  18. Wang, S. et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43, 289–303 (2015).

    PubMed  PubMed Central  Google Scholar 

  19. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Noval Rivas, M. et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42, 512–523 (2015). This article provides a mechanistic link between oral tolerance, development of food allergy, Treg cells and the microbiota.

    CAS  PubMed  Google Scholar 

  21. Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tamburini, S., Shen, N., Wu, H. C. & Clemente, J. C. The microbiome in early life: implications for health outcomes. Nat. Med. 22, 713–722 (2016).

    CAS  PubMed  Google Scholar 

  23. Kemter, A. M. & Nagler, C. R. Influences on allergic mechanisms through gut, lung, and skin microbiome exposures. J. Clin. Invest. 130, 1483–1492 (2019).

    Google Scholar 

  24. Arrieta, M.-C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl Med. 7, 307ra152 (2015). This study reports links between microbial colonization during early infancy, metabolic alterations and risk of childhood asthma.

    PubMed  Google Scholar 

  25. Huang, Y. J. et al. The microbiome in allergic disease: current understanding and future opportunities-2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. J. Allergy Clin. Immunol. 139, 1099–1110 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. Berni Canani, R. et al. Gut microbiota composition and butyrate production in children affected by non-IgE-mediated cow’s milk allergy. Sci. Rep. 8, 12500 (2018).

    PubMed  PubMed Central  Google Scholar 

  27. Wang, M. et al. Reduced diversity in the early fecal microbiota of infants with atopic eczema. J. Allergy Clin. Immunol. 121, 129–134 (2008).

    PubMed  Google Scholar 

  28. Abrahamsson, T. R. et al. Low diversity of the gut microbiota in infants with atopic eczema. J. Allergy Clin. Immunol. 129, 434–440 (2012).

    PubMed  Google Scholar 

  29. Byrd, A. L., Belkaid, Y. & Segre, J. A. The human skin microbiome. Nat. Rev. Microbiol. 16, 143–155 (2018).

    CAS  PubMed  Google Scholar 

  30. Paller, A. S. et al. The microbiome in patients with atopic dermatitis. J. Allergy Clin. Immunol. 143, 26–35 (2019).

    PubMed  Google Scholar 

  31. Huang, Y. J. & Boushey, H. A. The microbiome in asthma. J. Allergy Clin. Immunol. 135, 25–30 (2015).

    PubMed  PubMed Central  Google Scholar 

  32. Nowak-Wegrzyn, A., Szajewska, H. & Lack, G. Food allergy and the gut. Nat. Rev. Gastroenterol. Hepatol. 14, 241–257 (2017).

    CAS  PubMed  Google Scholar 

  33. Sampson, H. A. et al. Mechanisms of food allergy. J. Allergy Clin. Immunol. 141, 11–19 (2018).

    CAS  PubMed  Google Scholar 

  34. Cadwell, K. The virome in host health and disease. Immunity 42, 805–813 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Freer, G. et al. The virome and its major component, anellovirus, a convoluted system molding human immune defenses and possibly affecting the development of asthma and respiratory diseases in childhood. Front. Microbiol. 9, 686 (2018).

    PubMed  PubMed Central  Google Scholar 

  36. Lim, E. S. et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat. Med. 21, 1228–1234 (2015). These investigators characterize the gut virome and bacterial microbiota in a longitudinal cohort of healthy infant twins and show that the infant microbiota is highly dynamic.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lim, E. S., Wang, D. & Holtz, L. R. The bacterial microbiome and virome milestones of infant development. Trends Microbiol. 24, 801–810 (2016).

    CAS  PubMed  Google Scholar 

  38. Stewart, C. J. et al. Bacterial and fungal viability in the preterm gut: NEC and sepsis. Arch. Dis. Child. Fetal Neonatal Ed. 98, F298–F303 (2013).

    PubMed  Google Scholar 

  39. Findley, K. et al. Topographic diversity of fungal and bacterial communities in human skin. Nature 498, 367–370 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Limon, J. J., Skalski, J. H. & Underhill, D. M. Commensal fungi in health and disease. Cell Host Microbe 22, 156–165 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Jo, J.-H. et al. Diverse human skin fungal communities in children converge in adulthood. J. Invest. Dermatol. 136, 2356–2363 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kong, H. H. & Morris, A. The emerging importance and challenges of the human mycobiome. Virulence 8, 310–312 (2017).

    PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Gomez de Agüero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).

    PubMed  Google Scholar 

  45. Eggesbø, M., Botten, G., Stigum, H., Nafstad, P. & Magnus, P. Is delivery by cesarean section a risk factor for food allergy? J. Allergy Clin. Immunol. 112, 420–426 (2003).

    PubMed  Google Scholar 

  46. Koplin, J. J. et al. Do factors known to alter infant microbial exposures alter the risk of food allergy and eczema in a population-based infant study? J. Allergy Clin. Immunol. 129, AB231 (2012).

    Google Scholar 

  47. Laubereau, B. et al. Caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitisation during the first year of life. Arch. Dis. Child. 89, 993–997 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Thavagnanam, S., Fleming, J., Bromley, A., Shields, M. D. & Cardwell, C. R. A meta-analysis of the association between caesarean section and childhood asthma. Clin. Exp. Allergy 38, 629–633 (2008).

    CAS  PubMed  Google Scholar 

  49. Kristensen, K. & Henriksen, L. Cesarean section and disease associated with immune function. J. Allergy Clin. Immunol. 137, 587–590 (2016).

    PubMed  Google Scholar 

  50. Tollånes, M. C., Moster, D., Daltveit, A. K. & Irgens, L. M. Cesarean section and risk of severe childhood asthma: a population-based cohort study. J. Pediatr. 153, 112–116 (2008).

    PubMed  Google Scholar 

  51. Cho, C. E. & Norman, M. Cesarean section and development of the immune system in the offspring. Am. J. Obstet. Gynecol. 208, 249–254 (2013).

    PubMed  Google Scholar 

  52. Bager, P., Wohlfahrt, J. & Westergaard, T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin. Exp. Allergy 38, 634–642 (2008).

    CAS  PubMed  Google Scholar 

  53. Roduit, C. et al. Asthma at 8 years of age in children born by caesarean section. Thorax 64, 107–113 (2009).

    CAS  PubMed  Google Scholar 

  54. Pyrhönen, K., Näyhä, S., Hiltunen, L. & Läärä, E. Caesarean section and allergic manifestations: insufficient evidence of association found in population-based study of children aged 1 to 4 years. Acta Paediatr. 102, 982–989 (2013).

    PubMed  Google Scholar 

  55. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    PubMed  PubMed Central  Google Scholar 

  56. Romero, R. et al. The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome 2, 4 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. Gajer, P. et al. Temporal dynamics of the human vaginal microbiota. Sci. Transl Med. 4, 132ra52 (2012).

    PubMed  PubMed Central  Google Scholar 

  58. Miller, L. et al. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet. Gynecol. 96, 431–439 (2000).

    CAS  PubMed  Google Scholar 

  59. Chu, D. M. et al. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat. Med. 23, 314–326 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Penders, J. et al. Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood. J. Allergy Clin. Immunol. 132, 601–607.e8 (2013).

    PubMed  Google Scholar 

  61. Pistiner, M., Gold, D. R., Abdulkerim, H., Hoffman, E. & Celedón, J. C. Birth by cesarean section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy. J. Allergy Clin. Immunol. 122, 274–279 (2008).

    PubMed  PubMed Central  Google Scholar 

  62. Lee, S.-Y. et al. Additive effect between IL-13 polymorphism and cesarean section delivery/prenatal antibiotics use on atopic dermatitis. A birth cohort study (COCOA). PLoS ONE 9, e96603 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Liao, S.-L. et al. Caesarean section is associated with reduced perinatal cytokine response, increased risk of bacterial colonization in the airway, and infantile wheezing. Sci. Rep. 7, 9053 (2017).

    PubMed  PubMed Central  Google Scholar 

  64. Dominguez-Bello, M. G. et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat. Med. 22, 250–253 (2016). This proof-of-principle study shows that exposure of newborns born by caesarean delivery to maternal vaginal microbiota partially restores their gastrointestinal microbiota.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Stokholm, J. et al. Prevalence and predictors of antibiotic administration during pregnancy and birth. PLoS ONE 8, e82932 (2013).

    PubMed  PubMed Central  Google Scholar 

  67. Bailey, L. C. et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 168, 1063–1069 (2014).

    PubMed  Google Scholar 

  68. Saari, A., Virta, L. J., Sankilampi, U., Dunkel, L. & Saxen, H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics 135, 617–626 (2015).

    PubMed  Google Scholar 

  69. Mikkelsen, K. H., Knop, F. K., Frost, M., Hallas, J. & Pottegård, A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J. Clin. Endocrinol. Metab. 100, 3633–3640 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Risnes, K. R., Belanger, K., Murk, W. & Bracken, M. B. Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in a cohort of 1,401 US children. Am. J. Epidemiol. 173, 310–318 (2011).

    PubMed  Google Scholar 

  71. Hoskin-Parr, L., Teyhan, A., Blocker, A. & Henderson, A. J. W. Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent relationship. Pediatr. Allergy Immunol. 24, 762–771 (2013).

    PubMed  PubMed Central  Google Scholar 

  72. Hviid, A., Svanström, H. & Frisch, M. Antibiotic use and inflammatory bowel diseases in childhood. Gut 60, 49–54 (2011).

    PubMed  Google Scholar 

  73. Shaw, S. Y., Blanchard, J. F. & Bernstein, C. N. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am. J. Gastroenterol. 106, 2133–2142 (2011).

    PubMed  Google Scholar 

  74. Kronman, M. P., Zaoutis, T. E., Haynes, K., Feng, R. & Coffin, S. E. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130, e794–e803 (2012).

    PubMed  PubMed Central  Google Scholar 

  75. Metsälä, J. et al. Mother’s and offspring’s use of antibiotics and infant allergy to cow’s milk. Epidemiology 24, 303–309 (2013).

    PubMed  Google Scholar 

  76. Wu, P. et al. Relative importance and additive effects of maternal and infant risk factors on childhood asthma. PLoS ONE 11, e0151705 (2016).

    PubMed  PubMed Central  Google Scholar 

  77. Kozyrskyj, A. L., Ernst, P. & Becker, A. B. Increased risk of childhood asthma from antibiotic use in early life. Chest 131, 1753–1759 (2007).

    PubMed  Google Scholar 

  78. Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Pérez-Cobas, A. E. et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut 62, 1591–1601 (2013).

    PubMed  Google Scholar 

  80. Schulfer, A. F. et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat. Microbiol. 3, 234–242 (2018). This aticle shows that antibiotic exposure shapes the maternal gut microbiota and this effect extends to their offspring, with both ecological and long-term disease consequences.

    CAS  PubMed  Google Scholar 

  81. Murk, W., Risnes, K. R. & Bracken, M. B. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics 127, 1125–1138 (2011).

    PubMed  Google Scholar 

  82. Heintze, K. & Petersen, K.-U. The case of drug causation of childhood asthma: antibiotics and paracetamol. Eur. J. Clin. Pharmacol. 69, 1197–1209 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 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 

  86. Gonzalez-Perez, G. et al. Maternal antibiotic treatment impacts development of the neonatal intestinal microbiome and antiviral immunity. J. Immunol. 196, 3768–3779 (2016).

    CAS  PubMed  Google Scholar 

  87. Semic-Jusufagic, A. et al. Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study. Lancet Respir. Med. 2, 621–630 (2014).

    CAS  PubMed  Google Scholar 

  88. Lodge, C. J. et al. Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr. 104, 38–53 (2015).

    CAS  PubMed  Google Scholar 

  89. Heinrich, J. Modulation of allergy risk by breast feeding. Curr. Opin. Clin. Nutr. Metab. Care 20, 217–221 (2017).

    PubMed  Google Scholar 

  90. Stewart, C. J. et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562, 583–588 (2018). This is an extensive characterization of the microbiota in early life in a large multicentre population and provides the background for future mechanistic studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. van den Elsen, L. W. J., Garssen, J., Burcelin, R. & Verhasselt, V. Shaping the gut microbiota by breastfeeding: the gateway to allergy prevention? Front. Pediatr. 7, 47 (2019).

    PubMed  PubMed Central  Google Scholar 

  92. Bäckhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015). This article shows that the gut microbiota of infants born by caesarean delivery has less resemblance to their mother’s microbiota than vaginally delivered infants and describes breastfeeding cessation as being required for maturation into an adult-like microbiota.

    PubMed  Google Scholar 

  93. Alderete, T. L. et al. Associations between human milk oligosaccharides and infant body composition in the first 6 mo of life. Am. J. Clin. Nutr. 102, 1381–1388 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bode, L. et al. Overcoming the limited availability of human milk oligosaccharides: Challenges and opportunities for research and application. Nutr. Rev. 74, 635–644 (2016).

    PubMed  PubMed Central  Google Scholar 

  95. Seppo, A. E., Autran, C. A., Bode, L. & Järvinen, K. M. Human milk oligosaccharides and development of cow’s milk allergy in infants. J. Allergy Clin. Immunol. 139, 708–711.e5 (2017).

    CAS  PubMed  Google Scholar 

  96. Pannaraj, P. S. et al. Shared and distinct features of human milk and infant stool viromes. Front. Microbiol. 9, 1162 (2018).

    PubMed  PubMed Central  Google Scholar 

  97. Rekima, A. et al. A role for early oral exposure to house dust mite allergens through breast milk in IgE-mediated food allergy susceptibility. J. Allergy Clin. Immunol. 145, 1416–1429.e11 (2020).

    CAS  PubMed  Google Scholar 

  98. 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  PubMed Central  Google Scholar 

  99. Jackson, D. J. et al. Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life. Am. J. Respir. Crit. Care Med. 185, 281–285 (2012).

    PubMed  PubMed Central  Google Scholar 

  100. Kusel, M. M. H. et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J. Allergy Clin. Immunol. 119, 1105–1110 (2007).

    PubMed  PubMed Central  Google Scholar 

  101. Geerdink, R. J., Pillay, J., Meyaard, L. & Bont, L. Neutrophils in respiratory syncytial virus infection. A target for asthma prevention. J. Allergy Clin. Immunol. 136, 838–847 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Gavala, M. L., Bashir, H. & Gern, J. E. Virus/allergen interactions in asthma. Curr. Allergy Asthma Rep. 13, 298–307 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Krishnamoorthy, N. et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat. Med. 18, 1525–1530 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Edwards, M. R. et al. Viral infections in allergy and immunology. How allergic inflammation influences viral infections and illness. J. Allergy Clin. Immunol. 140, 909–920 (2017). Edwards et al. discuss evidence for a reciprocal inverse correlation between innate interferons and TH2 cell mediators and how biologics targeting TH2 cell mediators contribute in this regard.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Rupani, H. et al. Toll-like receptor 7 is reduced in severe asthma and linked to an altered MicroRNA profile. Am. J. Respir. Crit. Care Med. 194, 26–37 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Gill, M. A. et al. Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab. J. Allergy Clin. Immunol. 141, 1735–1743.e9 (2018).

    CAS  PubMed  Google Scholar 

  107. Fujimura, K. E. et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med. 22, 1187–1191 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Durack, J. et al. Delayed gut microbiota development in high-risk for asthma infants is temporarily modifiable by Lactobacillus supplementation. Nat. Commun. 9, 707 (2018). This study shows that early-life gut microbial development is distinct but plastic in infants at high risk of asthma.

    PubMed  PubMed Central  Google Scholar 

  109. Milani, C. et al. The first microbial colonizers of the human gut. composition, activities, and health implications of the infant gut microbiota. Microbiol. Mol. Biol. Rev. 81, e00036-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  110. Bunyavanich, S. & Berin, M. C. Food allergy and the microbiome. Current understandings and future directions. J. Allergy Clin. Immunol. 144, 1468–1477 (2019).

    PubMed  PubMed Central  Google Scholar 

  111. Russell, S. L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  114. Feehley, T. et al. Healthy infants harbor intestinal bacteria that protect against food allergy. Nat. Med. 25, 448–453 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Abdel-Gadir, A. et al. Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy. Nat. Med. 25, 1164–1174 (2019). Using a model of food allergy, these authors show that microbiota therapy can suppress food allergy via innate signalling pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Tan, J. et al. The role of short-chain fatty acids in health and disease. Adv. Immunol. 121, 91–119 (2014).

    CAS  PubMed  Google Scholar 

  117. Roduit, C. et al. High levels of butyrate and propionate in early life are associated with protection against atopy. Allergy 74, 799–809 (2019).

    CAS  PubMed  Google Scholar 

  118. Sandin, A., Bråbäck, L., Norin, E. & Björkstén, B. Faecal short chain fatty acid pattern and allergy in early childhood. Acta Paediatr. 98, 823–827 (2009).

    PubMed  Google Scholar 

  119. Bunyavanich, S. et al. Early-life gut microbiome composition and milk allergy resolution. J. Allergy Clin. Immunol. 138, 1122–1130 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Thio, C. L.-P., Chi, P.-Y., Lai, A. C.-Y. & Chang, Y.-J. Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by butyrate. J. Allergy Clin. Immunol. 142, 1867–1883.e12 (2018).

    CAS  PubMed  Google Scholar 

  121. Lewis, G. et al. Dietary fiber-induced microbial short chain fatty acids suppress ILC2-dependent airway inflammation. Front. Immunol. 10, 2051 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013). This article reports a mechanistic link between dietary fibre, commensal microorganisms, production of SCFAs and differentiation of Treg cells.

    CAS  PubMed  Google Scholar 

  123. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014). In this study, the effects of dietary fibre on microbiota-mediated effector responses in the lung (allergic airway diseases) and haematopoiesis are described.

    CAS  PubMed  Google Scholar 

  124. Ege, M. J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011). This is a cross-sectional study on the hygiene hypothesis: environmental microorganisms and asthma prevention.

    CAS  PubMed  Google Scholar 

  125. 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 

  126. 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 

  127. 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 

  128. Stein, K. et al. Endosomal recognition of Lactococcus lactis G121 and its RNA by dendritic cells is key to its allergy-protective effects. J. Allergy Clin. Immunol. 139, 667–678.e5 (2017).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  130. Ruokolainen, L. et al. Significant disparities in allergy prevalence and microbiota between the young people in Finnish and Russian Karelia. Clin. Exp. Allergy 47, 665–674 (2017).

    CAS  PubMed  Google Scholar 

  131. Seeley, J. J. & Ghosh, S. Molecular mechanisms of innate memory and tolerance to LPS. J. Leukoc. Biol. 101, 107–119 (2017).

    CAS  PubMed  Google Scholar 

  132. Brand, S. et al. Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J. Allergy Clin. Immunol. 128, 618–625.e7 (2011).

    CAS  PubMed  Google Scholar 

  133. Haahtela, T. A biodiversity hypothesis. Allergy 74, 1445–1456 (2019).

    PubMed  Google Scholar 

  134. 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.e11 (2019).

    CAS  PubMed  Google Scholar 

  135. Matysiak-Budnik, T. et al. Helicobacter pylori increases the epithelial permeability to a food antigen in human gastric biopsies. Am. J. Gastroenterol. 99, 225–232 (2004).

    PubMed  Google Scholar 

  136. Skevaki, C. et al. Influenza-derived peptides cross-react with allergens and provide asthma protection. J. Allergy Clin. Immunol. 142, 804–814 (2018). This is the first demonstration of virus-induced T cell-mediated heterologous immune responses to allergens with implications for asthma protection.

    CAS  PubMed  Google Scholar 

  137. Culley, F. J., Pennycook, A. M. J., Tregoning, J. S., Hussell, T. & Openshaw, P. J. M. Differential chemokine expression following respiratory virus infection reflects Th1- or Th2-biased immunopathology. J. Virol. 80, 4521–4527 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Yang, J.-Y. et al. Enteric viruses ameliorate gut inflammation via toll-like receptor 3 and toll-like receptor 7-mediated interferon-β production. Immunity 44, 889–900 (2016).

    CAS  PubMed  Google Scholar 

  139. Neil, J. A. & Cadwell, K. The intestinal virome and immunity. J. Immunol. 201, 1615–1624 (2018).

    CAS  PubMed  Google Scholar 

  140. Machiels, B. et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320 (2017). These investigators show that a murid herpesvirus may inhibit experimental asthma by replacing alveolar macrophages with regulatory monocytes and thus contributing to training of lung immune responses.

    CAS  PubMed  Google Scholar 

  141. De Vlaminck, I. et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155, 1178–1187 (2013).

    PubMed  PubMed Central  Google Scholar 

  142. Pifferi, M. et al. Associations between nasal torquetenovirus load and spirometric indices in children with asthma. J. Infect. Dis. 192, 1141–1148 (2005).

    PubMed  Google Scholar 

  143. Maggi, F. & Bendinelli, M. Immunobiology of the Torque teno viruses and other anelloviruses. Curr. Top. Microbiol. Immunol. 331, 65–90 (2009).

    CAS  PubMed  Google Scholar 

  144. Li, L. et al. AIDS alters the commensal plasma virome. J. Virol. 87, 10912–10915 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Tiew, P. Y. et al. The mycobiome in health and disease. emerging concepts, methodologies and challenges. Mycopathologia 185, 207–231 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Li, X. et al. Response to fungal dysbiosis by gut-resident CX3CR1+ mononuclear phagocytes aggravates allergic airway disease. Cell Host Microbe 24, 847–856.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Bacher, P. et al. Human anti-fungal Th17 immunity and pathology rely on cross-reactivity against Candida albicans. Cell 176, 1340–1355.e15 (2019). These authors identify heterologous immunity to a single ubiquitous member of the microbiota as the culprit in human antifungal TH17 cell responses, particularly in the context of airway inflammation.

    CAS  PubMed  Google Scholar 

  148. Rayner, S. et al. Identification of small RNAs in extracellular vesicles from the commensal yeast Malassezia sympodialis. Sci. Rep. 7, 39742 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sparber, F. et al. The skin commensal yeast Malassezia triggers a type 17 response that coordinates anti-fungal immunity and exacerbates skin inflammation. Cell Host Microbe 25, 389–403.e6 (2019). This article highlights the importance of Malassezia-induced type 17 responses in driving antifungal immunity and skin inflammation.

    CAS  PubMed  Google Scholar 

  150. Krause, R. et al. Mycobiome in the lower respiratory tract - a clinical perspective. Front. Microbiol. 7, 2169 (2016).

    PubMed  Google Scholar 

  151. Tipton, L., Ghedin, E. & Morris, A. The lung mycobiome in the next-generation sequencing era. Virulence 8, 334–341 (2017).

    CAS  PubMed  Google Scholar 

  152. Fraczek, M. G. et al. Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease. J. Allergy Clin. Immunol. 142, 407–414 (2018).

    CAS  PubMed  Google Scholar 

  153. 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 

  154. Goldman, D. L. et al. Lower airway microbiota and mycobiota in children with severe asthma. J. Allergy Clin. Immunol. 141, 808–811.e7 (2018).

    PubMed  Google Scholar 

  155. Mac Aogáin, M. et al. Distinct “immunoallertypes” of disease and high frequencies of sensitization in non-cystic fibrosis bronchiectasis. Am. J. Respir. Crit. Care Med. 199, 842–853 (2019).

    Google Scholar 

  156. Richardson, M., Bowyer, P. & Sabino, R. The human lung and aspergillus: you are what you breathe in? Med. Mycol. 57, S145–S154 (2019).

    PubMed  PubMed Central  Google Scholar 

  157. Kauth, M. & Heine, H. Allergy protection by cowshed bacteria - recent findings and future prospects. Pediatr. Allergy Immunol. 27, 340–347 (2016).

    PubMed  Google Scholar 

  158. Hesselmar, B. et al. Pacifier cleaning practices and risk of allergy development. Pediatrics 131, e1829–e1837 (2013).

    PubMed  Google Scholar 

  159. Alm, J. S., Swartz, J., Lilja, G., Scheynius, A. & Pershagen, G. Atopy in children of families with an anthroposophic lifestyle. Lancet 353, 1485–1488 (1999).

    CAS  PubMed  Google Scholar 

  160. Hesselmar, B., Hicke-Roberts, A. & Wennergren, G. Allergy in children in hand versus machine dishwashing. Pediatrics 135, e590–e597 (2015).

    PubMed  Google Scholar 

  161. Gern, J. E. Promising candidates for allergy prevention. J. Allergy Clin. Immunol. 136, 23–28 (2015).

    PubMed  PubMed Central  Google Scholar 

  162. Morisset, M., Aubert-Jacquin, C., Soulaines, P., Moneret-Vautrin, D.-A. & Dupont, C. A non-hydrolyzed, fermented milk formula reduces digestive and respiratory events in infants at high risk of allergy. Eur. J. Clin. Nutr. 65, 175–183 (2011).

    CAS  PubMed  Google Scholar 

  163. Kukkonen, A. K., Savilahti, E. M., Haahtela, T., Savilahti, E. & Kuitunen, M. Ovalbumin-specific immunoglobulins A and G levels at age 2 years are associated with the occurrence of atopic disorders. Clin. Exp. Allergy 41, 1414–1421 (2011).

    CAS  PubMed  Google Scholar 

  164. Kuitunen, M. et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J. Allergy Clin. Immunol. 123, 335–341 (2009).

    PubMed  Google Scholar 

  165. Marschan, E. et al. Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation. Clin. Exp. Allergy 38, 611–618 (2008).

    CAS  PubMed  Google Scholar 

  166. Osborn, D. A. & Sinn, J. K. H. Prebiotics in infants for prevention of allergy. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD006474.pub3 (2013).

  167. Osborn, D. A. & Sinn, J. K. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD006475.pub2 (2007).

  168. Grüber, C. et al. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J. Allergy Clin. Immunol. 126, 791–797 (2010).

    PubMed  Google Scholar 

  169. Prescott, S. L. et al. Early markers of allergic disease in a primary prevention study using probiotics: 2.5-year follow-up phase. Allergy 63, 1481–1490 (2008).

    CAS  PubMed  Google Scholar 

  170. Forsberg, A., West, C. E., Prescott, S. L. & Jenmalm, M. C. Pre- and probiotics for allergy prevention: time to revisit recommendations? Clin. Exp. Allergy 46, 1506–1521 (2016).

    CAS  PubMed  Google Scholar 

  171. Muraro, A. et al. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy 69, 590–601 (2014).

    CAS  PubMed  Google Scholar 

  172. Braegger, C. et al. Supplementation of infant formula with probiotics and/or prebiotics: a systematic review and comment by the ESPGHAN committee on nutrition. J. Pediatr. Gastroenterol. Nutr. 52, 238–250 (2011).

    PubMed  Google Scholar 

  173. Fiocchi, A. et al. World Allergy Organization-McMaster University guidelines for allergic disease prevention (GLAD-P). Probiotics. World Allergy Organ. J. 8, 4 (2015).

    PubMed  PubMed Central  Google Scholar 

  174. Niers, L. E. M. et al. Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines. Clin. Exp. Allergy 35, 1481–1489 (2005).

    CAS  PubMed  Google Scholar 

  175. Niers, L. E. M. et al. Selection of probiotic bacteria for prevention of allergic diseases: immunomodulation neonatal dendritic cells. Clin. Exp. Immunol. 149, 344–352 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Braat, H. et al. Lactobacillus rhamnosus induces peripheral hyporesponsiveness in stimulated CD4+ T cells via modulation of dendritic cell function. Am. J. Clin. Nutr. 80, 1618–1625 (2004).

    CAS  PubMed  Google Scholar 

  177. Rigby, R. J., Knight, S. C., Kamm, M. A. & Stagg, A. J. Production of interleukin (IL)-10 and IL-12 by murine colonic dendritic cells in response to microbial stimuli. Clin. Exp. Immunol. 139, 245–256 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Kim, J. Y., Choi, Y. O. & Ji, G. E. Effect of oral probiotics (Bifidobacterium lactis AD011 and Lactobacillus acidophilus AD031) administration on ovalbumin-induced food allergy mouse model. J. Microbiol. Biotechnol. 18, 1393–1400 (2008).

    CAS  PubMed  Google Scholar 

  179. So, J.-S. et al. Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis. Mol. Immunol. 46, 172–180 (2008).

    CAS  PubMed  Google Scholar 

  180. Hacini-Rachinel, F. et al. Oral probiotic control skin inflammation by acting on both effector and regulatory T cells. PLoS ONE 4, e4903 (2009).

    PubMed  PubMed Central  Google Scholar 

  181. Elazab, N. et al. Probiotic administration in early life, atopy, and asthma. A meta-analysis of clinical trials. Pediatrics 132, e666–e676 (2013).

    PubMed  Google Scholar 

  182. Kalliomäki, M., Salminen, S., Poussa, T., Arvilommi, H. & Isolauri, E. Probiotics and prevention of atopic disease. 4-year follow-up of a randomised placebo-controlled trial. Lancet 361, 1869–1871 (2003).

    PubMed  Google Scholar 

  183. 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 

  184. Hoarau, C., Lagaraine, C., Martin, L., Velge-Roussel, F. & Lebranchu, Y. Supernatant of Bifidobacterium breve induces dendritic cell maturation, activation, and survival through a Toll-like receptor 2 pathway. J. Allergy Clin. Immunol. 117, 696–702 (2006).

    CAS  PubMed  Google Scholar 

  185. 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 

  186. Briskey, D. et al. Probiotics modify tight-junction proteins in an animal model of nonalcoholic fatty liver disease. Ther. Adv. Gastroenterol. 9, 463–472 (2016).

    CAS  Google Scholar 

  187. Goldin, B. R. & Gorbach, S. L. Clinical indications for probiotics: an overview. Clin. Infect. Dis. 46 (Suppl. 2), S96-S100 (2008).

    PubMed  Google Scholar 

  188. Berni Canani, R. et al. Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants. ISME J. 10, 742–750 (2016).

    CAS  PubMed  Google Scholar 

  189. Kerperien, J. et al. Non-digestible oligosaccharides modulate intestinal immune activation and suppress cow’s milk allergic symptoms. Pediatr. Allergy Immunol. 25, 747–754 (2014).

    CAS  PubMed  Google Scholar 

  190. Moro, G. et al. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch. Dis. Child. 91, 814–819 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Arslanoglu, S. et al. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J. Nutr. 138, 1091–1095 (2008).

    CAS  PubMed  Google Scholar 

  192. Edwards, M. R. et al. The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations. Allergy 73, 50–63 (2018). This review article from the EAACI Anti-infectives in Asthma and Asthma Exacerbations Task Force summarizes the potential of anti-infectives and immunomodulators in asthma.

    CAS  PubMed  Google Scholar 

  193. 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  PubMed Central  Google Scholar 

  194. Holt, P. G., Strickland, D. H. & Sly, P. D. Virus infection and allergy in the development of asthma. What is the connection? Curr. Opin. Allergy Clin. Immunol. 12, 151–157 (2012).

    CAS  PubMed  Google Scholar 

  195. DesRoches, A., Infante-Rivard, C., Paradis, L., Paradis, J. & Haddad, E. Peanut allergy: is maternal transmission of antigens during pregnancy and breastfeeding a risk factor? J. Investig. Allergol. Clin. Immunol. 20, 289–294 (2010).

    CAS  PubMed  Google Scholar 

  196. Frank, L., Marian, A., Visser, M., Weinberg, E. & Potter, P. C. Exposure to peanuts in utero and in infancy and the development of sensitization to peanut allergens in young children. Pediatr. Allergy Immunol. 10, 27–32 (1999).

    CAS  PubMed  Google Scholar 

  197. Sicherer, S. H. & Burks, A. W. Maternal and infant diets for prevention of allergic diseases. Understanding menu changes in 2008. J. Allergy Clin. Immunol. 122, 29–33 (2008).

    PubMed  Google Scholar 

  198. Maslova, E. et al. Peanut and tree nut consumption during pregnancy and allergic disease in children-should mothers decrease their intake? Longitudinal evidence from the Danish National Birth Cohort. J. Allergy Clin. Immunol. 130, 724–732 (2012).

    PubMed  Google Scholar 

  199. Du Toit, G. et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. J N. Engl. J. Med. 372, 803–813 (2015).

    Google Scholar 

  200. Du Toit, G. et al. Effect of avoidance on peanut allergy after early peanut consumption. N. Engl. J. Med. 374, 1435–1443 (2016). This is a hallmark study on the role of avoidance of peanut allergens in the development of peanut allergy, a novel concept for oral tolerance.

    PubMed  Google Scholar 

  201. Turcanu, V. et al. Immune mechanisms of food allergy and its prevention by early intervention. Curr. Opin. Immunol. 48, 92–98 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Peters, R. L., Neeland, M. R. & Allen, K. J. Primary prevention of food allergy. Curr. Allergy Asthma Rep. 17, 52 (2017).

    PubMed  Google Scholar 

  203. Bellach, J. et al. Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. J. Allergy Clin. Immunol. 139, 1591–1599.e2 (2017).

    CAS  PubMed  Google Scholar 

  204. Natsume, O. et al. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT). A randomised, double-blind, placebo-controlled trial. Lancet 389, 276–286 (2017).

    PubMed  Google Scholar 

  205. Palmer, D. J., Sullivan, T. R., Gold, M. S., Prescott, S. L. & Makrides, M. Randomized controlled trial of early regular egg intake to prevent egg allergy. J. Allergy Clin. Immunol. 139, 1600–1607.e2 (2017).

    CAS  PubMed  Google Scholar 

  206. Perkin, M. R. et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N. Engl. J. Med. 374, 1733–1743 (2016).

    CAS  PubMed  Google Scholar 

  207. Mazzocchi, A., Venter, C., Maslin, K. & Agostoni, C. The role of nutritional aspects in food allergy: prevention and management. Nutrients 9, 850 (2017).

    PubMed Central  Google Scholar 

  208. Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012).

    CAS  PubMed  Google Scholar 

  209. Høst, A. et al. Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch. Dis. Child. 81, 80–84 (1999).

    PubMed  PubMed Central  Google Scholar 

  210. Hill, D. J., Murch, S. H., Rafferty, K., Wallis, P. & Green, C. J. The efficacy of amino acid-based formulas in relieving the symptoms of cow’s milk allergy: A systematic review. Clin. Exp. Allergy 37, 808–822 (2007).

    CAS  PubMed  Google Scholar 

  211. Chafen, J. J. S. et al. Diagnosing and managing common food allergies: a systematic review. JAMA 303, 1848–1856 (2010).

    PubMed  Google Scholar 

  212. Silva, D. de et al. Primary prevention of food allergy in children and adults. Syst. Rev. Allergy 69, 581–589 (2014).

    Google Scholar 

  213. Allen, C. W., Campbell, D. E. & Kemp, A. S. Food allergy: is strict avoidance the only answer? Pediatr. Allergy Immunol. 20, 415–422 (2009).

    CAS  PubMed  Google Scholar 

  214. Boyle, R. J. et al. Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ 352, i974 (2016).

    PubMed  PubMed Central  Google Scholar 

  215. Boyle, R. J. et al. Prebiotic-supplemented partially hydrolysed cow’s milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial. Allergy 71, 701–710 (2016).

    CAS  PubMed  Google Scholar 

  216. Vandenplas, Y. et al. Should partial hydrolysates be used as starter infant formula? A working group consensus. J. Pediatr. Gastroenterol. Nutr. 62, 22–35 (2016).

    CAS  PubMed  Google Scholar 

  217. Wong, G. W. K. & Chow, C. M. Childhood asthma epidemiology: insights from comparative studies of rural and urban populations. Pediatr. Pulmonol. 43, 107–116 (2008).

    PubMed  Google Scholar 

  218. Abreo, A., Gebretsadik, T., Stone, C. A. & Hartert, T. V. The impact of modifiable risk factor reduction on childhood asthma development. Clin. Transl Med. 7, 15 (2018).

    PubMed  PubMed Central  Google Scholar 

  219. Pelkonen, A. S. et al. Allergy in children: practical recommendations of the Finnish Allergy Programme 2008-2018 for prevention, diagnosis, and treatment. Pediatr. Allergy Immunol. 23, 103–116 (2012).

    Google Scholar 

  220. Tanno, L. K., Haahtela, T., Calderon, M. A., Cruz, A. & Demoly, P. Implementation gaps for asthma prevention and control. Respir. Med. 130, 13–19 (2017).

    PubMed  Google Scholar 

  221. Haahtela, T., Valovirta, E., Bousquet, J. & Mäkelä, M. The Finnish Allergy Programme 2008–2018 works. Eur. Respir. J. 49, 1700470 (2017).

    PubMed  Google Scholar 

  222. Burki, T. K. Asthma control. learning from Finland’s success. Lancet Respir. Med. 7, 207–208 (2019).

    PubMed  Google Scholar 

Download references

Acknowledgements

H.R. is supported by the Universities of Giessen and Marburg Lung Center, the German Center for Lung Research (82DZL00502/A2), and the Deutsche Forschungsgemeinschaft funded-SFB 1021 (C04). C.S. is supported by the Universities of Giessen and Marburg Lung Center, the German Center for Lung Research, University Hospital of Giessen and Marburg research funding according to article 2, section 3 cooperation agreement, the Foundation for Pathobiochemistry and Molecular Diagnostics, and the Deutsche Forschungsgemeinschaft-funded SFB 1021 (C04), KFO 309 (P10) and SK 317/1-1 (project number 428518790).

Author information

Authors and Affiliations

  1. Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, German Center for Lung Research (DZL), Marburg, Germany

    Harald Renz & Chrysanthi Skevaki

Authors
  1. Harald Renz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chrysanthi Skevaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.S. wrote and edited the manuscript. H.R. helped revise and edit the manuscript.

Corresponding author

Correspondence to Harald Renz.

Ethics declarations

Competing interests

C.S. has received consultancy fees and research funding from Hycor Biomedical and Thermo Fisher Scientific, consultancy fees from Bencard Allergie and research funding from Mead Johnson Nutrition. H.R. has received research support from Mead Johnson Nutrition and Beckman Coulter, has received speaker’s honoraria from Allergopharma, Novartis, Thermo Fisher, Danone, Mead Johnson Nutrition and Bencard Allergie, and has been a consultant for Bencard Allergie and Secarna Pharmaceuticals (co-founder).

Additional information

Peer review information

Nature Reviews Immunology thanks K. C. Nadeau, V. Verhass and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Centers for Disease Control and Prevention: most recent asthma data: https://www.cdc.gov/asthma/most_recent_data.htm

Glossary

Short-chain fatty acids

(SCFAs). Subgroup of fatty acids with only two to six carbon atoms. Important representatives are butyrate, acetate and propionate.

Dysbiosis

A condition in which there is a qualitative and quantitative imbalance of bacterial communities that constitute the microbiota, which could represent a predisposition factor for several diseases. Dysbiosis refers mostly to the intestinal microbiota, but it can also occur at other body sites and in other habitats.

Human milk oligosaccharides

(HMOs). Complex sugar molecules that are present in human breast milk in relatively high concentrations; their composition shows high interindividual and intraindividual variability.

Group 2 innate lymphoid cells

(ILC2s). Derived from lymphoid progenitors, these cells lack B and T cell receptors and produce type 2 cytokines such as IL-4, IL-5 and IL-9

Inflammasome

Cytosolic multiprotein oligomer of the innate immune system responsible for the activation of the inflammatory responses.

Asthma endotypes

Forms of asthma with distinct mechanistic pathways that have therapeutic and prognostic implications.

Neutrophil extracellular traps

Networks of extracellular fibres, produced by neutrophils, which bind to pathogens and thus allow neutrophils to kill them with minimal host damage. The extracellular fibril matrix is composed of decondensed chromatin.

Plasmacytoid dendritic cell

Derived from bone marrow haematopoietic stem cells, this type of immune cell circulates in the blood and in peripheral lymphoid organs and is known to secrete large quantities of type I interferon following viral infection.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Renz, H., Skevaki, C. Early life microbial exposures and allergy risks: opportunities for prevention. Nat Rev Immunol 21, 177–191 (2021). https://doi.org/10.1038/s41577-020-00420-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-020-00420-y

This article is cited by

Search

Advanced 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