Prenatal and early postnatal life represent key periods of immune system development. In addition to genetics and host biology, environment has a large and irreversible role in the immune maturation and health of an infant. One key player in this process is the gut microbiota, a diverse community of microorganisms that colonizes the human intestine. The diet, environment and medical interventions experienced by an infant determine the establishment and progression of the intestinal microbiota, which interacts with and trains the developing immune system. Several chronic immune-mediated diseases have been linked to an altered gut microbiota during early infancy. The recent rise in allergic disease incidence has been explained by the ‘hygiene hypothesis’, which states that societal changes in developed countries have led to reduced early-life microbial exposures, negatively impacting immunity. Although human cohort studies across the globe have established a correlation between early-life microbiota composition and atopy, mechanistic links and specific host–microorganism interactions are still being uncovered. Here, we detail the progression of immune system and microbiota maturation in early life, highlight the mechanistic links between microbes and the immune system, and summarize the role of early-life host–microorganism interactions in allergic disease development.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Park, J. E., Jardine, L., Gottgens, B., Teichmann, S. A. & Haniffa, M. Prenatal development of human immunity. Science 368, 600–603 (2020). This review describes in utero immune development in detail.
Semmes, E. C. et al. Understanding early-life adaptive immunity to guide interventions for pediatric health. Front. Immunol. 11, 595297 (2021).
Kollmann, T. R., Kampmann, B., Mazmanian, S. K., Marchant, A. & Levy, O. Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny. Immunity 46, 350–363 (2017).
Rudd, B. D. Neonatal T cells: a reinterpretation. Annu. Rev. Immunol. 38, 229–247 (2020). This review provides a thorough description of the features of neonatal T cells.
Robertson, R. C., Manges, A. R., Finlay, B. B. & Prendergast, A. J. The human microbiome and child growth — first 1000 days and beyond. Trends Microbiol. 27, 131–147 (2019).
Vandenplas, Y. et al. Factors affecting early-life intestinal microbiota development. Nutrition 78, 110812 (2020).
Humann, J. et al. Bacterial peptidoglycan transverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior. Cell Host Microbe 19, 388–399 (2016).
Van De Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).
De Agüero, M. G. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).
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). This review describes immune alterations observed in GF mice.
Torow, N. & Hornef, M. W. The neonatal window of opportunity: setting the stage for life-long host-microbial interaction and immune homeostasis. J. Immunol. 198, 557–563 (2017).
Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).
Derrien, M., Alvarez, A. S. & de Vos, W. M. The gut microbiota in the first decade of life. Trends Microbiol. 27, 997–1010 (2019). This work describes the progression of gut microbiota development early in life.
Pantoja-Feliciano, I. G. et al. Biphasic assembly of the murine intestinal microbiota during early development. Int. Soc. Microb. Ecol. J. 7, 1112–1115 (2013).
Al Nabhani, Z. et al. A weaning reaction to microbiota is required for resistance to immunopathologies in the adult. Immunity 50, 1276–1288 (2019).
Boutin, R. C. T. et al. Mining the infant gut microbiota for therapeutic targets against atopic disease. Allergy 75, 2065–2068 (2020).
Marra, F. et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics 123, 1003–1010 (2009).
Abrahamsson, T. R. et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin. Exp. Allergy 44, 842–850 (2014).
Wold, A. E. The hygiene hypothesis revised: is the rising frequency of allergy due to changes in rising the intestinal flora? Allergy 53, 20–25 (1998).
Okada, H., Kuhn, C., Feillet, H. & Bach, J.-F. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1–9 (2010).
Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108, 4578–4585 (2011).
Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014). This work uses mathematical modeling to describe neonatal immune development.
Stremmel, C. et al. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat. Commun. 9, 75 (2018).
Popescu, D. M. et al. Decoding human fetal liver haematopoiesis. Nature 574, 365–371 (2019).
St. John, A. L., Rathore, A. P. S. & Ginhoux, F. New perspectives on the origins and heterogeneity of mast cells. Nat. Rev. Immunol. 23, 55–68 (2023).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Krystel-Whittemore, M., Dileepan, K. N. & Wood, J. G. Mast cell: a multi-functional master cell. Front. Immunol. 6, 620 (2016).
Woidacki, K. et al. Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis. 4, e462 (2013).
Ngkelo, A. et al. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction. J. Exp. Med. 213, 1353–1374 (2016).
Angelo, L. S., Bimler, L. H., Nikzad, R., Aviles-Padilla, K. & Paust, S. CXCR6+ NK cells in human fetal liver and spleen possess unique phenotypic and functional capabilities. Front. Immunol. 10, 469 (2019).
Van De Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).
Ema, H. & Nakauchi, H. Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood 95, 2284–2288 (2000).
McGovern, N. et al. Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2. Nature 546, 662–666 (2017).
Olin, A. et al. Stereotypic immune system development in newborn children. Cell 174, 1277–1292 (2018). This study uses peripheral blood samples collected over time to describe immune maturation in infants.
Melville, J. M. & Moss, T. J. M. The immune consequences of preterm birth. Front. Neurosci. 7, 79 (2013).
Stras, S. F. et al. Maturation of the human intestinal immune system occurs early in fetal development. Dev. Cell 51, 357–373.e5 (2019).
Mold, J. E. et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695–1699 (2010).
Hall, T. D. et al. Murine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth. Nat. Commun. 13, 5403 (2022).
Mold, J. E. & McCune, J. M. Immunological tolerance during fetal development. From mouse to man. Adv. Immunol. 115, 73–111 (2012).
Kollman TR, L. O. E. A. Innate immune sensing by toll-like receptors in newborns and the elderly. Immunity 37, 771–783 (2012).
Basha, S., Surendran, N. & Pichichero, M. Immune responses in neonates. Expert. Rev. Clin. Immunol. 10, 1171–1184 (2014).
Melvan, J. N., Bagby, G. J., Welsh, D. A., Nelson, S. & Zhang, P. Neonatal sepsis and neutrophil insufficiencies. Int. Rev. Immunol. 29, 315–348 (2010).
Willems, F., Vollstedt, S. & Suter, M. Phenotype and function of neonatal DC. Eur. J. Immunol. 39, 26–35 (2009).
Mestas, J. & Hughes, C. C. W. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004). This paper highlights major differences in immunity between humans and murine models.
Jones, C. A., Holloway, J. A. & Warner, J. O. Phenotype of fetal monocytes and B lymphocytes during the third trimester of pregnancy. J. Reprod. Immunol. 56, 45–60 (2002).
Corbett, N. P. et al. Ontogeny of toll-like receptor mediated cytokine responses of human blood mononuclear cells. PLoS ONE 5, e15041 (2010).
Langrish, C. L., Buddle, J. C., Thrasher, A. J., Molecular, D. G. & Unit, I. Neonatal dendritic cells are intrinsically biased against Th-1 immune responses. Clin. Exp. Immunol. 128, 118–123 (2002).
Elahi, S. et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504, 158–162 (2013).
Maximilian, L. & Lochner, M. Development and function of secondary and tertiary lymphoid organs in the small intestine and the colon. Front. Immunol. 7, 342 (2016).
Torow, N., Marsland, B. J., Hornef, M. W. & Gollwitzer, E. S. Neonatal mucosal immunology. Mucosal Immunol. 10, 5–17 (2017).
Ménard, S. et al. Developmental switch of intestinal antimicrobial peptide expression. J. Exp. Med. 205, 183–193 (2008).
Griffiths-chu, S., Patterson, J. A. K., Berger, C. L., Edelson, R. L. & Chu, A. C. Characterization of immature T cell subpopulations in neonatal blood. Blood 64, 296–300 (1984).
Gammon, G. et al. Neonatal T-cell tolerance to minimal immunogenic peptides is caused. Nature 319, 413–415 (1986).
Rackaityte, E. & Halkias, J. Mechanisms of fetal T cell tolerance and immune regulation. Front. Immunol. 11, 588 (2020).
Michaëlsson, J., Mold, J. E., McCune, J. M. & Nixon, D. F. Regulation of T cell responses in the developing human fetus. J. Immunol. 176, 5741–5748 (2006).
Hebel, K. et al. CD4+ T cells from human neonates and infants are poised spontaneously to run a nonclassical IL-4 program. J. Immunol. 192, 5160–5170 (2014).
Adkins, B. Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally. J. Immunol. 171, 5157–5164 (2003).
Mascart, F. et al. Bordetella pertussis infection in 2-month-old infants promotes type 1 T cell responses. J. Immunol. 170, 1504–1509 (2003).
Mccarron, M. & Reen, D. J. Activated human neonatal CD8+ T cells are subject to immunomodulation by direct TLR2 or TLR5 stimulation. J. Immunol. 182, 55–62 (2022).
Pekalski, M. L. et al. Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. J. Clin. Invest. Insights 2, e93739 (2017).
Smith, N. L. et al. Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J. Immunol. 193, 177–184 (2014).
Siefker, D. T. & Adkins, B. Rapid CD8+ function is critical for protection of neonatal mice from an extracellular bacterial enteropathogen. Front. Pediatr. 4, 141 (2017).
Yang, S. et al. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348, 589–594 (2015).
Budeus, B. et al. Human cord blood B cells differ from the adult counterpart by conserved Ig repertoires and accelerated response dynamics. J. Immunol. 206, 2839–2851 (2021).
Sarvaria, A. et al. IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation. Blood 128, 1346–1361 (2016).
Rackaityte, E. et al. Viable bacterial colonization is highly limited in the human intestine in utero. Nat. Med. 26, 599–607 (2020).
de Goffau, M. C. et al. Human placenta has no microbiome but can contain potential pathogens. Nature 572, 329–334 (2019).
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).
Reyman, M. et al. Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life. Nat. Commun. 10, 4997 (2019).
Dominguez-Bello, M. G., Costello, E. K., Contreras, M., Magris, M. & Hidalgo, G. 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).
Yang, R. et al. Dynamic signatures of gut microbiota and influences of delivery and feeding modes during the first 6 months of life. Physiol. Genet. 51, 368–378 (2019).
Wampach, L. et al. Birth mode is associated with earliest strain-conferred gut microbiome functions and immunostimulatory potential. Nat. Commun. 9, 5091 (2018).
Galazzo, G. et al. Development of the microbiota and associations with birth mode, diet, and atopic disorders in a longitudinal analysis of stool samples, collected from infancy through early childhood. Gastroenterology 158, 1584–1596 (2020).
Chichlowski, M., De Lartigue, G., German, B. J., Raybould, H. E. & Mills, D. A. Bifidobacteria isolated from infants and cultured on human milk oligosaccharides. J. Pediatr. Gastroenerol. Nutr. 55, 321–327 (2012).
Lee, S. A. et al. Comparison of the gut microbiota profile in breast-fed and formula-fed Korean infants using pyrosequencing. Nutr. Res. Pract. 9, 242–248 (2015).
Pärnänen, K. M. M. et al. Early-life formula feeding is associated with infant gut microbiota alterations and an increased antibiotic resistance load. Am. J. Clin. Nutr. 115, 407–421 (2022).
Blanton, L. V. et al. Gut bacteria that prevent gowth impairments transmitted by microbita from malnourished children. Science 351, 1–18 (2016).
Stewart, C. J. et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562, 583–588 (2018).
Gillilland, M. G. et al. Ecological succession of bacterial communities during conventionalization of germ-free mice. Appl. Environ. Microbiol. 78, 2359–2366 (2012).
Gopalakrishna, K. P. et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat. Med. 25, 1110–1115 (2019).
Chernikova, D. A. et al. The premature infant gut microbiome during the first 6 weeks of life differs based on gestational maturity at birth. Pediatr. Res. 84, 71–79 (2018).
Jia, Q. et al. Dynamic changes of the gut microbiota in preterm infants with different gestational age. Front. Microbiol. 13, 923273 (2022).
Azad, M. B. et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. Br. J. Obstet. Gynaecol. 123, 983–993 (2016).
Korpela, K. et al. Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort. Pediatr. Res. 88, 438–443 (2020).
Stevens, J. et al. The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota. Sci. Transl. Med. 14, 649 (2022).
Reyman, M. et al. Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial. Nat. Commun. 13, 893 (2022).
Gupta, R. S. et al. Hygiene factors associated with childhood food allergy and asthma. Allergy Asthma Proc. 37, 140–146 (2016).
Hornef, M. W. & Torow, N. ‘Layered immunity’ and the ‘neonatal window of opportunity’ — timed succession of non-redundant phases to establish mucosal host–microbial homeostasis after birth. Immunology 159, 15–25 (2020).
Li, Y. et al. In utero human intestine harbors unique metabolome, including bacterial metabolites. J. Clin. Invest. Insights 5, e138751 (2020).
Pessa-Morikawa, T. et al. Maternal microbiota-derived metabolic profile in fetal murine intestine, brain and placenta. BioMed. Cent. Microbiol. 22, 46 (2022).
Zeng, B. et al. ILC3 function as a double-edged sword in inflammatory bowel diseases. Cell Death Dis. 10, 315 (2019).
Kimura, I. et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 367, 6481 (2020).
Lee, J. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–151 (2012).
Lu, P. et al. Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis. Nat. Commun. 12, 1042 (2021).
Malek, A., Sager, R., Kuhn, P., Nicolaides, K. H. & Schneider, H. Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am. J. Reprod. Immunol. 36, 248–255 (1996).
Koch, M. A. et al. Maternal IgG and IgA antibodies dampen mucosal T helper cell responses in early life. Cell 165, 827–841 (2016).
Macpherson, A. J., De Agüero, M. G. & Ganal-Vonarburg, S. C. How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol. 17, 508–517 (2017).
Nakata, K., Kobayashi, K., Ishikawa, Y. & Yamamoto, M. The transfer of maternal antigen-specific IgG regulates the development of allergic airway inflammation early in life in an FcRn-dependent manner. Biochem. Biophys. Res. Commun. 395, 238–243 (2014).
Zheng, W. et al. Microbiota-targeted maternal antibodies protect neonates from enteric infection. Nature 577, 543–548 (2020).
May, K. et al. Antibody-dependent transplacental transfer of malaria blood-stage antigen using a human ex vivo placental perfusion model. PLoS ONE 4, e7986 (2009).
Hu, M. et al. Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia. Nat. Commun. 10, 3031 (2019).
Thorburn, A. N. et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat. Commun. 6, 7320 (2015).
Vuillermin, P. J. et al. Maternal carriage of Prevotella during pregnancy associates with protection against food allergy in the offspring. Nat. Commun. 11, 1452 (2020).
Apostol, A. C., Jensen, K. D. C. & Beaudin, A. E. Training the fetal immune system through maternal inflammation — a layered hygiene hypothesis. Front. Immunol. 11, 123 (2020).
Gbédandé, K. et al. Malaria modifies neonatal and early-life Toll-like receptor cytokine responses. Infect. Immun. 81, 2686–2696 (2013).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
Ohnmacht, C. et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349, 989–993 (2015).
Narushima, S. et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5, 333–339 (2014).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Prinz, I. et al. Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 9, 444–457 (2016).
Pandiyan, P. et al. Microbiome dependent regulation of Tregs and Th17 cells in mucosa. Front. Immunol. 10, 426 (2019).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Wingender, G. et al. Neutrophilic granulocytes modulate invariant NKT cell function in mice and humans. J. Immunol. 188, 3000–3008 (2012).
An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156, 123–133 (2014).
Yang, Y., Xu, C., Wu, D. & Wang, Z. γδ T cells: crosstalk between microbiota, chronic inflammation, and colorectal cancer. Front. Immunol. 9, 1483 (2018).
Constantinides, M. G. et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science 366, eaax6624 (2019).
Huus, K. E., Petersen, C. & Finlay, B. B. Diversity and dynamism of IgA−microbiota interactions. Nat. Rev. Immunol. 2, 514–525 (2021).
Pabst, O. & Slack, E. IgA and the intestinal microbiota: the importance of being specific. Mucosal Immunol. 13, 12–21 (2020).
Flannigan, K. L. & Denning, T. L. Segmented filamentous bacteria-induced immune responses: a balancing act between host protection and autoimmunity. Immunology 154, 537–546 (2018).
Cahenzli, J., Köller, Y., Wyss, M., Geuking, M. B. & McCoy, K. D. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14, 559–570 (2013).
Dogra, S. K. et al. Nurturing the early life gut microbiome and immune maturation for long term health. Microorganisms 9, 2110 (2021).
Chassin, C. et al. MiR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8, 358–368 (2010).
Schuijs, M. J. et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349, 1106–1110 (2015). This study provides a mechanism for the protective effects of farm environments against allergic disease.
Wang, J., Ouyang, Y., Guner, Y., Ford, H. R. & Grishin, A. V. Ubiquitin-editing enzyme A20 promotes tolerance to lipopolysaccharide in enterocytes. J. Immunol. 183, 1384–1392 (2009).
Mazmanian, S. K., Cui, H. L., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).
Jain, N. The early life education of the immune system: moms, microbes and (missed) opportunities. Gut Microbes 12, 1824564 (2020).
Donald, K., Petersen, C., Turvey, S. E., Finlay, B. B. & Azad, M. B. Secretory IgA: linking microbes, maternal health, and infant health through human milk. Cell Host Microbe 30, 650–659 (2022).
Wilson, E. & Butcher, E. C. CCL28 controls immunoglobulin (Ig)A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate. J. Exp. Med. 200, 805–809 (2004).
Rousseaux, A. et al. Human milk oligosaccharides: their effects on the host and their potential as therapeutic agents. Front. Immunol. 12, 680911 (2021).
Bode, L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 22, 1147–1162 (2012).
Henrick, B. M. et al. Bifidobacteria-mediated immune system imprinting early in life. Cell 184, 3884–3898 (2021). This study identified the metabolite produced by bifidobacteria that affects immune development.
Laursen, M. F. et al. Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut. Nat. Microbiol. 6, 1367–1382 (2021).
Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–549 (2011).
Hiippala, K. et al. Isolation of anti-inflammatory and epithelium reinforcing Bacteroides and Parabacteroides spp. from a healthy fecal donor. Nutrients 12, 935 (2020).
Russell, S. L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. Eur. Mol. Biol. Organ. Rep. 13, 440–447 (2012).
Patrick, D. M. et al. Decreasing antibiotic use, the gut microbiota, and asthma incidence in children: evidence from population-based and prospective cohort studies. Lancet Respir. Med. 8, 1094–1105 (2020).
Arnold, I. C. et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J. Clin. Invest. 121, 3088–3093 (2011).
Knoop, K. A. et al. Microbial antigen encounter during a pre-weaning interval is critical for tolerance to gut bacteria. Sci. Immunol. 2, 18 (2017).
Al Nabhani, Z. & Eberl, G. Imprinting of the immune system by the microbiota early in life. Mucosal Immunol. 13, 183–189 (2020).
Arildsen, A. W. et al. Delayed gut colonization shapes future allergic responses in a murine model of atopic dermatitis. Front. Immunol. 12, 650621 (2021).
Lundblad, L. K. A., Gülec, N. & Poynter, M. E. The role of iNKT cells on the phenotypes of allergic airways in a mouse model. Pulm. Pharmacol. Ther. 45, 80–89 (2017).
Matangkasombut et al. Natural killer T cells and the regulation of asthma. Mucosal Immunol. 2, 383–392 (2009).
Reddel, S. et al. Gut microbiota profile in children affected by atopic dermatitis and evaluation of intestinal persistence of a probiotic mixture. Sci. Rep. 9, 4996 (2019).
Nance, C. L. et al. The role of the microbiome in food allergy: a review. Children 7, 50 (2020).
Burbank, A. J., Sood, A. K., Kesic, M. J., Peden, D. B. & Hernandez, M. L. Environmental determinants of allergy and asthma in early life. J. Allergy Clin. Immunol. 140, 1–12 (2018).
Azad, M. B. et al. Infant gut microbiota and food sensitization: associations in the first year of life. Clin. Exp. Allergy 45, 632–643 (2015).
Russell, S. L. et al. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 4, 158–164 (2013).
Kaplan, J. L., Shi, H. N. & Walker, W. A. The role of microbes in developmental immunologic programming. Pediatr. Res. 69, 465–472 (2011).
Penders, J., Stobberingh, E. E., van den Brandt, P. A. & Thijs, C. The role of the intestinal microbiota in the development of atopic disorders. Allergy 62, 1223–1236 (2007).
Roduit, C. et al. High levels of butyrate and propionate in early life are associated with protection against atopy. Allergy 74, 799–809 (2019).
Di Costanzo, M., De Paulis, N. & Biasucci, G. Butyrate: a link between early life nutrition and gut microbiome in the development of food allergy. Life 11, 384 (2021).
Venegas, D. P. et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front. Immunol. 10, 277 (2019).
Lyons, A. et al. Bacterial strain-specific induction of Foxp3+ T regulatory cells is protective in murine allergy models. Clin. Exp. Allergy 40, 811–819 (2010).
Zheng, N., Gao, Y., Zhu, W., Meng, D. & Id, W. A. W. Short chain fatty acids produced by colonizing intestinal commensal bacterial interaction with expressed breast milk are anti- inflammatory in human immature enterocytes. PLoS ONE 15, e0229283 (2020).
Dai, D. L. Y. et al. Breastfeeding enrichment of B. longum subsp. infantis mitigates the effect of antibiotics on the microbiota and childhood asthma risk. Med 4, 92–112.e5 (2022).
Nuzzi, G., Di Cicco, M. E. & Peroni, D. G. Breastfeeding and allergic diseases: what’s new? Children 8, 330 (2021).
McCall, L. I. et al. Home chemical and microbial transitions across urbanization. Nat. Microbiol. 5, 108–115 (2020).
Kirjavainen, P. V. et al. Farm-like indoor microbiota in non-farm homes protects children from asthma development. Nat. Med. 25, 1089–1095 (2019).
Bisgaard, H. 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. 128, 646–652.e5 (2011).
Ege, M. J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).
Garn, H., Potaczek, D. P. & Pfefferle, P. I. The hygiene hypothesis and new perspectives — current challenges meeting an old postulate. Front. Immunol. 12, 637087 (2021). This review describes important recent updates to the hygiene hypothesis.
Petersen, C. et al. A rich meconium metabolome in human infants is associated with early-life gut microbiota composition and reduced allergic sensitization. Cell Rep. Med. 2, 5 (2021).
Stinson, L. F., Trevenen, M. L. & Geddes, D. T. The viable microbiome of human milk differs from the metataxonomic profile. Nutrients 13, 4445 (2021).
Meyer, K. M., Prince, A. L. & Aagaard, K. M. Maternal IgA targets commensal microbiota in breast milk and the maternal and infant gut microbiomes. Am. J. Obstet. Gynecol. 220, S604–S605 (2019).
Prentice, P. M. et al. Human milk short-chain fatty acid composition is associated with adiposity outcomes in infants. J. Nutr. 149, 716–722 (2019).
Stinson, L. F. et al. Human milk from atopic mothers has lower levels of short chain fatty acids. Front. Immunol. 11, 1427 (2020).
Stinson, L. F. & Geddes, D. T. Microbial metabolites: the next frontier in human milk. Trends Microbiol. 30, 408–410 (2022).
Bantz, S. K., Zhu, Z. & Zheng, T. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. J. Clin. Cell. Immunol. 5, 2 (2014).
Sullivan, P. W. et al. The burden of adult asthma in the United States: evidence from the medical expenditure panel survey. J. Allergy Clin. Immunol. 127, 363–369 (2011).
Licona-Limón, P., Kim, L. K., Palm, N. W. & Flavell, R. A. TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol. 14, 536–542 (2013).
Liu, D., Tan, Y., Bajinka, O., Wang, L. & Tang, Z. Th17/IL-17 axis regulated by airway microbes get involved in the development of asthma. Curr. Allergy Asthma Rep. 20, 11 (2020).
Zhao, Y., Yang, J., Gao, Y. D. & Guo, W. Th17 immunity in patients with allergic asthma. Int. Arch. Allergy Immunol. 151, 297–307 (2010).
Zhang, Z. et al. Association of infant antibiotic exposure and risk of childhood asthma: a meta-analysis. World Allergy Organ. J. 14, 11 (2021).
Donovan, B. M. et al. Dose, timing, and type of infant antibiotic use and the risk of childhood asthma. Clin. Infect. Dis. 70, 1658–1665 (2020).
Lee, G. C. et al. Outpatient antibiotic prescribing in the United States: 2000 to 2010. BioMed. Centr Med. 12, 96 (2014).
King, L. M., Bartoces, M., Fleming-Dutra, K. E., Roberts, R. M. & Hicks, L. A. Changes in US outpatient antibiotic prescriptions from 2011-2016. Clin. Infect. Dis. 70, 370–377 (2020).
Xue, M. et al. Breastfeeding and risk of childhood asthma: a systematic review and meta-analysis. Eur. Respir. J. Open Res. 7, 4 (2021).
Bloch, A. M., Mimouni, D., Mimouni, M. & Gdalevich, M. Does breastfeeding protect against allergic rhinitis during childhood? A meta-analysis of prospective studies. Acta Paediatr. Int. J. Paediatr. 91, 275–279 (2002).
Azad, M. B. et al. Human milk oligosaccharide concentrations are associated with multiple fixed and modifiable maternal characteristics, environmental factors, and feeding practices. J. Nutr. 148, 1733–1742 (2018).
Lasekan, J. et al. Growth and gastrointestinal tolerance in healthy term infants fed milk-based infant formula supplemented with five human milk oligosaccharides (HMOs): a randomized multicenter trial. Nutrients 14, 2625 (2022).
Puccio, G. et al. Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. J. Pediatr. Gastroenterol. Nutr. 64, 624–631 (2017).
Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).
Tan-Lim, C. S. C. & Esteban-Ipac, N. A. R. Probiotics as treatment for food allergies among pediatric patients: a meta-analysis. World Allergy Organ. J. 11, 25 (2018).
Tang, R. B., Chang, J. K. & Chen, H. L. Can probiotics be used to treat allergic diseases? J. Chin. Med. Assoc. 78, 154–157 (2015).
Kuitunen, M., Kukkonen, K., Juntunen-Backman, K. & Korpela, R. 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).
Colquitt, A. S., Miles, E. A. & Calder, P. C. Do probiotics in pregnancy reduce allergies and asthma in infancy and childhood? A systematic review. Nutrients 14, 1852 (2022).
More, D., Shepard, C., More, C. & Mayol-Kreiser, S. The perinatal use of probiotics, prebiotics, and synbiotics for the primary prevention of allergic diseases in children: a systematic review. Hum. Nutr. Metab. 25, 200125 (2021).
Blümer, N. et al. Perinatal maternal application of Lactobacillus rhamnosus GG suppresses allergic airway inflammation in mouse offspring. Clin. Exp. Allergy 37, 348–357 (2007).
Singh, T. P. & Natraj, B. H. Next-generation probiotics: a promising approach towards designing personalized medicine. Crit. Rev. Microbiol. 47, 479–498 (2021).
B.B.F’s lab is supported by a Canadian Institutes for Health Research (CIHR) Foundation Grant. B.B.F. is also a Canadian Institute for Advanced Research (CIFAR) Senior Fellow. K.D. is supported by the Four Year Fellowship Tuition Award, President’s Academic Excellence Initiative PhD Award and International Tuition Award at the University of British Columbia.
The authors declare no competing interests.
Peer review information
Nature Reviews Immunology thanks H. Deshmukh, S. Way 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.
- Germ-free mice
(GF mice). Mice that are kept in sterile conditions and are devoid of microbes, often used to study what happens in the absence of a microbiota.
- Hygiene hypothesis
Hypothesis stating that reduced contact with environmental microbes has contributed to the recent rise in immune-mediated diseases.
- Isolated lymphoid follicles
Organized centres of lymphoid tissue lining the intestine.
- Paneth cells
Cells that line the intestine and modulate the gut microbiota; important producers of antimicrobial peptides.
- Polymeric Ig receptor
(PIgR). Receptor responsible for carrying antibodies including IgA across mucosal surfaces for secretion into the lumen; donates a peptide to secreted antibodies and contributes to antibody stability.
- Window of opportunity
Period of early life when the immune system is still developing and is susceptible to the influence of microbes and environmental factors, affecting lifelong immunity; often thought to be represented by the first 3 months after birth.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Donald, K., Finlay, B.B. Early-life interactions between the microbiota and immune system: impact on immune system development and atopic disease. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00874-w