Breastfeeding, a personalized Medicine with Influence on Short- and Long-Term Immune Health

Abstract

The neonatal immune system has its own reactivity, constraints, and challenges, which profoundly differ from the adult. Breast milk is most probably a key requirement both for optimal immune function in early life and for imprinting of the immune system for long-term immune health. Here, we will highlight how breast milk fills the needs and the gaps of the developing immune system and thereby represents the unbeatable way to prevent infectious disease. We will further focus on some factors in breast milk that we extensively studied and found to actively influence the immune trajectory and long-term immune health. More specifically, we will review how the presence of allergens in breast milk together with maternal milk cofactors such as TGF-β, vitamin A, and immunoglobulins influence mucosal immunity in early life with long-term effects on allergic disease susceptibility. We will see that, depending on the content and the nature of allergens in breast milk as well as the presence of immune modulators, very different outcomes are observed, ranging from protection to an increased allergy risk. We are starting to decipher the specific requirements for the neonatal immune system to function optimally. We are discovering how breast milk fulfills these requirements and guides immune trajectories from early life. Answering these questions will provide the infant with preventive and curative approaches that are tailored to this very specific period of life and will ensure long-term immune health.

Genetic Programming, Environment, and Growth Render Infancy a Period of High Susceptibility to Infectious and Allergic Diseases

As compared to adulthood, early postnatal life is a period that is characterized by
rapid changes and multiple immune challenges. The neonates’ tissues are constantly
changing due to the growth process. Therefore, the immune system has to respect growth constraints in this period of life, and strong inflammatory immune responses, such as Th1 immune responses, should be avoided as they may lead to scars. Furthermore, tissue development requires the secretion of cytokines such as IL-33, which are also involved in the differentiation of Th2 immunity and allergic immune responses [1]. Thus, in early life, tissue growth results in the predisposition to mount low inflammatory and pro-Th2 immune responses, which can explain the propensity of the neonate to be susceptible to infectious diseases (lack of strong inflammatory responses) and to allergic diseases (bias towards Th2 immune responses). Another characteristic of early life is that the immune system is developing, and gut microbiota, which are a major promotor of immune development [2, 3], are establishing. Genetically programmed immune system development and lack of microbiota in early life result in immune deficiency, where the levels of mucosal antibodies and immune cells in the tissues are much lower than in the adult [4, 5]. The neonate is also exposed to multiple
new antigens, which are found in the environment, are present in the diet, or are associated with gut microbiota colonization. With all these antigens being new to the immune system, immune memory in early life is much lower than in the adult [6–8]. Naïve immune responses are known to be slower and less intense than memory ones, which also contribute to higher susceptibility to infection. Finally, yet importantly, requirements for immune activation in early life are different from adulthood. Elegant studies demonstrated that neonates are fully able to mount a cytotoxic immune response towards a viral infection when exposed to a dose that is 10,000 times lower than in the adult [9]. This has important implications for vaccination strategies and highlight the necessity of good hygiene especially in early life to prevent infection. Altogether, these observations indicate that for multiple reasons, early-life immune responses tend to be much less efficient in the fight against pathogens than in adulthood, and neonatal infection remains a common tragedy, with about 7 million cases and 700,000 deaths per year, accounting for 40% of mortality in those under 5 years of age [10]. Immune homeostasis also requires immune tolerance, an immune response that is characterized by the absence of inflammation and largely mediated by regulatory T cells. The induction of regulatory immune responses towards innocuous antigens, such as self-antigens and exogenous antigens derived from the diet, is critical
to avoid autoimmune and allergic diseases, respectively. A pioneer study by Billingham et al. [11] demonstrated that immune tolerance is easily induced upon systemic antigen exposure in utero and early postnatal life, and 70 years later, studies are still ongoing to decipher the mechanisms underlying these characteristics

[12]. However, the high prevalence of allergic diseases in infancy also indicates that mechanisms of tolerance towards exogenous innocuous antigens upon exposure through the skin and/or the mucosa are defective [13]. Instead, Th2 immune responses are preferentially induced [13]. As discussed here above, the liberation of mediators necessary for tissue growth contributes to this predisposition. The exposure to allergens through a skin barrier that is not fully developed can also favor allergic sensitization [14]. Furthermore, there is strong evidence from mouse models that the neonatal period is refractory to oral tolerance induction [15–19], the process by which immune tolerance to an antigen is acquired following its exposure through the digestive tract [20]. The spontaneous resolution of the majority of infant food allergies suggests a physiological maturation of the mechanisms of oral immune tolerance during the first years of life
[13, 21]. Gut colonization with microbiota plays certainly a major role in the setup of immune tolerance and the inhibition of allergic responses. This is clear from studies in germ-free mice, which have elevated levels of serum IgE (a hallmark of allergic immune responses) and are refractory to oral tolerance [22, 23].

Importantly, gut colonization with microbiota must occur in early postnatal life to efficiently regulate IgE immune responses [23], highlighting the concept of a window of opportunity to influence long-term immune responses [24]. There is accumulating evidence that the specific composition and the metabolites produced by the gut microbiota are critical for the generation of regulatory T cells and oral tolerance to be fully effective [2, 3, 20, 25]. In summary, the immune system in early life is not the one of a “small adult” and neither immature nor tolerance prone. The neonatal immune system is different from the adult one with specific requirements for activation and regulation. In the absence of specific interventions, the infant is highly susceptible to
both infectious and allergic diseases. Infant vaccination to elicit memory immune
responses and maternal vaccination during pregnancy to increase the levels of circulating antibodies during the first months are possible intervention targets, which are successful to a certain extent, to decrease morbidity and mortality due to infectious diseases in early childhood [10, 26]. Changes in allergy prevention guidelines and earlier introduction of potential allergens in the diet are promising strategies for food allergy prevention, with some limitations as we will discuss later on. A natural intervention does also exist, i.e., breastfeeding. We can distinguish the influence of breastfeeding on short-term immune outcomes, i.e. its effects while the infant is breastfed, and on long-term immune outcomes, i.e., months to years after breastfeeding has ceased (Fig. 1).

Breast Milk as a Physiological and Critical Strategy to Prevent Infectious Diseases in the Short Term

For years, breast milk was considered mainly as a source of nutrients for the developing
child. The extensive observations that breastfeeding affords protection towards infectious diseases and could reduce the mortality rate of common infections by more than half have added another key role to breastfeeding [27]. A recent meta-analysis concludes that scaling up breastfeeding to a near universal level could prevent 823,000 annual deaths in children younger than 5 years, mostly due to infectious disease. This protection relies in great part on the transfer of mucosal immunity through breast milk, which importantly relies on multiple, various, and adapting mechanisms (Fig. 1). Breast milk contains potent antibiotics, such as lactoferrin, lysozyme, and antimicrobial peptides [27, 28].

The presence of prebiotics such as human milk oligosaccharides [29] and probiotics
[30, 31] interferes with pathogenic bacterial expansion and invasion. Growth factors such as EGF and TGF-β contribute to maintain and repair potential pathogen-induced mucosal barrier breaks. Importantly, secretory IgA (SIgA) delivers personalized medicine. SIgA is present at high concentrations in colostrum (∼10 g/L) and at somewhat lower concentrations in mature breast milk (∼1 g/L). SIgA is specific for intestinal and respiratory pathogens in the maternal environment due to the selective migration of B cells originating from the maternal mu-cosa to the mammary gland [32]. They are thus providing mucosal immunity against pathogens, which are specifically found in the environment of the child. By their non-antigen-specific part, maternal SIgA will also contribute to the establishment of infant gut microbiota and protect the child form pathogens [33].

Breast Milk as a Key Player in the Education of the Immune System and Long-Term Susceptibility to Immune-Dependent Diseases

In addition to the provision of passive immunity and compensation for neonatal
immune deficiencies, breast milk actively influences the development of the immune
system (Fig. 1). Thereby, breast milk can guide immune trajectories and long-term susceptibility to diseases, which have an immune component in their physiopathology. There is evidence that breastfeeding decreases the risk of obesity and metabolic complications associated with obesity, such as type 2 diabetes [34]. However, there is lack of consistency regarding the possibility of long-term prevention of infectious diseases [35] and allergy [34, 36–40] by breastfeeding. Despite this, there are accumulating data indicating that breast milk has the potential to prevent these diseases by at least two major ways: by shaping the infant microbiota and by exposing the neonatal immune system to microbial antigens and allergens. The gut microbiota, and more specifically the microbiota-derived metabolites, are key for influencing the balance between health and disease [41]. In particular, gut microbiota influences susceptibility to infection and efficacy of vaccination [42], as well as susceptibility to allergy as we recently reviewed [2].

By the presence of prebiotics, probiotics, and antigen-specific and non-antigenspecific
antimicrobial compounds, breastfeeding plays a major role in the initial seeding of the infant gut microbiota and in its constant evolution in postnatal life [2]. The major event being known to affect microbiota composition is cessation of breastfeeding [43]. Therefore, we can speculate that the various concentrations of microbiota-shaping compounds in each mother’s breast milk will contribute to the heterogeneity in gut microbiota found in children and thereby influence their susceptibility to disease [2]. Finding which microbiota is best adapted to each environment and how to influence microbiota-shaping molecules in breast milk will open up new avenues for long-term immune health.

Breast milk also contains exogenous antigens, and our research in the last decade has been aimed at deciphering the long-term outcomes of the presence of allergens in breast milk on allergy susceptibility in the offspring. Recently, we expanded this research to infectious disease prevention. In the last part of this review, we will synthesize our main findings related to the presence of exogenous antigens in breast milk and discuss their implications for long-term immune health.

Allergy is a rising public health issue, with respiratory and food allergy affecting up to 20% of children (the Global Asthma Report 2018; http://
globalasthmareport.org/) [13]. After an era of avoidance, there has been a paradigm
shift, and new strategies for allergy prevention aim now at inducing tolerance
by antigen exposure. Following impressive results in large randomized clinical trials, the early introduction of eggs and peanuts in the diet is now recommended for food allergy prevention [13]. However, recent studies also demonstrated a significant proportion of infants already have egg sensitization and clinical reactivity (including anaphylaxis) prior to the first introduction of eggs into their solid food diet [13, 44–46]. This underscores the necessity to identify earlier and safer ways to promote oral tolerance development to food allergens in young infants, which may be particularly challenging knowing the refractoriness of early life to oral tolerance. We proposed the hypothesis that early oral
exposure to exogenous allergens in the presence of maternal milk immune modulators would alleviate oral tolerance induction in early life. Our experiments in mouse experimental settings demonstrated the key findings: 1. Mice exposed to only low amounts (ng/mL) of the egg-derived allergen ovalbumin (OVA) through breastfeeding are protected from allergic reactions to OVA when reexposed in adulthood via the oral (as a model of food allergy) [47] or respiratory route (as a model for respiratory allergy) [48–50]. This echoes to observations referenced here above indicating that the early-life immune system reacts to very low amounts of antigens. Importantly, other reports have shown the presence of dietary antigens in breast milk in the same range at very low concentrations (ng/mL), such as cow milk β-lactoglobulin [51–53], peanut allergens
(Ara h 1 and Ara h 2) [54, 55], or wheat antigen (gliadin) [56]. By comparison, it
is worth noting that allergen levels in cow’s milk are found in the range of mg/ mL. Thus, through breast milk, infants are exposed to a wide variety of dietary allergens at low concentrations while formula-fed infants are only exposed to cow milk-derived allergens and at much higher concentrations (unless hydrolyzed formulas are used). We can speculate this will lead to very different outcomes in terms of oral tolerance induction and allergy prevention in the offspring.

Our recent observation in a human birth cohort demonstrated that the risk of egg allergy in children was reduced by a factor of 4 at 2.5 years when comparing children exposed to breast milk with or without egg antigen [57]. To fully confirm that OVA in breast milk is responsible for a decreased egg allergy risk in children, further randomized controlled trials will need to be conducted. The next steps will be to identify maternal interventions leading to the consistent presence of OVA in breast milk in order to move towards a successful prevention of egg allergy by breastfeeding. 

2. Successful oral tolerance and allergy prevention upon OVA exposure through breast milk required the concomitant presence of maternal immunomodulatoryfactors. We identified TGF-β, OVA-specific IgG, and vitamin A to stimulate oral tolerance induction in the offspring. Each cofactor was shown to act by different mechanisms of action. TGF-β promoted the induction of OVAspecific Th1 cells, which counteract allergic Th2 responses [48, 58]. Vitamin A accelerated gut epithelium maturation resulting in a stronger barrier in the first week of life [50]. It also promoted the expression of RALDH in small-intestine dendritic cells, which was associated with their increased efficiency at activating T lymphocytes [50]. Maternal vitamin A supplementation resulted in the possibility to induce oral tolerance to OVA in breast milk in the offspring from birth, which otherwise is only efficient from the third week of life [50]. OVAspecific IgG in breast milk was necessary for a protected transfer of OVA though the neonatal gut barrier and the induction of a prolonged and strong protection from allergy, which was found to be mediated by FoxP3 Tregs [59]. Recently, another group confirmed these findings and showed that OVA-specific IgG also promoted antigen presentation by neonatal dendritic cells [60]. In other words, early life is characterized by a relative lack of TGF-β in mucosal tissue, a physiological deficiency in vitamin A, and low mucosal and systemic immunoglobulin secretion, which contribute to the lack of oral tolerance induction in early life in the absence of breast milk. Breast milk is providing infants with
these cofactors, which will affect gut epithelium barrier integrity, and antigen transfer and presentation for successful regulatory immune response induction.

This will result in a long-term low risk for allergic disease as we showed for egg allergy both in an experimental mouse model and in a human birth cohort. Altogether, these data suggest that, according to the levels of immune modulators in breast milk, oral tolerance to dietary antigens in breast milk will be induced with more or less efficiency, which will condition long-term susceptibility to allergy.

3. Unexpectedly, we found allergens from respiratory sources such as from the house dust mites Dermatophagoides pteronyssinus (Der p) and Blomia tropicalis in breast milk in similar amounts as dietary antigen [61, 62]. Since we detected Der p 1 in the digestive fluid of healthy adults [63], we propose that respiratory allergens are ingested by being trapped in the oropharynx or pulled back by the mucociliary epithelium, and follow the same route as dietary antigens to the mammary gland. In contrast to the observation with OVA, the transfer of Der p 1 through breast milk induced Th2 immune response priming and increased susceptibility to allergic disease in adult mice [64]. Importantly, in a human birth cohort, there was a positive association between allergic sensitization and respiratory allergies in children and the presence of Der p 1 levels in breast milk [61]. This observation stresses that not all the antigens in breast milk induce oral tolerance, even though they reach the gut mucosa together with breast milk-tolerogenic factors. Our most recent findings further showed that Der p allergen in maternal milk abolished the capacity of neonatal mice to mount oral tolerance to bystander OVA egg antigen, which resulted in an increased risk of egg food allergy in the long term [65]. Importantly, human data showed heterogeneity in breast milk content in Der p and OVA. Based on the presence of Der p and/or OVA in breast milk, we could
identify groups of lactating mothers which mirror the ones found in mice responsible for the different egg allergy risk [65]. These observations stress the need to identify how to counteract deleterious actions of some allergens in breast milk, such as those derived from house dust mite allergens, which prime for allergic sensitization to themselves and break oral tolerance induction to bystander ones.

We have started to identify some potential targets as we showed that protease from
Der p allergens are key players for the induction of gut Th2 mucosal immune imbalance
in mice breastfed by mothers inhaling Der p [65]. Ongoing research is aimed at identifying how to modulate Der p levels and their enzymatic activity in breast milk and/or in the breastfed child. Ultimately, this should contribute to ensure food allergy prevention in children.

4. Based on the findings that house dust mite allergens in breast milk could prime immune reactivity in the long term, we proposed that novel strategies of early life prevention of infectious disease may take advantage of the possibility to stimulate antigen-specific immune responses through breast milk. Microbial antigen transfer through breast milk would be a way to naturally vaccinate the infant [26, 66]. Some evidence in the literature supports this hypothesis, such as the observation that maternal HIV infection of noninfected breastfed children is associated with infant stimulation of IgG and IgA secretion in their gut mucosa [67] and HIV-specific interferon-γ-secreting PBMC are found in 50% of cases [68]. Recently, we addressed the original hypothesis that the presence of malaria antigen in breast milk may stimulate antimalarial immune defenses and reduce the malaria risk in breastfed infants [69]. As a first critical step to address this hypothesis, we investigated whether Plasmodium falciparum histidine- rich protein 2 (pHRP-2) and lactate dehydrogenase (pLDH) are detectable in breast milk of mothers from Uganda, a country with endemic malaria
[70]. We found that 15% of breast milk samples from mothers with asymptomatic
malaria do contain malaria antigens. Our preliminary data indicate that blood levels of malaria antigens determine their levels in breast milk. These landmark findings may have significant implications for susceptibility to malaria in children from endemic countries since malaria antigens in breast milk may strongly influence the immune responses to natural malaria infections and to malaria vaccines in breastfed children [26].

Concluding Remarks and Perspectives

The way breast milk composition constantly adapts to the needs of each infant in each setting is fascinating. This results in a major success for the prevention of many infectious diseases in breastfed infants. There is also evidence that breastfeeding could have long-term protective effects on infections, even after breastfeeding has ceased, and this may open new avenues for infant vaccination. Unfortunately, and maybe unexpectedly, breastfeeding does not provide a consistent protection from allergy. A hypothesis behind this lack of protection may be that the lifestyle of modern societies has resulted in changes in breast milk composition, which is not suitable anymore for allergy prevention. Research conducted to identify which factors in breast milk condition protection versus susceptibility is providing new clues, which ultimately will result in the protection of breastfed children from allergy.

Disclosure Statement
Valérie Verhasselt has no conflict of interest with regard to the writing of this chapter.

References
1. de Kleer IM, Kool M, de Bruijn MJ, et al: Perinatal activation of the interleukin-33 pathway promotes type 2 immunity in the developing lung. Immunity 2016; 45: 1285–1298.
2. van den Elsen LWJ, Garssen J, Burcelin R, Verhasselt V: Shaping the gut microbiota by breastfeeding: the gateway to allergy prevention? Front Pediatr 2019; 7: 47.
3. van den Elsen LWJ, Rekima A, Verhasselt V: Early- life nutrition and gut immune development.Nestle Nutr Inst Workshop Ser 2019; 90: 137–149.
4. Torow N, Marsland BJ, Hornef MW, Gollwitzer ES: Neonatal mucosal immunology. Mucosal Immunol 2017; 10: 5–17.
5. 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.
6. Li N, van Unen V, Abdelaal T, et al: Memory CD4(+) T cells are generated in the human fetal intestine. Nat Immunol 2019; 20: 301–312.
7. Zhang X, Mozeleski B, Lemoine S, et al: CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus. Sci Transl Med 2014; 6: 238ra72.
8. Thome JJ, Bickham KL, Ohmura Y, et al: Earlylife compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat Med 2016; 22: 72–77.
9. Sarzotti M, Robbins DS, Hoffman PM: Induction of protective CTL responses in newborn mice by a murine retrovirus. Science 1996; 271: 1726– 1728.
10. Kollmann TR, Kampmann B, Mazmanian SK, et al: Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny. Immunity 2017; 46: 350–363.
11. Billingham RE, Brent L, Medawar PB: Actively acquired tolerance of foreign cells. Nature 1953; 172: 603–606.
12. Ng MSF, Roth TL, Mendoza VF, et al: Helios enhances the preferential differentiation of human fetal CD4(+) naive T cells into regulatory T cells. Sci Immunol 2019; 4:eaav5947.
13. Sicherer SH, Sampson HA: Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol 2018; 141: 41–58.
14. Du Toit G, Sampson HA, Plaut M, et al: Food allergy: update on prevention and tolerance. J Allergy Clin Immunol 2018; 141: 30–40.
15. Strobel S: Neonatal oral tolerance. Ann NY Acad Sci 1996; 778: 88–102.
16. Strobel S: Immunity induced after a feed of antigen during early life: oral tolerance v. sensitisation. Proc Nutr Soc 2001; 60: 437–442.
17. Strobel S, Ferguson A: Immune responses to fed antigens in mice. 3. Systemic tolerance or priming is related to age at which antigen is first encountered. Pediatr Res 1984; 18: 588–594.
18. Hanson DG: Ontogeny of orally induced tolerance to soluble proteins in mice. I. Priming and tolerance in newborns. J Immunol 1981; 127: 1518–1524.
19. Miller A, Lider O, Abramsky O, Weiner HL: Orally administered myelin basic protein in neonates primes for immune responses and enhances experimental autoimmune encephalomyelitis in adult animals. Eur J Immunol 1994; 24: 1026– 1032.
20. Pabst O, Mowat AM: Oral tolerance to food protein. Mucosal Immunol 2012; 5: 232–239.
21. Wang J, Ji H: Influence of probiotics on dietary protein digestion and utilization in the gastrointestinal tract. Curr Protein Pept Sci 2019; 20: 125– 131.
22. Sudo N, Sawamura S, Tanaka K, et al: The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997; 159: 1739–1745.
23. Cahenzli J, Koller Y, Wyss M, et al: Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 2013; 14: 559–570.
24. Renz H, Adkins BD, Bartfeld S, et al: The neonatal window of opportunity-early priming for life. J Allergy Clin Immunol 2018; 141: 1212–1214.
25. Rooks MG, Garrett WS: Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016; 16: 341–352.
26. Marchant A, Sadarangani M, Garand M, et al: Maternal immunisation: collaborating with mother nature. Lancet Infect Dis 2017; 17:e197– e208.
27. Labbok MH, Clark D, Goldman AS: Breastfeeding: maintaining an irreplaceable immunological resource. Nat Rev Immunol 2004; 4: 565–572.
28. Lawrence RM, Pane CA: Human breast milk: current concepts of immunology and infectious diseases. Curr Probl Pediatr Adolesc Health Care 2007; 37: 7–36.
29. Bode L: Human milk oligosaccharides: structure and functions. Nestle Nutr Inst Workshop Ser 2020; 94. DOI: 10.1159/000505339.
30. Rautava S: Milk microbiome and neonatal colonization – overview. Nestle Nutr Inst Workshop Ser 2020; 94. DOI: 10.1159/000505030.
31. Fernández L, Rodriguez JM: Human milk microbiota: origin and potential uses. Nestle Nutr Inst Workshop Ser 2020; 94. DOI: 10.1159/000505031.
32. Brandtzaeg P: Mucosal immunity: integration between mother and the breast-fed infant. Vaccine 2003; 21: 3382–3388.
33. Dunne-Castagna VP, Mills DA, Lönnerdal B: Effects of milk secretory immunoglobulin A on the commensal microbiota. Nestle Nutr Inst Workshop Ser 2020; 94. DOI: 10.1159/000505335.
34. Victora CG, Bahl R, Barros AJ, et al: Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 2016; 387: 475– 490.
35. Hanson LA, Korotkova M, Lundin S, et al: The transfer of immunity from mother to child. Ann NY Acad Sci 2003; 987: 199–206.
36. Dogaru CM, Nyffenegger D, Pescatore AM, et al: Breastfeeding and childhood asthma: systematic review and meta-analysis. Am J Epidemiol 2014; 179: 1153–1167.
37. Lodge CJ, Tan DJ, Lau MX, et al: Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr 2015; 104: 38–53.
38. Gungor D, Nadaud P, LaPergola CC, et al: Infant milk-feeding practices and food allergies, allergic rhinitis, atopic dermatitis, and asthma throughout the life span: a systematic review. Am J Clin Nutr 2019; 109(suppl 7): 772S–799S.
39. Greer FR, Sicherer SH, Burks AW: Committee on Nutrition, Section on Allergy and Immunology: The effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. Pediatrics 2019; 143:e20190281.
40. Muraro A, Halken S, Arshad SH, et al: EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy 2014; 69: 590– 601.
41. Hand TW, Vujkovic-Cvijin I, Ridaura VK, Belkaid Y: Linking the microbiota, chronic disease, and the immune system. Trends Endocrinol Metab 2016; 27: 831–843.
42. Lynn DJ, Pulendran B: The potential of the microbiota to influence vaccine responses. J Leukocyte Biol 2018; 103: 225–231.
43. Backhed F, Roswall J, Peng Y, et al: Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 2015; 17: 852.
44. Bellach J, Schwarz V, Ahrens B, et al: Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. J Allergy Clin Immunol 2017; 139: 1591–1599.e2.
45. Palmer DJ, Metcalfe J, Makrides M, et al: Early regular egg exposure in infants with eczema: a randomized controlled trial. J Allergy Clin Immunol 2013; 132: 387–392.e1.
46. Palmer DJ, Sullivan TR, Gold MS, et al: Randomized controlled trial of early regular egg intake to prevent egg allergy. J Allergy Clin Immunol 2017; 139: 1600–1607.e2.
47. Rekima A, Macchiaverni P, Turfkruyer M, et al: Long-term reduction in food allergy susceptibility in mice by combining breastfeeding-induced tolerance and TGF-beta-enriched formula after weaning. Cli Exp Allergy 2017; 47: 565–576.
48. Verhasselt V, Milcent V, Cazareth J, et al: Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 2008; 14: 170–175.
49. Mosconi E, Rekima A, Seitz-Polski B, et al: Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunol 2010; 3: 461– 474.
50. Turfkruyer M, Rekima A, Macchiaverni P, et al: Oral tolerance is inefficient in neonatal mice dueto a physiological vitamin A deficiency. Mucosal Immunol 2016; 9: 479–491.
51. Fukushima Y, Kawata Y, Onda T, Kitagawa M: Consumption of cow milk and egg by lactating women and the presence of beta-lactoglobulin and ovalbumin in breast milk. Am J Clin Nutr 1997; 65: 30–35.
52. Host A, Husby S, Hansen LG, Osterballe O: Bovine eta-lactoglobulin in human milk from atopic and non-atopic mothers. Relationship to maternal intake of homogenized and unhomogenized mi. Clin Exp Allergy 1990; 20: 383–387.
53. Sorva R, Makinen-Kiljunen S, Juntunen-Backman K: Beta-lactoglobulin secretion in human milk varies widely after cow’s milk ingestion in mothers of infants with cow’s milk allergy. J Allergy Clin Immunol 1994; 93: 787–792.
54. Vadas P, Wai Y, Burks W, Perelman B: Detection of peanut allergens in breast milk of lactating women. JAMA 2001; 285: 1746–1748.
55. Bernard H, Ah-Leung S, Drumare MF, et al: Peanut allergens are rapidly transferred in human breast milk and can prevent sensitization in mice. Allergy 2014; 69: 888–897.
56. Chirdo FG, Rumbo M, Anon MC, Fossati CA: Presence of high levels of non-degraded gliadin in breast milk from healthy mothers. Scand J Gastroenterol 1998; 33: 1186–1192.
57. Verhasselt V, Genuneit J, Metcalfe JR, et al: Ovalbumin in breast milk is associated with a decreased risk of IgE-mediated egg allergy in children. Allergy 2019. DOI: 10.1111/all.14142.
58. Turfkruyer M, Verhasselt V: Breast milk and its impact on maturation of the neonatal immune system. Curr Opin Infect Dis 2015; 28: 199–206.
59. Mosconi É: Mise en évidence des propriétés immuno- régulatrices des complexes immuns du lait maternel: implications dans la prévention des maladies allergiques; thesis. Nice, 2010.
60. Yoshida M, Claypool SM, Wagner JS, et al: Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 2004; 20: 769–783.
61. Baiz N, Macchiaverni P, Tulic MK, et al: Early oral exposure to house dust mite allergen through breast milk: a potential risk factor for allergic sensitization and respiratory allergies in children. J Allergy Clin Immunol 2017; 139: 369–372.e10.
62. Macchiaverni P, Ynoue LH, Arslanian C, et al:
Early exposure to respiratory allergens by placental
transfer and breastfeeding. PLoS One 2015;
10:e0139064.
63. Tulic MK, Vivinus-Nebot M, Rekima A, et al: Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction. Gut 2016; 65: 757–766.
64. Macchiaverni P, Rekima A, Turfkruyer M, et al: Respiratory allergen from house dust mite is present in human milk and primes for allergic sensitization in a mouse model of asthma. Allergy 2014; 69: 395–398.
65. Rekima A, Bonnart C, Macchiaverni P, 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 2020. DOI: 10.1016/j.jaci.2019.12.912.
66. Verhasselt V: Is infant immunization by breastfeeding possible? Philos Trans R Soc Lond B Biol Sci 2015; 370: 20140139.
67.Moussa S, Jenabian MA, Gody JC, et al: Adaptive HIV-specific B cell-derived humoral immune defenses of the intestinal mucosa in children exposed to HIV via breast-feeding. PLoS One 2013; 8:e63408.
68. John-Stewart GC, Mbori-Ngacha D, Payne BL, et al: HV-1-specific cytotoxic T lymphocytes and breast milk HIV-1 transmission. J Infect Dis 2009; 199: 889–898.
69. van den Elsen LWJ, Verhasselt V, Egwang T: Malaria antigen shedding in the breast milk of mothers from a region with endemic malaria. JAMA Pediatr 2020. DOI: 10.1001/jamapediatrics. 2019.5209.
70. World Health Organization: World Malaria Report 2018. https://www.who.int/malaria/
publications/world-malaria-report-2018/en/.