REVIEW URRENT C OPINION

Breast milk and its impact on maturation of the neonatal immune system Mathilde Turfkruyer and Valerie Verhasselt

Purpose of review This article aims to review the evidence that breast milk can actively shape neonate gut immune system development toward a mature immune system capable of responding appropriately to encountered antigens. Recent findings Recent findings in the adult have demonstrated the critical role of the interaction between diet, gut microbiota, gut epithelial cells and gut-associated lymphoid tissue in the development of immune responses. Here, we will review what is known in this field in the neonate, compare these data to those obtained in the adult and review how milk factors impact gut immune function in the short and long term. Summary We propose that the neonate immune system and maternal milk represent an entity necessary to ensure not only appropriate function in early life but also long term immune homeostasis. Keywords breast milk, gut mucosa, neonate, oral tolerance

INTRODUCTION: DEFICIENT IMMUNE DEFENSE AND REGULATION IN NEONATES CALL FOR HELP Early-life susceptibility to infections and allergic diseases is a major problem of public health and needs to be better understood. Each year, almost 3 million children die in their first month of life and 50% of these deaths is due to infectious diseases [1]. Most neonatal infections involve mucosal surfaces highlighting specific defects in neonatal mucosal immunity. In parallel with higher susceptibility to infections, allergies develop also preferentially early in life [2], adding defective mucosal immune regulation to immune deficiencies of early life. Breastfeeding plays a major role in infectious disease prevention with less than half of the mortality rate attributed to common infections [3,4]. Reported mechanisms underlying such potent effect of breastfeeding include passive immunotherapy by transfer through breast milk of maternal immunoglobulin A that are specific for mucosal respiratory and enteric pathogens and compensate the immunoglobulin synthesis defects of neonates [5]. Breast milk also brings antimicrobial factors such as lactoferrin, lysozyme and oligosaccharides that help in microbial clearance [3,4]. In addition to compensation for neonate immune deficiencies,

breast milk can also actively influence the maturation of the neonatal immune system that may have not only short-term but also long-term effects on child immune responses. Studies on breastfed children compared with formula fed showed enhanced antibody response to vaccine and long-term protection from infection (reviewed in [6]). Breastfeeding is also associated with prevention of immune-mediated disease such as allergies, inflammatory bowel disease or type 1 diabetes, highlighting a possible active impact of breastfeeding on the induction of immune regulatory mechanisms [7–11]. Here, we will review recent evidence indicating that breast milk can actively affect neonatal immune system function, with a particular focus on induction of antigen-specific immune responses in the gut and their long-term impact on immune reactivity.

University Nice Sophia Antipolis, Tole´rance Immunitaire, Nice, France Correspondence to Vale´rie Verhasselt, EA 6302 ‘‘Tole´rance Immunitaire’’ – Universite´ de Nice Sophia-Antipolis, Hoˆpital de l’Archet 1, Route Saint Antoine de Ginestie`re, BP3079 06202 Nice, France. Tel: +33 4 92 15 77 06; fax: +33 4 92 15 77 09; e-mail: [email protected] Curr Opin Infect Dis 2015, 28:199–206 DOI:10.1097/QCO.0000000000000165

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KEY POINTS  The neonatal immune system is complete only if associated with maternal milk factors.  Endogenous growth and immunomodulatory factors, dietary compounds and immunoglobulins present in maternal milk stimulate neonatal immune system maturation allowing immune autonomy of the child after weaning.  Breast milk-mediated neonatal immune system maturation is indirectly induced by its impact on gut microbiota composition and directly by its impact on gut epithelial cell and dendritic cell function.  Breast milk affects immune responses during breastfeeding and for a long time after weaning.

MAMMAL NEONATAL GUT IS PHYSIOLOGICALLY BATHED IN BREAST MILK: IMPACT ON ITS FUNCTION The gut barrier, which will cover up to 300 m2 in the adult, provides a surface for nutrient absorption to ensure optimal growth of the neonate. It also controls the selective transfer of antigen in the small intestine, which will lead to the establishment of immune tolerance to food antigens (oral tolerance), and prevents microbiota and pathogens from penetrating into the body. Here, we will review how gut epithelium architecture, antigen transfer and immunomodulatory function contribute to the development of immune response both in the adult and in the neonate and how maternal milk affects these processes.

Gut epithelium architecture The particular gut anatomy with crypts and villi, the specialization of its epithelium cells into absorptive enterocytes, enteroendocrine, goblet and Paneth cells, and the secretion of factors both on the luminal side, such as immunoglobulin A, antimicrobial peptide (Paneth cells) and mucus (goblet cells), and on the serosal side of immunomodulatory factors (enterocytes) are known in the adult to be necessary for immune homeostasis of the gut [12,13]. At birth, gut epithelium is immature in different aspects, anatomically, metabolically and immunologically, and the combination of genetic, microbial colonization and nutrition, including maternal milk, will condition this maturation process. The level of maturity depends on the species with a more pronounced immaturity in mice than in humans. In mice, the maturation process observed during the first 10 days consists of the development of the 200

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crypt–villi architecture, increasing numbers of goblet and Paneth cells and a shift of enzymatic activities of enterocytes specialized for milk metabolism toward solid food metabolism [14,15]. Blimp-1 transcription factor was recently demonstrated to genetically control this process of maturation [16,17]. In addition, it has been known for a long time that gut trophic factors found in human milk, and more particularly in milk from early days, colostrum, actively stimulate crypt and villi formation [18]. Milk epidermal growth factor is certainly critical in this process through its capacity to activate proliferation and differentiation of epithelial cells and stimulate tissue repair and would be one of the essential components associated with prevention of necrotizing enterocolitis by human milk [19,20]. Interestingly, the concentration of epidermal growth factor seems to be adapted to gestational age with higher levels found in preterm milk than in milk from mothers that deliver at term [20]. Insulin growth factor, lactoferrin, transforming growth factor (TGF)-b, leptin or steroids will also affect neonate gut development [21,22]. In addition to maternal endogenous growth factors, levels of which can hardly be controlled, some factors found at different levels in maternal diet, and then in their milk, may also affect neonate gut growth. In particular, vitamin A levels in maternal milk may be important as vitamin A is a major differentiation factor of the epithelial cells [23]. It is found in high amount in colostrum and low amount in later milk [24,25], and we found that vitamin A supplementation in breast milk increased neonate gut maturation in terms of crypt formation and antigen transfer (unpublished data). Research on fatty acid also suggests that fatty acid diet composition may be important in gut maturation. Fatty acids and their metabolites are major components of cell membranes and also act as cell signalization molecules, and immunomodulators and dietary supplement of polyunsaturated fatty acid (PUFA) to lactating pigs were shown to stimulate gut maturation and repair in piglet (reviewed in [22]).

Antigen transfer across the gut barrier Evidence in the adult indicates that a tight control of antigen transfer is most probably a key step to prevent inflammatory reaction to microbial and food antigen, and increased gut permeability is associated with allergic disease and gut inflammatory disease development [26,27]. Protein can be transported through enterocytes, with less than 10% being transported intact; antigens and, in particular, microbial antigen can also be transferred by M cells present on the dome of Peyer patches. The Volume 28  Number 3  June 2015

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Breast milk and its impact on neonatal immune system Turfkruyer and Verhasselt

role of CX3CR1-expressing macrophages present in the underlying lamina propria and extending dendrites in the lumen is now controversial [28], whereas goblet cells were recently shown to be involved also in antigen transfer across the gut barrier [29]. Anatomical immaturity of neonatal gut is associated with specificity in the control of antigen transfer. Gut epithelium permeability to intact protein is increased in the first week of life both in humans [30] and in rodents [31,32]; the physiological reason underlying this conserved process is unknown and maternal milk is critical to induce permeability maturation toward the adult one [30,31]. In addition, there is a specific increased transport of immunoglobulin G by gut duodenal cells during the first 10 days of rodents’ life because of the specific expression in this period of the neonatal Fc receptor (FcRn), an immunoglobulin G-binding receptor that was shown to be critical for transfer of immunoglobulin G from mother to young across placental and gut barriers [33,34]. In mouse models, we have analyzed the impact of the transfer of antigen present in the breast milk to neonate on the long-term immune reactivity to it [35,36]. We found clear distinct immunological outcomes according to the fact that antigen [ovalbumin (OVA)] was present in soluble form or bound to maternal OVA-specific immunoglobulin G ([35,36] and Turfkruyer et al., unpublished observation). In the absence of maternal immunoglobulin G, we observed that OVA in breast milk could prevent allergic disease in later life only if transferred during the third week of life whereas protection could be induced from birth in the presence of maternal immunoglobulin G (Turfkruyer et al., unpublished observation); protection was also more profound in the presence of maternal OVA-specific immunoglobulin G and mechanisms involved in protection relied in this case on induction of FoxP3 Tregs [35], whereas Th1 cells were necessary in the case of soluble antigen administration (Turfkruyer et al., unpublished observation). Finally, in the absence of FcRn expression, mice could not be tolerized to OVA and this coincided with a very low OVA transfer across the gut barrier [35]. These data suggest that a protected antigen transfer, here by the mean of FcRn-mediated antigen immune complex transfer, is a limiting step in the process of immune tolerance induction in early life and that neonatal altered epithelial permeability is involved in the lack of efficient gut immune regulation induction in neonates. More recently, we observed that maternal vitamin A allowed oral tolerance induction to OVA from birth, even in the absence of maternal immunoglobulin G, while it stimulates maturation

of neonatal gut; this further supports this hypothesis. Protected FcRn-mediated antigen transport in early life may also be important for effector immune responses induction toward pathogens as shown in models of antigen and pathogen oral exposure in the presence of specific immunoglobulin G [37–39]. In human milk, immunoglobulin A is the most represented immunoglobulin (5–10 g/l); the role of milk immunoglobulin G (0.1 g/l) is poorly studied although FcRn is expressed as lasting for lifetime in the human gut [40]. Maternal vaccination during late pregnancy has been encouraged in the past few years in order to increase infant immunoglobulin G levels to specific pathogens by inutero transfer and protect them passively until they can mount efficient active immune response by vaccination [41]. In this regard, we believe that the impact of maternal immunoglobulin G transfer through breast milk on infant’s immune reactivity to mucosal microbial antigen would be worth studying. The significance of the paucity of goblet cells in the neonatal gut on deficient immune regulation in early life has not yet been investigated.

Immunomodulatory function of the gut Recent research in the adult has highlighted the importance of the cross-talk between gut epithelial cell and microbiota on the luminal side and on the serosal side, with immune cells present in the lamina propria on gut homeostasis (reviewed recently in [12,13,42]). Thus, by engaging pattern recognition receptors including toll-like receptors (TLRs) and NOD-like receptors on gut epithelial cells, microbiota stimulates goblet cells to secrete mucins that create a first line of defense against microbiota encroachment; enterocytes will contribute to mucosal immune defense by their production of antimicrobial peptides and transport of immunoglobulin A from serosal to luminal side. Specialized secretory Paneth cells constitutively secrete antimicrobial peptide including defensin and lysozyme [13]. In the neonate, Paneth cells are absent and this defect in antimicrobial peptide secretion is in part compensated by the selective secretion of CRAMP of the family of cathelecidins by neonatal epithelial cells [43]. In addition, immunoglobulin A is poorly produced by the neonate mucosal immune system. The presence of numerous molecules with antimicrobial properties in breast milk including immunoglobulin A, lysozyme, lactoferrin and oligosaccharides most probably compensates for deficit in immunoglobulin A secretion, in goblet and Paneth cells, and in antimicrobial function of enterocytes in neonates [3]; thereby, breast milk will not

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only help the neonate for defense against gut pathogens but also markedly affect gut microbiota establishment that is well known for its impact on immune maturation [12,44]. In particular, maternal immunoglobulin A present in breast milk has specificities that have been shaped by the maternal microbiota itself and, in turn, will shape neonate microbiota [12]; this was elegantly shown in a mouse model in which absence of maternal immunoglobulins in breast milk was associated with earlier colonization of the neonate gut by segmented filamentous bacteria [45], a bacteria turning the immune system toward Th17 differentiation [44]. Human milk oligosaccharides, which are absent in other milks, are also most probably crucial for pathogen defense and selective neonatal microbiota colonization [46]. Human milk oligosaccharides compete for mucosal cell surface glycans and serve as soluble decoy receptors to prevent pathogen binding and reduce the risk of infections; in addition, there are substrates that specifically sustain the growth of Bifidobacterium longum subsp infantis, which are considered as bacteria that are good for the health and will then compete with pathogenic bacteria [46]. Illustrating the complex interaction between milk, microbiota and epithelial cells, Bifidobacteria are able to metabolize glycan from diet or mucus into short-chain fatty acid such as butyrate and propionate that will in turn serve as a major nutrient source for colonic epithelial cells [47]. Gut epithelial cells are also known in the adult to dialog with the immune cells present in the lamina propria and, in particular, with macrophages, innate lymphocytes (ILCs), dendritic cells and T-helper lymphocytes (reviewed recently in [13,42]). At steady state, their secretion of TSLP, TGF-b and retinoic acid stimulates development of dendritic cell with tolerogenic properties and some protolerogenic commensal bacteria such as Clostridia were shown to induce TGF-b secretion that in turn favors Treg differentiation; they are also hyporesponsive to TLR signaling that most probably prevent inflammation induction by gut microbiota. On the contrary, pathogens will induce proinflammatory cytokine secretion such as interleukin-1 and interleukin-8 or cytokines that can affect ILC2 activation such as TSLP, interleukin-25 and interleukin33. Inversely, lamina propria cells can affect epithelial cell function, and, in particular, interleukin22 secretion by ILC3 stimulates repair capacities of epithelial cells [13,42]. Some immunomodulatory functions of neonatal gut epithelial cells have been described. A major developmental immaturity in the small intestine of human and mouse is its propensity to 202

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respond to stimuli by mounting inflammatory response such as interleukin-8, tumor necrosis factor-a and interleukin-1b upon bacterial stimuli [48]; this was shown to be at least because of the fact that neonatal epithelial cells are not tolerant to LPS in contrast with the adult [49]. Endogenous levels of regulatory cytokine TGF-b in the intestine are also low at birth and increase toward weaning [50]. Neonatal epithelial cells were also found to produce less chemokines capable of attracting dendritic cells that may explain the paucity of dendritic cell in neonatal lamina propria [51 ]. Physiologically, maternal milk will compensate for lack of secretion of factors by epithelial cells and considerably affects epithelial cell function. A recent analysis of exfoliated gut epithelial cells in stools of 3-month-old children who were breastfed versus formula fed showed a total of 1214 genes differentially expressed between breastfed and formula fed [52]. Analysis of gene networks reflected broad differences with respect to signal transduction (WNT, NOTCH, TGF-b), cytoskeletal remodeling, cell adhesion and immune response. Factors in breast milk that may affect epithelial cells include soluble pattern recognition receptors, such as sTLR and sCD14, that can interfere with microbial signaling [53], suppressive cytokines, such as TGF-b and interleukin-10, and other factors, such as hydrocortisone and lactoferrin that also dampens inflammatory cytokine secretion by epithelial cells [48,54]. TGF-b is particularly abundant in human milk and was shown to impact local and short-term immunity as well as long-term and distant immunity. Indeed, milk TGF-b was shown to decrease interleukin-18 secretion by neonatal gut epithelial secretion and reduce early-life mucosal infiltration by dendritic cells, eosinophils and mast cells found in formula-fed rats [55,56]. We found that milk TGF-b was necessary to induce tolerance to orally administered antigen and induce long-term prevention from respiratory allergies [36]. Recently, the impact of human colostrum oligosaccharides on fetal human epithelial cells was assessed and results demonstrated a significant decrease of acute-phase inflammatory cytokine secretion whereas cytokines involved in tissue repair and homeostasis were increased [57 ]. Secretion of other immunomodulatory factors such as retinoic acid and TSLP, interleukin-25 and interleukin-33 by neonatal epithelial cells, in the presence or absence of maternal milk, has not yet been reported. From these scattered data, we can conclude that neonatal mucosal epithelium function in the physiological condition of being bathed in maternal milk is very different than in absence of maternal milk; these difference will affect gut microbiota establishment, antigen transfer and local immune milieu &

&

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that will in turn affect the short-term and long-term development of antigen-specific immune response as discussed in the following section.

CAN BREAST MILK AFFECT THE DEVELOPMENT OF ANTIGEN-SPECIFIC IMMUNE RESPONSES INDUCED AT MUCOSAL SURFACES? ROLE FOR IMMUNOMODULATORY FACTORS AND EXOGENOUS ANTIGENS PRESENT IN BREAST MILK CD103 expressing dendritic cell in the control of gut immunity CD103 expressing dendritic cells in mice have been identified as key cells in the control of adult mucosal immunity [58]. These cells are present in the gut lamina propria and can migrate to the mesenteric draining lymph node where they will control T-cell differentiation and homing due to their expression of retinaldehyde dehydrogenase (RALDH) enzyme. RALDH is an enzyme that converts retinol into retinoic acid; this molecule potently enhances the differentiation of naı¨ve CD4 T lymphocytes into any class of lymphocytes and stimulates the expression of receptors a4b7 and CCR9 on differentiated lymphocytes allowing their migration to the gut lamina propria where they can exert their effector or regulatory function. The path of differentiation favored by retinoic acid was shown to depend on the local environment and, in particular, the presence of specific cytokines such as TGF-b for Treg induction, interleukin-6 with TGF-b for Th17 and interleukin-15 for Th1 [59–61]. Retinoic acid will also stimulate the differentiation and migration of immunoglobulin A-secreting cells in the gut mucosa. Only few studies have analyzed the presence of CD103 and dendritic cell in neonates and they have demonstrated a lack of these cells in neonatal period both in the lamina propria, due to low levels of chemokine secretion by gut epithelial cells [51 ], and in the lung [62]. In the neonatal MLN, we found a similar percentage of CD103pos dendritic cells as compared with the adult but they expressed lower levels of RALDH. We identified that this defect was linked to low vitamin A levels in neonatal mice although they were born from a mother receiving a regular diet containing an appropriate supply in vitamin A. We found that defective RALDH expression in neonatal dendritic cells was responsible for poor antigen uptake and capacity to induce T-cell proliferation and differentiation resulting in oral antigen ignorance in the neonate. Importantly, vitamin A supplementation through breast milk was sufficient to restore efficient antigen presentation &

in the neonate and allow oral tolerance induction and prevention of allergic disease from birth (Turfkruyer et al., unpublished observation). Physiological low levels of vitamin A in early life are in agreement with previous publication in mice [63] and, importantly, also in well nourished humans reporting low vitamin A levels in infants from countries with vitamin A-sufficient diet [24,64– 69]. Infants are born with low body stores of vitamin A regardless of maternal vitamin A status because of a strict control of transplacental transfer of vitamin A, most probably due to possible effect of retinol on morphogenesis [24,70]. During the first 6 months, neonates will multiply by five the liver concentration in vitamin A to obtain levels comparable to the adults thanks to the supply by colostrum and mature milk [24,25]. In vitamin A-deficient developing countries, it is estimated that vitamin A supply through breast milk is reduced in half, making any liver storage impossible and infants will stay vitamin A-deficient except if supplementation is initiated at birth. Interestingly, we also found that defect in antigen capture by neonatal dendritic cells could be improved by the presence of antigen in the form of immune complexes [35]. It appears from these observations that, compared to what is known in the adult, the neonate is programmed not to respond to mucosal antigens or to have reduced sensitivity to them, when administered by mucosal route and that this unresponsiveness is controlled, at least by maternal supply of vitamin A through breast milk and by their immune status. Those two factors will both affect antigen transfer across the gut barrier and antigen capture by mucosal dendritic cells in the neonate and condition their long-term immune reactivity.

Immunomodulatory dietary factors Vitamin A is one of the many maternal diet compounds that will be found in breast milk. The recent understanding in the adult of how diet can affect gut microbiota and immune system function [47,71] is likely to lead to major advance in how maternal diet will affect milk composition, including fat, presence of aryl hydrocarbon receptor ligand and complex carbohydrates, which in turn will affect neonate immune function. The milk content in (n-6) and (n-3) PUFAs and their impact on immune differentiation have been particularly well studied, n-3 PUFA being considered as anti-inflammatory in addition to their protective effect on gut barrier. In a rodent model, increasing the amount of n-3 fatty acids in breast milk increased the capacity to induce oral tolerance to OVA [72]; low amounts of

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Gut epithelium

Breast milk

(3) ILC

Microbiota

Colonization with healthy bacteria Defense against pathogenic bacteria

Improved antigen transfer and immunomodulatory function

Dietary and respiratory antigens

Vitamin A, IgG

Antigen capture and presentation

(1) Dendritic cells IgA, lactoferrin, lysosyme, oligosaccharides, …

(2) Growth factors, vitamin A, oligosaccharides, IgG, SCFA, PUFA, TGF-beta, SCD14

T lymphocytes Proliferation and differentiation Vitamin A, TGF-beta, …

Optimal immune function during physiological breastfeeding period Neonatal immune system maturation allowing its autonomy after weaning Appropriate effector and regulatory immune responses in the long term

FIGURE 1. Breast milk-neonatal immune system entity for optimal short and long term immune function. Neonates need maternal factors brought through breast-milk to (1) ensure optimal gut microbiota colonization which will condition immune homeostasis: IgA and anti-microbial factors prevent pathogen entry in the neonate and oligosaccharides can specifically select for protective bacteria proliferation (2) allow optimal gut barrier function: milk will stimulate gut barrier anatomical maturation (growth factors, vitamin A), improve antigen transfer (along with maturation and via milk IgG improved transfer of antigen in IgG-immune complexes) and dampen epithelial inflammatory responses factors (oligosaccharides, TGF-beta, sCD14, . . .) (3) induce appropriate antigen specific long term immune responses: antigens are transferred to the neonate immune system through breast milk along with immune-modulatory factors that will improve DC function (IgG/vitamin A) and condition the type of immune response induced (TGF-beta, vitamin A, . . . ).

n-3 fatty acids in breast milk is directly correlated to a high atopic risk in infant [73] and an enrichment of maternal alimentation with fish oil, rich in n-3 fatty acids, can inhibit some markers of atopic risk [74,75]. Effect of fatty acids on neonatal protection against infections is controversial, with some studies demonstrating a positive effect [76] and some others a negative one [77].

Antigens in breast milk We have been particularly looking at the impact of antigens coming from the maternal environment and present in breast milk on the induction of immune response in later life. Breast milk is known 204

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to possibly contain various antigens from maternal diet such as egg, peanut and wheat antigens [78]. In addition, we showed that respiratory antigen, house dust mite Dermatophagoides pteronyssinus (Der p) 1, could also be found in human milk from various regions of the world [79 ]. Using a mouse model of oral antigen transfer through breast milk, we found that a very different immunological outcome was observed according to the timing, nature of antigen administered and maternal immune status. As described earlier, we found that, in the case of an antigen with poor intrinsic adjuvant properties such as OVA, antigen transfer through breast milk resulted in no prevention of allergic disease due to antigen ignorance or allergy prevention by FoxP3 &&

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Breast milk and its impact on neonatal immune system Turfkruyer and Verhasselt

Treg induction or Th1 differentiation according to the pup age and the presence of maternal milk factors. In contrast to these observations using OVA, we observed that the transfer of Der p1 through breast milk induced a priming of Th2 immune responses and increased susceptibility to allergic disease in adulthood [79 ]. Compared with OVA, Der p displays strong intrinsic adjuvant properties [80], and our current work is assessing how Der p affects neonatal gut mucosal immune system maturation. We think that these observations made in the field of allergic disease prevention may benefit development of strategies for prevention of infectious disease and that the impact of microbial antigen transfer on later susceptibility to infection would be worthwhile to study. &&

CONCLUSION In conclusion, the complex, unique and dynamic components of breast milk will interact with the developing gut microbiota, epithelium and immune system of the child to induce their maturation and allow immune autonomy of the child after weaning (Fig. 1). The full understanding of this early-life symbiosis for optimal immune development is necessary to ensure best health in adulthood. Acknowledgements The authors would like to thank Akila Rekima, Vale´rie Milcent, Eric Mosconi, Patricia Macchiaverni and Meri Tulic for their contribution to the experiments presented in this work and discussion on this thematic. Financial support and sponsorship This work was supported by the Institut National de la Sante´ et Recherche Me´dicale (INSERM), Universite´ de Nice Sophia-Antipolis (UNS), Fondation Princesse Grace, Agence Nationale de la Recherche and Fondation de Recherche en Sante´ Respiratoire. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Oza S, Lawn JE, Hogan DR, et al. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013. Bull World Health Organ 2015; 93:19–28. 2. Rona RJ, Keil T, Summers C, et al. The prevalence of food allergy: a metaanalysis. J Allergy Clin Immunol 2007; 120:638–646. 3. Lawrence RM. Pane CA: human breast milk: current concepts of immunology and infectious diseases. Curr Probl Pediatr Adolesc Healthcare 2007; 37: 7–36.

4. Labbok MH, Clark D, Goldman AS. Breastfeeding: maintaining an irreplaceable immunological resource. Nat Rev Immunol 2004; 4:565–572. 5. Brandtzaeg P. Mucosal immunity: integration between mother and the breastfed infant. Vaccine 2003; 21:3382–3388. 6. Hanson LA, Korotkova M, Lundin S, et al. The transfer of immunity from mother to child. Ann NY Acad Sci 2003; 987:199–206. 7. Muraro A, Halken S, Arshad SH, et al. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy 2014; 69:590–601. 8. Verhasselt V. Neonatal tolerance under breastfeeding influence. Curr Opin Immunol 2010; 22:623–630. 9. Verhasselt V. Oral tolerance in neonates: from basics to potential prevention of allergic disease. Mucosal Immunol 2010; 3:326–333. 10. Barclay AR, Russell RK, Wilson ML, et al. Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease. J Pediatr 2009; 155:421–426. 11. Pereira PF, Alfenas Rita de CG, Araujo RM. Does breastfeeding influence the risk of developing diabetes mellitus in children? A review of current evidence. J Pediatr (Rio J) 2014; 90:7–15. 12. Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012; 489:231–241. 13. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 2014; 14:141–153. 14. Henning SJ. Postnatal development: coordination of feeding, digestion, and metabolism. Am J Physiol 1981; 241:G199–G214. 15. de Santa Barbara P, van den Brink GR, Roberts DJ. Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 2003; 60: 1322–1332. 16. Harper J, Mould A, Andrews RM, et al. The transcriptional repressor Blimp1/ Prdm1 regulates postnatal reprogramming of intestinal enterocytes. Proc Natl Acad Sci USA 2011; 108:10585–10590. 17. Muncan V, Heijmans J, Krasinski SD, et al. Blimp1 regulates the transition of neonatal to adult intestinal epithelium. Nat Commun 2011; 2:452. 18. Tapper D, Klagsbrun M, Neumann J. The identification and clinical implications of human breast milk mitogen. J Pediatr Surg 1979; 14:803–808. 19. Berseth CL. Enhancement of intestinal growth in neonatal rats by epidermal growth factor in milk. Am J Physiol 1987; 253:G662–G665. 20. Dvorak B. Milk epidermal growth factor and gut protection. J Pediatr 2010; 156:S31–S35. 21. Blum JW, Baumrucker CR. Insulin-like growth factors (IGFs), IGF binding proteins, and other endocrine factors in milk: role in the newborn. Adv Exp Med Biol 2008; 606:397–422. 22. Garcia C, Duan RD, Brevaut-Malaty V, et al. Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview. Cell Mol Biol (Noisy-le-grand) 2013; 59:108–131. 23. McCullough FS, Northrop-Clewes CA, Thurnham DI. The effect of vitamin A on epithelial integrity. Proc Nutr Soc 1999; 58:289–293. 24. Haskell MJ, Brown KH. Maternal vitamin A nutriture and the vitamin A content of human milk. J Mammary Gland Biol Neoplasia 1999; 4:243–257. 25. Chappell JE, Francis T, Clandinin MT. Vitamin A and E content of human milk at early stages of lactation. Early Hum Dev 1985; 11:157–167. 26. Menard S, Cerf-Bensussan N, Heyman M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol 2010; 3:247–259. 27. Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 2009; 124:3–20. 28. Persson EK, Scott CL, Mowat AM, Agace WW. Dendritic cell subsets in the intestinal lamina propria: ontogeny and function. Eur J Immunol 2013; 43:3098–3107. 29. McDole JR, Wheeler LW, McDonald KG, et al. Goblet cells deliver luminal antigen to CD103 þ dendritic cells in the small intestine. Nature 2012; 483:345–349. 30. Catassi C, Bonucci A, Coppa GV, et al. Intestinal permeability changes during the first month: effect of natural versus artificial feeding. J Pediatr Gastroenterol Nutr 1995; 21:383–386. 31. Udall JN, Colony P, Fritze L, et al. Development of gastrointestinal mucosal barrier. II. The effect of natural versus artificial feeding on intestinal permeability to macromolecules. Pediatr Res 1981; 15:245–249. 32. Heyman M, Crain-Denoyelle AM, Corthier G, et al. Postnatal development of protein absorption in conventional and germ-free mice. Am J Physiol 1986; 251:G326–G331. 33. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7:715–725. 34. Qiao SW, Kobayashi K, Johansen FE, et al. Dependence of antibodymediated presentation of antigen on FcRn. Proc Natl Acad Sci USA 2008; 105:9337–9342. 35. 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. 36. 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. 37. 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.

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Paediatric and neonatal infections 38. Yoshida M, Kobayashi K, Kuo TT, et al. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 2006; 116: 2142–2151. 39. Harris NL, Spoerri I, Schopfer JF, et al. Mechanisms of neonatal mucosal antibody protection. J Immunol 2006; 177:6256–6262. 40. Israel EJ, Taylor S, Wu Z, et al. Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology 1997; 92:69–74. 41. Lindsey B, Kampmann B, Jones C. Maternal immunization as a strategy to decrease susceptibility to infection in newborn infants. Curr Opin Infect Dis 2013; 26:248–253. 42. Pott J, Hornef M. Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep 2012; 13:684–698. 43. Menard S, Forster V, Lotz M, et al. Developmental switch of intestinal antimicrobial peptide expression. J Exp Med 2008; 205:183–193. 44. Gaboriau-Routhiau V, Lecuyer E, Cerf-Bensussan N. Role of microbiota in postnatal maturation of intestinal T-cell responses. Curr Opin Gastroenterol 2011; 27:502–508. 45. Jiang HQ, Bos NA, Cebra JJ. Timing, localization, and persistence of colonization by segmented filamentous bacteria in the neonatal mouse gut depend on immune status of mothers and pups. Infect Immun 2001; 69:3611–3617. 46. Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 2012; 22:1147–1162. 47. Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol 2011; 12:5–9. 48. Walker A. Breast milk as the gold standard for protective nutrients. J Pediatr 2010; 156:S3–S7. 49. Lotz M, Gutle D, Walther S, et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006; 203:973–984. 50. Penttila IA, van Spriel AB, Zhang MF, et al. Transforming growth factor-beta levels in maternal milk and expression in postnatal rat duodenum and ileum. Pediatr Res 1998; 44:524–531. 51. Lantier L, Lacroix-Lamande S, Potiron L, et al. Intestinal CD103 þ dendritic & cells are key players in the innate immune control of Cryptosporidium parvum infection in neonatal mice. PLoS Pathog 2013; 9:e1003801. One of the rare articles looking at mucosal immunity in neonates and demonstrating that paucity of CD103pos dendritic cells in neonatal lamina propria is due to defective chemokine secretion by neonatal epithelial cells. 52. Chapkin RS, Zhao C, Ivanov I, et al. Noninvasive stool-based detection of infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells. Am J Physiol Gastrointest Liver Physiol 2010; 298:G582–G589. 53. LeBouder E, Rey-Nores JE, Raby AC, et al. Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk. J Immunol 2006; 176:3742–3752. 54. Chatterton DE, Nguyen DN, Bering SB, Sangild PT. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int J Biochem Cell Biol 2013; 45:1730–1747. 55. Penttila IA, Flesch IE, McCue AL, et al. Maternal milk regulation of cell infiltration and interleukin 18 in the intestine of suckling rat pups. Gut 2003; 52:1579–1586. 56. Penttila IA. Milk-derived transforming growth factor-beta and the infant immune response. J Pediatr 2010; 156:S21–S25. 57. He Y, Liu S, Leone S, Newburg DS. Human colostrum oligosaccharides & modulate major immunologic pathways of immature human intestine. Mucosal Immunol 2014; 7:1326–1339. A comprehensive gene analysis of impact of human colostrum on human neonatal gut cell function. 58. Cassani B, Villablanca EJ, De Calisto J, et al. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med 2012; 33:63–76. 59. Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic acid in tolerance and immunity. Immunity 2011; 35:13–22.

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www.co-infectiousdiseases.com

60. Agace WW, Persson EK. How vitamin A metabolizing dendritic cells are generated in the gut mucosa. Trends Immunol 2012; 33:42–48. 61. Cassani B, Villablanca EJ, De Calisto J, et al. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med 2012; 33:63–76. 62. Ruckwardt TJ, Malloy AM, Morabito KM, Graham BS. Quantitative and qualitative deficits in neonatal lung-migratory dendritic cells impact the generation of the CD8 þ T cell response. PLoS Pathog 2014; 10:e1003934. 63. Garcia AL, Ruhl R, Schweigert FJ. Retinoid concentrations in the mouse during postnatal development and after maternal vitamin A supplementation. Ann Nutr Metab 2005; 49:333–341. 64. Olson JA, Gunning DB, Tilton RA. Liver concentrations of vitamin A and carotenoids, as a function of age and other parameters, of American children who died of various causes. Am J Clin Nutr 1984; 39:903–910. 65. Malvy DJ, Burtschy B, Dostalova L, Amedee-Manesme O. Serum retinol, betacarotene, alpha-tocopherol and cholesterol in healthy French children. Int J Epidemiol 1993; 22:237–246. 66. Delvin EE, Salle BL, Reygrobellet B, et al. Vitamin A and E supplementation in breast-fed newborns. J Pediatr Gastroenterol Nutr 2000; 31:562–565. 67. Shenai JP, Chytil F, Jhaveri A, Stahlman MT. Plasma vitamin A and retinolbinding protein in premature and term neonates. J Pediatr 1981; 99:302– 305. 68. Mitchell GV, Young M, Seward CR. Vitamin A and carotene levels of a selected population in metropolitan Washington, D.C. Am J Clin Nutr 1973; 26:992–997. 69. Pesonen M, Kallio MJ, Siimes MA, Ranki A. Retinol concentrations after birth are inversely associated with atopic manifestations in children and young adults. Clin Exp Allergy 2007; 37:54–61. 70. Rothman KJ, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995; 333:1369–1373. 71. Tilg H, Moschen AR. Food, immunity, and the microbiome. Gastroenterology 2015. [Epub ahead of print] 72. Korotkova M, Telemo E, Yamashiro Y, et al. The ratio of n-6 to n-3 fatty acids in maternal diet influences the induction of neonatal immunological tolerance to ovalbumin. Clin Exp Immunol 2004; 137:237–244. 73. Duchen K, Yu G, Bjorksten B. Atopic sensitization during the first year of life in relation to long chain polyunsaturated fatty acid levels in human milk. Pediatr Res 1998; 44:478–484. 74. Dunstan JA, Mori TA, Barden A, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol 2003; 112:1178–1184. 75. D’Vaz N, Meldrum SJ, Dunstan JA, et al. Postnatal fish oil supplementation in high-risk infants to prevent allergy: randomized controlled trial. Pediatrics 2012; 130:674–682. 76. Pierre M, Husson MO, Le Berre R, et al. Omega-3 polyunsaturated fatty acids improve host response in chronic Pseudomonas aeruginosa lung infection in mice. Am J Physiol Lung Cell Mol Physiol 2007; 292:L1422– 1431. 77. Anderson M, Fritsche KL. (n-3) Fatty acids and infectious disease resistance. J Nutr 2002; 132:3566–3576. 78. Macchiaverni P, Tulic MK, Verhasselt V. Antigens in breast milk: possible impact on immune system education. In: Zibadi S, Watson RR, Preedy VR, editors. Dietary and nutritional aspects of human milk. Wageningen, The Netherlands: Wageningen Academic Publishers; 2013. vol 5. pp. 447–460. 79. 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. The first demonstration that environmental respiratory antigens can be found in human milk and may affect development of respiratory allergies in later life. 80. Gregory LG, Lloyd CM. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol 2011; 32:402–411.

Volume 28  Number 3  June 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Breast milk and its impact on maturation of the neonatal immune system.

This article aims to review the evidence that breast milk can actively shape neonate gut immune system development toward a mature immune system capab...
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