The immune system of the infant is functionally immature and naïve. Human milk contains bioactive proteins, lipids, and carbohydrates that protect the newborn and stimulate innate and adaptive immune development. This review will focus on the role human milk oligosaccharides (HMO) play in neonatal gastrointestinal and systemic immune development and function. For the past decade, intense research has been directed at defining the complexity of oligosaccharides in the milk of many species and is beginning to delineate their diverse functions. These studies have shown that human milk contains a higher concentration as well as a greater structural diversity and degree of fucosylation than the milk oligosaccharides in other species, particularly bovine milk from which many infant formulae are produced. The commercial availability of large quantities of certain HMO has furthered our understanding of the functions of specific HMO, which include protecting the infant from pathogenic infections, facilitating the establishment of the gut microbiota, promoting intestinal development, and stimulating immune maturation. Many of these actions are exerted through carbohydrate-carbohydrate interactions with pathogens or host cells. Two HMOs, 2′-fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT), have recently been added to infant formula. Although this is a first step in narrowing the compositional gap between human milk and infant formula, it is unclear whether 1 or 2 HMO will recapitulate the complexity of actions exerted by the complex mixture of HMO ingested by breastfed infants. Thus, as more HMO become commercially available, either isolated from bovine milk or chemically or microbially synthesized, it is anticipated that more oligosaccharides will be added to infant formula either alone or in combination with other prebiotics.

Levy O, Wynn JL: A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 2014;105:136-141.
Walker WA, Iyengar RS: Breast milk, microbiota, and intestinal immune homeostasis. Pediatr Res 2015;77:220-228.
Andreas NJ, Kampmann B, Mehring Le- Doare K: Human breast milk: a review on its composition and bioactivity. Early Hum Dev 2015;91:629-635.
Turfkruyer M, Verhasselt V: Breast milk and its impact on maturation of the neonatal immune system. Curr Opin Infect Dis 2015;28:199-206.
Donovan SM: Role of human milk components in gastrointestinal development: current knowledge and future needs. J Pediatr 2006;149:S49-S61.
American Academy of Pediatrics, Section on Breastfeeding: Breastfeeding and the use of human milk. Pediatrics 2012;129;e827-e841.
Horta BL, Victora CG: Long-term Effects of Breastfeeding. Geneva, World Health Organization, 2013. (accessed September 15, 2016).
Li M, Wang M, Donovan SM: Early development of the gut microbiome and immune-mediated childhood disorders. Semin Reprod Med 2014;32:74-86.
Wang M, Monaco MH, Donovan SM: Impact of early gut microbiota on immune and metabolic development and function. Semin Fetal Neonat Med 2016, Epub ahead of print.
Smilowitz JT, Lebrilla CB, Mills DA, German JB, Freeman SL: Breast milk oligosaccharides: structure-function relationships in the neonate. Annu Rev Nutr 2014;34:143-169.
Kunz C, Meyer C, Collado MC, Geiger L, García-Mantrana I, Bertua-Ríos B, Martínez-Costa C, Borsch C, Rudloff S: Influence of gestational age, secretor and Lewis blood group status on the oligosaccharide content of human milk. J Pediatr Gastroenterol Nutr 2016, Epub ahead of print.
Thurl S, Munzert M, Henker J, Boehm G, Müller-Werner B, Jelinek J, Stahl B: Variation of human milk oligosaccharides in relation to milk groups and lactational periods. Br J Nutr 2010;104:1261-1271.
Martín-Sosa S, Martín MJ, García-Pardo LA, Hueso P: Sialyloligosaccharides in human and bovine milk and in infant formulas: variations with the progression of lactation. J Dairy Sci 2003;86:52-59.
Newburg DS, He Y: Neonatal gut microbiota and human milk glycans cooperate to attenuate infection and inflammation. Clin Obstet Gynecol 2015;58:814-826.
Kulinich A, Liu L: Human milk oligosaccharides: the role in the fine-tuning of innate im- mune responses. Carbohydr Res 2016;432:62-70.
Lewis ZT, Totten SM, Smilowitz JT, Popovic M, Parker E, Lemay DG, Van Tassell ML, Miller MJ, Jin YS, German JB, Lebrilla CB, Mills DA: Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome 2015; 3:13.
Newburg DS, Ruiz-Palacios GM, Altaye M, Chaturvedi P, Meinzen-Derr J, Guerrero MDL, et al: Innate protection conferred by fucosylated oligosaccharides of human milk against diarrhea in breastfed infants. Glycobiology 2004;14:253-263.
Underwood MA, German JB, Lebrilla CB, Mills DA: Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut. Pediatr Res 2015;77:229-235.
Garrido D, Barile D, Mills DA: A molecular basis for bifidobacterial enrichment in the infant gastrointestinal tract. Adv Nutr 2012;3:415S-421S.
Steenhout P, Sperisen P, Martin F-P, Sprenger N, Wernimont S, Pecquet S, Berger B: Term infant formula supplemented with human milk oligosaccharides (2′fucosyllactose and lacto-N-neotetraose) shifts stool microbiota and metabolic signatures closer to that of breastfed infants. FASEB J 2016;30 (suppl 1): 275.7
Li M, Bauer LL, Chen X, Wang M, Kuhlenschmidt TB, Kuhlenschmidt MS, Fahey GC Jr, Donovan SM: Microbial composition and in vitro fermentation patterns of human milk oligosaccharides and prebiotics differ between formula-fed and sow-reared piglets. J Nutr 2012;142:681-689.
Li M, Monaco MH, Wang M, Comstock SS, Kuhlenschmidt TB, Fahey GC Jr, Miller MJ, Kuhlenschmidt MS, Donovan SM: Human milk oligosaccharides shorten rotavirus-induced diarrhea and modulate piglet mucosal immunity and colonic microbiota. ISME J 2014;8:1609-1620.
Goto Y, Kiyono H: Epithelial barrier: an interface for the cross-communication between gut flora and immune system. Immunol Rev 2012;245:147-163.
Sassone-Corsi M, Raffatellu M: No vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance to pathogens. J Immunol 2015;194:4081-4087.
Hester SN, Donovan SM: Individual and combined effects of nucleotides and human milk oligosaccharides on proliferation, apoptosis and necrosis in a human fetal intestinal cell line. Food Nutr Sci 2012;3:1567-1576.
Holscher HD, Davis SR, Tappenden KA: Human milk oligosaccharides influence maturation of human intestinal Caco-2Bbe and HT-29 cell lines. J Nutr 2014;144:586-591.
Bhatia S, Prabhu PN, Benefiel AC, Miller MJ, Chow J, Davis SR, Gaskins HR: Galacto-oligosaccharides may directly enhance intestinal barrier function through the modulation of goblet cells. Mol Nutr Food Res 2015;59:566-573.
Lane JA, O'Callaghan J, Carrington SD, Hickey RM: Transcriptional response of HT-29 intestinal epithelial cells to human and bovine milk oligosaccharides. Br J Nutr 2013;110:2127-2137.
He Y, Liu S, Kling DE, Leone S, Lawlor NT, Huang Y, Feinberg SB, Hill DR, Newburg DS: The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 2016;65:33-46.
Mezoff EA, Hawkins JA, Ollberding NJ, Karns R, Morrow AL, Helmrath MA: The human milk oligosaccharide 2′-fucosyllactose augments the adaptive response to extensive intestinal resection. Am J Physiol Gastrointest Liver Physiol 2016;310:G427-G438.
Wickramasinghe S, Pacheco AR, Lemay DG, Mills DA: Bifidobacteria grown on human milk oligosaccharides downregulate the expression of inflammation-related genes in Caco-2 cells. BMC Microbiol 2015;15:172.
Marcobal A, Sonnenburg JL: Human milk oligosaccharide consumption by intestinal microbiota. Clin Microbiol Infect 2012;18(suppl 4):12-15.
Kavanaugh D, O'Callaghan J, Kilcoyne M, Kane M, Joshi L, Hickey RM: The intestinal glycome and its modulation by diet and nutrition. Nutr Rev 2015;73:359-375.
Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmytrash A, Backer J, Looijer-van Langen M, Madsen KL: Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 2008;295:1025-1034.
Macpherson AJ, Geuking MB, McCoy KD: Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 2005;115:153-162.
Comstock SS, Wang M, Hester SN, Li M, Donovan SM: Select human milk oligosaccharides directly modulate peripheral blood mononuclear cells isolated from 10-d-old pigs. Br J Nutr 2014;111:819-828.
Goehring KC, Kennedy AD, Prieto PA, Buck RH: Direct evidence for the presence of human milk oligosaccharides in the circulation of breastfed infants. PLoS One 2014;9: e101692.
Marriage BJ, Buck RH, Goehring KC, Oliver JS, Williams JA: Infants fed a lower calorie formula with 2′-fucosyllactose (2′FL) show growth and 2′FL uptake like breast-fed infants. J Pediatr Gastroenterol Nutr 2015;61:649-658.
Ruhaak LR, Stroble C, Underwood MA, Lebrilla CB: Detection of milk oligosaccharides in plasma of infants. Anal Bioanal Chem 2014;406:5775-5784.
Bode L, Kunz C, Muhly-Reinholz M, Mayer K, Seeger W, Rudloff S: Inhibition of monocyte, lymphocyte, and neutrophil adhesion to endothelial cells by human milk oligosaccharides. Thromb Haemost 2004;92:1402-1410.
Bode L, Rudloff S, Kunz C, Strobel S, Klein N: Human milk oligosaccharides reduce platelet-neutrophil complex formation leading to a decrease in neutrophil beta 2 integrin expression. J Leukoc Biol 2004;76:820-826.
Rabinovich GA, Croci DO: Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. Immunity 2012;36:322-335.
Schnaar RL: Glycans and glycan-binding proteins in immune regulation: a concise introduction to glycobiology for the allergist. J Allergy Clin Immunol 2015;135:609-615.
Geijtenbeek TB, van Vliet SJ, Engering A, ‘t Hart BA, van Kooyk Y: Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol 2004;22:33-54.
Koning N, Kessen SF, Van Der Voorn JP, Appelmelk BJ, Jeurink PV, Knippels LM, Garssen J, Van Kooyk Y: Human milk blocks DC-SIGN-pathogen interaction via MUC1. Front Immunol 2015;6:112.
Macauley MS, Crocker PR, Paulson JC: Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 2014;14:653-666.
Stephenson HN, Mills DC, Jones H, Milioris E, Copland A, Dorrell N, Wren BW, Crocker PR, Escors D, Bajaj-Elliott M: Pseudaminic acid on Campylobacter jejuni flagella modulates dendritic cell IL-10 expression via Siglec-10 receptor: a novel flagellin-host interaction. J Infect Dis 2014;210:1487-1498.
Earl LA, Bi S, Baum LG: N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. J Biol Chem 2010;285:2232-2244.
Hester SN, Chen X, Li M, Monaco MH, Comstock SS, Kuhlenschmidt TB, Kuhlenschmidt MS, Donovan SM: Human milk oligosaccharides inhibit rotavirus infectivity in vitro and in acutely infected piglets. Br J Nutr 2013;110:1233-1242.
Luhn K, Wild MK: Human deficiencies of fucosylation and sialylation affecting selectin ligands. Semin Immunopathol 2012;34:383-399.
Castillo-Courtade L, Han S, Lee S, Mian FM, Buck R, Forsythe P: Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model. Allergy 2015;70:1091-1102.
Kurakevich E, Hennet T, Hausmann M, Rogler G, Borsig L: Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c+ cells through TLR4. Proc Natl Acad Sci USA 2013;110:17444-17449.
Goerhring KC, Marriage BJ, Oliver JS, Wilder JA, Barrett EG, Buck RH: Similar to those who are breastfed, infants fed a formula containing 2′-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr 2016, DOI: 10.3945/jn.116.236919.
Puccio G, Alliet P, Cajozzo C, Janssens E, Corsello G, Wernimont S, Egli D, Gosoniu L, Sprenger N, Steenhout P: Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial. JPGN, in press.
Hanlon PR, Thorsrud BA: A 3-week pre-clinical study of 2′-fucosyllactose in farm piglets. Food Chem Toxicol 2014;74:343-348.
Kashyap PC, Marcobal A, Ursell LK, Smits SA, Sonnenburg ED, Costello EK, Higginbottom SK, Domino SE, Holmes SP, Relman DA, Knight R, Gordon JI, Sonnenburg JI: Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota. Proc Natl Acad Sci USA 2013;110:17059-17064.
Okano M, Satoskar AR, Nishizaki K, Harn DA Jr: Lacto-N-fucopentaose III found on Schistosoma mansoni egg antigens functions as adjuvant for proteins by inducing Th2-type response. J Immunol 2001;167:442-450.
Seppo AE, Autran CA, Bode L, Järvinen KM: Human milk oligosaccharides and development of cow's milk allergy in infants. J Allergy Clin Immunol 2016, Epub ahead of print.
Huang YL, Chassard C, Hausmann M, von Itzstein M, Hennet T: Sialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice. Nat Commun 2015;6:8141.
Severi E, Hood DW, Thomas GH: Sialic acid utilization by bacterial pathogens. Microbiology 2007;153:2817-2822.
Audry M, Jeanneau C, Imberty A, Harduin-Lepers A, Delannoy P, Breton C: Current trends in the structure-activity relationships of sialyltransferases. Glycobiology 2011;21:716-726.
Kuijf ML, Samsom JN, van Rijs W, Bax M, Huizinga R, Heikema AP, van Doorn PA, van Belkum A, van Kooyk Y, Burgers PC, Luider TM, Endtz HP, Nieuwenhuis EE, Jacobs BC: TLR4-mediated sensing of Campylobacter jejuni by dendritic cells is determined by sialylation. J Immunol 2010;185:748-755.
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