Human milk is a complete source of nourishment for the infant. Exclusive breastfeeding not only sustains the infant’s development but also guides the proliferation of a protective intestinal microbiota. Among the many components of milk that modulate the infant gut microbiota, the milk glycans, which comprise free oligosaccharides, glycoproteins, and glycolipids, are increasingly recognized as drivers of microbiota development and overall gut health. These glycans may display pleiotropic functions, conferring protection against infectious diseases and also acting as prebiotics, selecting for the growth of beneficial intestinal bacteria. The prebiotic effect of milk glycans has direct application to prevention of diseases such as necrotizing enterocolitis, a common and devastating disease of preterm infants. In this article, we review the impact of the human (and bovine) milk glycome on gut health through establishment of a milk-oriented microbiota in the neonate.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Am. Acad. Pediatr 2012. Breastfeeding and the use of human milk. Pediatrics 129:e827–41 [Google Scholar]
  2. Ballard O, Morrow AL. 2013. Human milk composition: nutrients and bioactive factors. Pediatr. Clin. North Am. 60:49–74 [Google Scholar]
  3. Haschke F, Haiden N, Detzel P, Yarnoff B, Allaire B, Haschke-Becher E. 2013. Feeding patterns during the first 2 years and health outcome. Ann. Nutr. Metab. 62:Suppl. 316–25 [Google Scholar]
  4. Ruiz-Palacios GM, Calva JJ, Pickering LK, Lopez-Vidal Y, Volkow P et al. 1990. Protection of breast-fed infants against Campylobacter diarrhea by antibodies in human milk. J. Pediatr. 116:707–13 [Google Scholar]
  5. Clavano NR. 1982. Mode of feeding and its effect on infant mortality and morbidity. J. Trop. Pediatr. 28:287–93 [Google Scholar]
  6. Chen A, Rogan WJ. 2004. Breastfeeding and the risk of postneonatal death in the United States. Pediatrics 113:e435–39 [Google Scholar]
  7. Andres A, Cleves MA, Bellando JB, Pivik RT, Casey PH, Badger TM. 2012. Developmental status of 1-year-old infants fed breast milk, cow's milk formula, or soy formula. Pediatrics 129:1134–40 [Google Scholar]
  8. Alvarez-Uria G, Midde M, Pakam R, Bachu L, Naik PK. 2012. Effect of formula feeding and breastfeeding on child growth, infant mortality, and HIV transmission in children born to HIV-infected pregnant women who received triple antiretroviral therapy in a resource-limited setting: data from an HIV cohort study in India. ISRN Pediatr. 2012:763591 [Google Scholar]
  9. Thior I, Lockman S, Smeaton LM, Shapiro RL, Wester C et al. 2006. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA 296:794–805 [Google Scholar]
  10. Chatterton DE, Nguyen DN, Bering SB, Sangild PT. 2013. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int. J. Biochem. Cell Biol. 45:1730–47 [Google Scholar]
  11. Zivkovic AM, German JB, Lebrilla CB, Mills DA. 2011. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. PNAS 108:Suppl. 14653–58 [Google Scholar]
  12. Apweiler R, Hermjakob H, Sharon N. 1999. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim. Biophys. Acta 1473:4–8 [Google Scholar]
  13. Peterson R, Cheah WY, Grinyer J, Packer N. 2013. Glycoconjugates in human milk: protecting infants from disease. Glycobiology 23:1425–38 [Google Scholar]
  14. Ruhaak LR, Lebrilla CB. 2012. Analysis and role of oligosaccharides in milk. BMB Rep. 45:442–51 [Google Scholar]
  15. Wu S, Tao N, German JB, Grimm R, Lebrilla CB. 2010. Development of an annotated library of neutral human milk oligosaccharides. J. Proteome Res. 9:4138–51 [Google Scholar]
  16. Bode L. 2012. Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology 22:1147–62 [Google Scholar]
  17. Oftedal OT. 2012. The evolution of milk secretion and its ancient origins. Animal 6:355–68 [Google Scholar]
  18. Albrecht S, Schols HA, van den Heuvel EG, Voragen AG, Gruppen H. 2011. Occurrence of oligosaccharides in feces of breast-fed babies in their first six months of life and the corresponding breast milk. Carbohydr. Res. 346:2540–50 [Google Scholar]
  19. Rudloff S, Kunz C. 2012. Milk oligosaccharides and metabolism in infants. Adv. Nutr. 3:398S–405S [Google Scholar]
  20. Gnoth MJ, Kunz C, Kinne-Saffran E, Rudloff S. 2000. Human milk oligosaccharides are minimally digested in vitro. J. Nutr. 130:3014–20 [Google Scholar]
  21. Albrecht S, Schols HA, van den Heuvel EGHM, Voragen AGJ, Gruppen H. 2010. CE-LIF-MSn profiling of oligosaccharides in human milk and feces of breast-fed babies. Electrophoresis 31:1264–73 [Google Scholar]
  22. Rudloff S, Pohlentz G, Diekmann L, Egge H, Kunz C. 1996. Urinary excretion of lactose and oligosaccharides in preterm infants fed human milk or infant formula. Acta Paediatr. 85:598–603 [Google Scholar]
  23. Rudloff S, Pohlentz G, Borsch C, Lentze MJ, Kunz C. 2012. Urinary excretion of in vivo13C-labelled milk oligosaccharides in breastfed infants. Br. J. Nutr. 107:957–63 [Google Scholar]
  24. Ruhaak LR, Lebrilla CB. 2012. Advances in analysis of human milk oligosaccharides. Adv. Nutr. 3:406S–14S [Google Scholar]
  25. Ninonuevo MR, Park Y, Yin H, Zhang J, Ward RE et al. 2006. A strategy for annotating the human milk glycome. J. Agric. Food Chem. 54:7471–80 [Google Scholar]
  26. Wu S, Grimm R, German JB, Lebrilla CB. 2011. Annotation and structural analysis of sialylated human milk oligosaccharides. J. Proteome Res. 10:856–68 [Google Scholar]
  27. Zivkovic AM, Barile D. 2011. Bovine milk as a source of functional oligosaccharides for improving human health. Adv. Nutr. 2:284–89 [Google Scholar]
  28. Tao N, DePeters EJ, Freeman S, German JB, Grimm R, Lebrilla CB. 2008. Bovine milk glycome. J. Dairy Sci. 91:3768–78 [Google Scholar]
  29. Tao N, DePeters EJ, German JB, Grimm R, Lebrilla CB. 2009. Variations in bovine milk oligosaccharides during early and middle lactation stages analyzed by high-performance liquid chromatography-chip/mass spectrometry. J. Dairy Sci. 92:2991–3001 [Google Scholar]
  30. Barile D, Marotta M, Chu C, Mehra R, Grimm R et al. 2010. Neutral and acidic oligosaccharides in Holstein-Friesian colostrum during the first 3 days of lactation measured by high performance liquid chromatography on a microfluidic chip and time-of-flight mass spectrometry. J. Dairy Sci. 93:3940–49 [Google Scholar]
  31. Aldredge DL, Geronimo MR, Hua S, Nwosu CC, Lebrilla CB, Barile D. 2013. Annotation and structural elucidation of bovine milk oligosaccharides and determination of novel fucosylated structures. Glycobiology 23:664–76 [Google Scholar]
  32. Barile D, Tao N, Lebrilla CB, Coisson JD, Arlorio M, German JB. 2009. Permeate from cheese whey ultrafiltration is a source of milk oligosaccharides. Int. Dairy J. 19:524–30 [Google Scholar]
  33. Lonnerdal B. 2003. Nutritional and physiologic significance of human milk proteins. Am. J. Clin. Nutr. 77:1537S–43S [Google Scholar]
  34. Le Parc A, Dallas DC, Duaut S, Leonil J, Martin P, Barile D. 2014. Characterization of goat milk lactoferrin N-glycans and comparison with the N-glycomes of human and bovine milk. Electrophoresis 35:1560–70 [Google Scholar]
  35. Tomita M, Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K. 1991. Potent antibacterial peptides generated by pepsin digestion of bovine lactoferrin. J. Dairy Sci. 74:4137–42 [Google Scholar]
  36. Yamauchi K, Tomita M, Giehl TJ, Ellison RT 3rd. 1993. Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect. Immun. 61:719–28 [Google Scholar]
  37. O'Riordan N, Kane M, Joshi L, Hickey RM. 2014. Structural and functional characteristics of bovine milk protein glycosylation. Glycobiology 24:220–36 [Google Scholar]
  38. Davidson LA, Lonnerdal B. 1987. Persistence of human milk proteins in the breast-fed infant. Acta Paediatr. Scand. 76:733–40 [Google Scholar]
  39. Wang B, Brand-Miller J, McVeagh P, Petocz P. 2001. Concentration and distribution of sialic acid in human milk and infant formulas. Am. J. Clin. Nutr. 74:510–15 [Google Scholar]
  40. Idota T, Kawakami H, Nakajima I. 1994. Growth-promoting effects of N-acetylneuraminic acid-containing substances on Bifidobacteria. Biosci. Biotechnol. Biochem. 58:1720–22 [Google Scholar]
  41. Yvon M, Beucher S, Guilloteau P, Le Huerou-Luron I, Corring T. 1994. Effects of caseinomacropeptide (CMP) on digestion regulation. Reprod. Nutr. Dev. 34:527–37 [Google Scholar]
  42. Lloyd KO, Furukawa K. 1998. Biosynthesis and functions of gangliosides: recent advances. Glycoconj. J. 15:627–36 [Google Scholar]
  43. Lee H, An HJ, Lerno LA Jr, German JB, Lebrilla CB. 2011. Rapid profiling of bovine and human milk gangliosides by matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry. Int. J. Mass Spectrom. 305:138–50 [Google Scholar]
  44. Pan XL, Izumi T. 2000. Variation of the ganglioside compositions of human milk, cow's milk and infant formulas. Early Hum. Dev. 57:25–31 [Google Scholar]
  45. Lee H, German JB, Kjelden R, Lebrilla CB, Barile D. 2013. Quantitative analysis of gangliosides in bovine milk and colostrum-based dairy products by ultrahigh performance liquid chromatography-tandem mass spectrometry. J. Agric. Food Chem. 61:9689–96 [Google Scholar]
  46. Ley RE, Peterson DA, Gordon JI. 2006. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:837–48 [Google Scholar]
  47. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L et al. 2005. Diversity of the human intestinal microbial flora. Science 308:1635–38 [Google Scholar]
  48. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. 2005. Host-bacterial mutualism in the human intestine. Science 307:1915–20 [Google Scholar]
  49. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G et al. 2012. Host-gut microbiota metabolic interactions. Science 336:1262–67 [Google Scholar]
  50. Spees AM, Lopez CA, Kingsbury DD, Winter SE, Bäumler AJ. 2013. Colonization resistance: Battle of the bugs or ménage à trois with the host?. PLOS Pathog. 9:e1003730 [Google Scholar]
  51. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG et al. 2012. Human gut microbiome viewed across age and geography. Nature 486:222–27 [Google Scholar]
  52. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE et al. 2014. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–63 [Google Scholar]
  53. Cho I, Blaser MJ. 2012. The human microbiome: at the interface of health and disease. Nat. Rev. Genet. 13:260–70 [Google Scholar]
  54. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. 2005. Obesity alters gut microbial ecology. PNAS 102:11070–75 [Google Scholar]
  55. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–31 [Google Scholar]
  56. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E et al. 2006. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55:205–11 [Google Scholar]
  57. Normann E, Fahlen A, Engstrand L, Lilja HE. 2013. Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis. Acta Paediatr. 102:129–36 [Google Scholar]
  58. Mai V, Young CM, Ukhanova M, Wang X, Sun Y et al. 2011. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLOS ONE 6:e20647 [Google Scholar]
  59. Wu N, Yang X, Zhang R, Li J, Xiao X et al. 2013. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb. Ecol. 66:462–70 [Google Scholar]
  60. Walker A. 2010. Breast milk as the gold standard for protective nutrients. J. Pediatr. 156:S3–7 [Google Scholar]
  61. Caicedo RA, Schanler RJ, Li N, Neu J. 2005. The developing intestinal ecosystem: implications for the neonate. Pediatr. Res. 58:625–28 [Google Scholar]
  62. Claud EC, Lu L, Anton PM, Savidge T, Walker WA, Cherayil BJ. 2004. Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. PNAS 101:7404–8 [Google Scholar]
  63. Walker WA. 2013. Initial intestinal colonization in the human infant and immune homeostasis. Ann. Nutr. Metab. 63:Suppl. 28–15 [Google Scholar]
  64. Biasucci G, Rubini M, Riboni S, Morelli L, Bessi E, Retetangos C. 2010. Mode of delivery affects the bacterial community in the newborn gut. Early Hum. Dev. 86:Suppl. 113–15 [Google Scholar]
  65. Penders J, Thijs C, Vink C, Stelma FF, Snijders B et al. 2006. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118:511–21 [Google Scholar]
  66. Huurre A, Kalliomaki M, Rautava S, Rinne M, Salminen S, Isolauri E. 2008. Mode of delivery—effects on gut microbiota and humoral immunity. Neonatology 93:236–40 [Google Scholar]
  67. Huda MN, Lewis Z, Kalanetra KM, Rashid M, Ahmad SM et al. 2014. Stool microbiota and vaccine responses of infants. Pediatrics 134:2e362–72 [Google Scholar]
  68. Fanaro S, Chierici R, Guerrini P, Vigi V. 2003. Intestinal microflora in early infancy: composition and development. Acta Paediatr. Suppl. 91:48–55 [Google Scholar]
  69. Mackie RI, Sghir A, Gaskins HR. 1999. Developmental microbial ecology of the neonatal gastrointestinal tract. Am. J. Clin. Nutr. 69:1035S–45S [Google Scholar]
  70. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M et al. 2014. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510:417–21 [Google Scholar]
  71. Scholtens PA, Oozeer R, Martin R, Amor KB, Knol J. 2012. The early settlers: intestinal microbiology in early life. Annu. Rev. Food Sci. Technol. 3:425–47 [Google Scholar]
  72. Berni Canani R, Passariello A, Buccigrossi V, Terrin G, Guarino A. 2008. The nutritional modulation of the evolving intestine. J. Clin. Gastroenterol. 42:Suppl. 3 Pt. 2S197–200 [Google Scholar]
  73. Turroni F, Peano C, Pass DA, Foroni E, Severgnini M et al. 2012. Diversity of bifidobacteria within the infant gut microbiota. PLOS ONE 7:e36957 [Google Scholar]
  74. Avershina E, Storro O, Oien T, Johnsen R, Wilson R et al. 2013. Bifidobacterial succession and correlation networks in a large unselected cohort of mothers and their children. Appl. Environ. Microbiol. 79:497–507 [Google Scholar]
  75. Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N et al. 2000. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J. Pediatr. Gastroenterol. Nutr. 30:61–67 [Google Scholar]
  76. Jost T, Lacroix C, Braegger CP, Chassard C. 2012. New insights in gut microbiota establishment in healthy breast fed neonates. PLOS ONE 7:e44595 [Google Scholar]
  77. Roger LC, McCartney AL. 2010. Longitudinal investigation of the faecal microbiota of healthy full-term infants using fluorescence in situ hybridization and denaturing gradient gel electrophoresis. Microbiology 156:3317–28 [Google Scholar]
  78. Turroni F, Foroni E, Pizzetti P, Giubellini V, Ribbera A et al. 2009. Exploring the diversity of the bifidobacterial population in the human intestinal tract. Appl. Environ. Microbiol. 75:1534–45 [Google Scholar]
  79. De Leoz MLA, Gaerlan SC, Strum JS, Dimapasoc LM, Mirmiran M et al. 2012. Lacto-N-tetraose, fucosylation, and secretor status are highly variable in human milk oligosaccharides from women delivering preterm. J. Proteome Res. 11:4662–72 [Google Scholar]
  80. Neu J, Walker WA. 2011. Necrotizing enterocolitis. N. Engl. J. Med. 364:255–64 [Google Scholar]
  81. Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA. 2001. Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr. Res. 49:589–93 [Google Scholar]
  82. Arboleya S, Binetti A, Salazar N, Fernandez N, Solis G et al. 2012. Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol. Ecol. 79:763–72 [Google Scholar]
  83. Butel MJ, Suau A, Campeotto F, Magne F, Aires J et al. 2007. Conditions of bifidobacterial colonization in preterm infants: a prospective analysis. J. Pediatr. Gastroenterol. Nutr. 44:577–82 [Google Scholar]
  84. Johnson TJ, Patel AL, Jegier BJ, Engstrom JL, Meier PP. 2013. Cost of morbidities in very low birth weight infants. J. Pediatr. 162:243–49.e1 [Google Scholar]
  85. Morrow AL, Meinzen-Derr J, Huang P, Schibler KR, Cahill T et al. 2011. Fucosyltransferase 2 non-secretor and low secretor status predicts severe outcomes in premature infants. J. Pediatr. 158:745–51 [Google Scholar]
  86. Downard CD, Grant SN, Maki AC, Krupski MC, Matheson PJ et al. 2012. Maternal cigarette smoking and the development of necrotizing enterocolitis. Pediatrics 130:78–82 [Google Scholar]
  87. Torrazza RM, Ukhanova M, Wang X, Sharma R, Hudak ML et al. 2013. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLOS ONE 8:e83304 [Google Scholar]
  88. Morrow AL, Lagomarcino AJ, Schibler KR, Taft DH, Yu Z et al. 2013. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome 1:13 [Google Scholar]
  89. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO et al. 2009. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 3:944–54 [Google Scholar]
  90. Jenke AC, Postberg J, Mariel B, Hensel K, Foell D et al. 2013. S100A12 and hBD2 correlate with the composition of the fecal microflora in ELBW infants and expansion of E. coli is associated with NEC. BioMed. Res. Int. 2013:150372 [Google Scholar]
  91. Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI et al. 2009. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 123:58–66 [Google Scholar]
  92. Gupta RW, Tran L, Norori J, Ferris MJ, Eren AM et al. 2013. Histamine-2 receptor blockers alter the fecal microbiota in premature infants. J. Pediatr. Gastroenterol. Nutr. 56:397–400 [Google Scholar]
  93. Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G et al. 2012. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 129:e40–45 [Google Scholar]
  94. Underwood MA, Kalanetra KM, Bokulich NA, Lewis ZT, Mirmiran M et al. 2013. A comparison of two probiotic strains of bifidobacteria in premature infants. J. Pediatr 163:1585–91.e9 [Google Scholar]
  95. AlFaleh K, Anabrees J, Bassler D, Al-Kharfi T. 2014. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst. Rev. 4:CD005496 [Google Scholar]
  96. Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. 2009. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J. Perinatol. 29:57–62 [Google Scholar]
  97. Underwood MA. 2013. Human milk for the premature infant. Pediatr. Clin. North Am. 60:189–207 [Google Scholar]
  98. Hunter CJ, Bean JF. 2013. Cronobacter: an emerging opportunistic pathogen associated with neonatal meningitis, sepsis and necrotizing enterocolitis. J. Perinatol. 33:581–85 [Google Scholar]
  99. Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R et al. 2013. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J. Pediatr. 163:1592–95.e1 [Google Scholar]
  100. Gyorgy P, Norris RF, Rose CS. 1954. Bifidus factor. I. A variant of Lactobacillus bifidus requiring a special growth factor. Arch. Biochem. Biophys. 48:193–201 [Google Scholar]
  101. Gauhe A, Gyorgy P, Hoover JRE, Kuhn R, Rose CS et al. 1954. Bifidus factor. 4. Preparations obtained from human milk. Arch. Biochem. Biophys. 48:214–24 [Google Scholar]
  102. Garrido D, Dallas DC, Mills DA. 2013. Consumption of human milk glycoconjugates by infant-associated bifidobacteria: mechanisms and implications. Microbiology 159:649–64 [Google Scholar]
  103. Marcobal A, Sonnenburg JL. 2012. Human milk oligosaccharide consumption by intestinal microbiota. Clin. Microbiol. Infect. 18:Suppl. 412–15 [Google Scholar]
  104. Ward RE, Niñonuevo M, Mills DA, Lebrilla CB, German JB. 2006. In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri. Appl. Environ. Microbiol. 72:4497–99 [Google Scholar]
  105. Marcobal A, Barboza M, Froehlich JW, Block DE, German JB et al. 2010. Consumption of human milk oligosaccharides by gut-related microbes. J. Agric. Food Chem. 58:5334–40 [Google Scholar]
  106. LoCascio RG, Niñonuevo MR, Freeman SL, Sela DA, Grimm R et al. 2007. Glycoprofiling of bifidobacterial consumption of human milk oligosaccharides demonstrates strain specific, preferential consumption of small chain glycans secreted in early human lactation. J. Agric. Food Chem. 55:8914–19 [Google Scholar]
  107. Locascio RG, Niñonuevo MR, Kronewitter SR, Freeman SL, German JB et al. 2009. A versatile and scalable strategy for glycoprofiling bifidobacterial consumption of human milk oligosaccharides. Microb. Biotechnol. 2:333–42 [Google Scholar]
  108. Ruiz-Moyano S, Totten SM, Garrido D, Smilowitz JT, German JB et al. 2013. Variation in consumption of human milk oligosaccharides by infant-gut associated strains of Bifidobacterium breve. Appl. Environ. Microbiol 79:6040–49 [Google Scholar]
  109. Yu ZT, Chen C, Newburg DS. 2013. Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. Glycobiology 23:1281–92 [Google Scholar]
  110. Marcobal A, Barboza M, Sonnenburg ED, Pudlo N, Martens EC et al. 2011. Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe 10:507–14 [Google Scholar]
  111. LoCascio RG, Desai P, Sela DA, Weimer B, Mills DA. 2010. Broad conservation of milk utilization genes in Bifidobacterium longum subsp. infantis as revealed by comparative genomic hybridization. Appl. Environ. Microbiol. 76:7373–81 [Google Scholar]
  112. Kim JH, An HJ, Garrido D, German JB, Lebrilla CB, Mills DA. 2013. Proteomic analysis of Bifidobacterium longum subsp. infantis reveals the metabolic insight on consumption of prebiotics and host glycans. PLOS ONE 8:e57535 [Google Scholar]
  113. Sela DA, Garrido D, Lerno L, Wu S, Tan K et al. 2012. Bifidobacterium longum subsp. infantis ATCC 15697 α-fucosidases are active on fucosylated human milk oligosaccharides. Appl. Environ. Microbiol. 78:795–803 [Google Scholar]
  114. Ashida H, Miyake A, Kiyohara M, Wada J, Yoshida E et al. 2009. Two distinct α-l-fucosidases from Bifidobacterium bifidum are essential for the utilization of fucosylated milk oligosaccharides and glycoconjugates. Glycobiology 19:1010–17 [Google Scholar]
  115. Sela DA, Li Y, Lerno L, Wu S, Marcobal AM et al. 2011. An infant-associated bacterial commensal utilizes breast milk sialyloligosaccharides. J. Biol. Chem. 286:11909–18 [Google Scholar]
  116. Garrido D, Ruiz-Moyano S, Mills DA. 2012. Release and utilization of N-acetyl-d-glucosamine from human milk oligosaccharides by Bifidobacterium longum subsp. infantis. Anaerobe 18:430–35 [Google Scholar]
  117. Yoshida E, Sakurama H, Kiyohara M, Nakajima M, Kitaoka M et al. 2012. Bifidobacterium longum subsp. infantis uses two different β-galactosidases for selectively degrading type-1 and type-2 human milk oligosaccharides. Glycobiology 22:361–68 [Google Scholar]
  118. Miwa M, Horimoto T, Kiyohara M, Katayama T, Kitaoka M et al. 2010. Cooperation of β-galactosidase and β-N-acetylhexosaminidase from bifidobacteria in assimilation of human milk oligosaccharides with type 2 structure. Glycobiology 20:1402–9 [Google Scholar]
  119. Wada J, Ando T, Kiyohara M, Ashida H, Kitaoka M et al. 2008. Bifidobacterium bifidum lacto-N-biosidase, a critical enzyme for the degradation of human milk oligosaccharides with a type 1 structure. Appl. Environ. Microbiol. 74:3996–4004 [Google Scholar]
  120. Sela DA, Mills DA. 2010. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 18:298–307 [Google Scholar]
  121. Egan M, O'Connell Motherway M, Ventura M, van Sinderen D. 2014. Metabolism of sialic acid by Bifidobacterium breve UCC2003. Appl. Environ. Microbiol 80:4414–26 [Google Scholar]
  122. Katayama T, Sakuma A, Kimura T, Makimura Y, Hiratake J et al. 2004. Molecular cloning and characterization of Bifidobacterium bifidum 1,2-α-l-fucosidase (AfcA), a novel inverting glycosidase (glycoside hydrolase family 95). J. Bacteriol. 186:4885–93 [Google Scholar]
  123. Kiyohara M, Tanigawa K, Chaiwangsri T, Katayama T, Ashida H, Yamamoto K. 2011. An exo-α-sialidase from bifidobacteria involved in the degradation of sialyloligosaccharides in human milk and intestinal glycoconjugates. Glycobiology 21:437–47 [Google Scholar]
  124. Pacheco AR, Curtis MM, Ritchie JM, Munera D, Waldor MK et al. 2012. Fucose sensing regulates bacterial intestinal colonization. Nature 492:113–17 [Google Scholar]
  125. Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC et al. 2013. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502:96–99 [Google Scholar]
  126. Tang XS, Shao H, Li TJ, Tang ZR, Huang RL et al. 2012. Dietary supplementation with bovine lactoferrampin-lactoferricin produced by Pichia pastoris fed-batch fermentation affects intestinal microflora in weaned piglets. Appl. Biochem. Biotechnol. 168:887–98 [Google Scholar]
  127. Hu W, Zhao J, Wang J, Yu T, Li N. 2012. Transgenic milk containing recombinant human lactoferrin modulates the intestinal flora in piglets. Biochem. Cell Biol. 90:485–96 [Google Scholar]
  128. Bruck WM, Graverholt G, Gibson GR. 2003. A two-stage continuous culture system to study the effect of supplemental α-lactalbumin and glycomacropeptide on mixed cultures of human gut bacteria challenged with enteropathogenic Escherichia coli and Salmonella serotype Typhimurium. J. Appl. Microbiol. 95:44–53 [Google Scholar]
  129. Chen Q, Cao J, Jia Y, Liu X, Yan Y, Pang G. 2012. Modulation of mice fecal microbiota by administration of casein glycomacropeptide. Microbiol. Res. 3:e3 [Google Scholar]
  130. Rahman MM, Kim WS, Ito T, Kumura H, Shimazaki K. 2009. Growth promotion and cell binding ability of bovine lactoferrin to Bifidobacterium longum. Anaerobe 15:133–37 [Google Scholar]
  131. Petschow BW, Talbott RD, Batema RP. 1999. Ability of lactoferrin to promote the growth of Bifidobacterium spp. in vitro is independent of receptor binding capacity and iron saturation level. J. Med. Microbiol. 48:541–49 [Google Scholar]
  132. Oda H, Wakabayashi H, Yamauchi K, Sato T, Xiao JZ et al. 2013. Isolation of a bifidogenic peptide from the pepsin hydrolysate of bovine lactoferrin. Appl. Environ. Microbiol. 79:1843–49 [Google Scholar]
  133. Liepke C, Adermann K, Raida M, Magert HJ, Forssmann WG, Zucht HD. 2002. Human milk provides peptides highly stimulating the growth of bifidobacteria. Eur. J. Biochem. 269:712–18 [Google Scholar]
  134. Garrido D, Nwosu C, Ruiz-Moyano S, Aldredge D, German JB et al. 2012. Endo-β-N-acetylglucosaminidases from infant gut-associated bifidobacteria release complex N-glycans from human milk glycoproteins. Mol. Cell. Proteomics 11:775–85 [Google Scholar]
  135. Kiyohara M, Nakatomi T, Kurihara S, Fushinobu S, Suzuki H et al. 2012. α-N-acetylgalactosaminidase from infant-associated bifidobacteria belonging to novel glycoside hydrolase family 129 is implicated in alternative mucin degradation pathway. J. Biol. Chem. 287:693–700 [Google Scholar]
  136. Rueda R, Sabatel JL, Maldonado J, Molina-Font JA, Gil A. 1998. Addition of gangliosides to an adapted milk formula modifies levels of fecal Escherichia coli in preterm newborn infants. J. Pediatr. 133:90–94 [Google Scholar]
  137. Lee H, Garrido D, Mills DA, Barile D. 2014. Hydrolysis of milk gangliosides by infant-gut associated bifidobacteria determined by microfluidic chips and high-resolution mass spectrometry. Electrophoresis 35:1742–50 [Google Scholar]
  138. Morrow AL, Rangel JM. 2004. Human milk protection against infectious diarrhea: implications for prevention and clinical care. Semin. Pediatr. Infect. Dis. 15:221–28 [Google Scholar]
  139. Lanari M, Prinelli F, Adorni F, Di Santo S, Faldella G et al. 2013. Maternal milk protects infants against bronchiolitis during the first year of life. Results from an Italian cohort of newborns. Early Hum. Dev. 89:Suppl. 1S51–57 [Google Scholar]
  140. Duffy LC, Faden H, Wasielewski R, Wolf J, Krystofik D. 1997. Exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media. Pediatrics 100:E7 [Google Scholar]
  141. Abdel-Hafeez EH, Belal US, Abdellatif MZ, Naoi K, Norose K. 2013. Breast-feeding protects infantile diarrhea caused by intestinal protozoan infections. Korean J. Parasitol. 51:519–24 [Google Scholar]
  142. Newburg DS, Ruiz-Palacios GM, Morrow AL. 2005. Human milk glycans protect infants against enteric pathogens. Annu. Rev. Nutr. 25:37–58 [Google Scholar]
  143. Krachler AM, Orth K. 2013. Targeting the bacteria-host interface: strategies in anti-adhesion therapy. Virulence 4:284–94 [Google Scholar]
  144. Jiang X, Huang PW, Zhong WM, Morrow AL, Ruiz-Palacios GM, Pickering LK. 2004. Human milk contains elements that block binding of noroviruses to histo-blood group antigens in saliva. Prot. Infants Hum. Milk 554:447–50 [Google Scholar]
  145. Lanata CF, Fischer-Walker CL, Olascoaga AC, Torres CX, Aryee MJ, Black RE. 2013. Global causes of diarrheal disease mortality in children <5 years of age: a systematic review. PLOS ONE 8:e72788 [Google Scholar]
  146. Zhang XF, Tan M, Chhabra M, Dai YC, Meller J, Jiang X. 2013. Inhibition of histo-blood group antigen binding as a novel strategy to block norovirus infections. PLOS ONE 8:e69379 [Google Scholar]
  147. Morrow AL, Ruiz-Palacios GM, Altaye M, Jiang X, Guerrero ML et al. 2004. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J. Pediatr 145:297–303 [Google Scholar]
  148. Kaper JB, Nataro JP, Mobley HL. 2004. Pathogenic Escherichia coli. Nat. Rev. Microbiol. 2:123–40 [Google Scholar]
  149. Manthey CF, Autran CA, Eckmann L, Bode L. 2013. Human milk oligosaccharides protect against enteropathogenic Escherichia coli attachment in vitro and EPEC colonization in suckling mice. J. Pediatr. Gastroenterol. Nutr 58:167–70 [Google Scholar]
  150. Weichert S, Jennewein S, Hufner E, Weiss C, Borkowski J et al. 2013. Bioengineered 2′-fucosyllactose and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and enteric pathogens to human intestinal and respiratory cell lines. Nutr. Res. 33:831–38 [Google Scholar]
  151. Martin-Sosa S, Martin MJ, Hueso P. 2002. The sialylated fraction of milk oligosaccharides is partially responsible for binding to enterotoxigenic and uropathogenic Escherichia coli human strains. J. Nutr. 132:3067–72 [Google Scholar]
  152. Lin AE, Autran CA, Espanola SD, Bode L, Nizet V. 2014. Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J. Infect. Dis. 209:389–98 [Google Scholar]
  153. Hannan TJ, Totsika M, Mansfield KJ, Moore KH, Schembri MA, Hultgren SJ. 2012. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol. Rev. 36:616–48 [Google Scholar]
  154. Greenhow TL, Hung YY, Herz AM, Losada E, Pantell RH. 2013. The changing epidemiology of serious bacterial infections in young infants. Pediatr. Infect. Dis. J 33:595–99 [Google Scholar]
  155. Jantscher-Krenn E, Lauwaet T, Bliss LA, Reed SL, Gillin FD, Bode L. 2012. Human milk oligosaccharides reduce Entamoeba histolytica attachment and cytotoxicity in vitro. Br. J. Nutr. 108:1839–46 [Google Scholar]
  156. Barboza M, Pinzon J, Wickramasinghe S, Froehlich JW, Moeller I et al. 2012. Glycosylation of human milk lactoferrin exhibits dynamic changes during early lactation enhancing its role in pathogenic bacteria-host interactions. Mol. Cell. Proteomics 11:M111.015248 [Google Scholar]
  157. Marr AK, Jenssen H, Moniri MR, Hancock RE, Pante N. 2009. Bovine lactoferrin and lactoferricin interfere with intracellular trafficking of Herpes simplex virus-1. Biochimie 91:160–64 [Google Scholar]
  158. Shestakov A, Jenssen H, Nordstrom I, Eriksson K. 2012. Lactoferricin but not lactoferrin inhibit herpes simplex virus type 2 infection in mice. Antiviral Res. 93:340–45 [Google Scholar]
  159. Valimaa H, Tenovuo J, Waris M, Hukkanen V. 2009. Human lactoferrin but not lysozyme neutralizes HSV-1 and inhibits HSV-1 replication and cell-to-cell spread. Virol. J. 6:53 [Google Scholar]
  160. Hooper LV, Macpherson AJ. 2010. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10:159–69 [Google Scholar]
  161. Rogier EW, Frantz AL, Bruno ME, Wedlund L, Cohen DA et al. 2014. Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. PNAS 111:3074–79 [Google Scholar]
  162. Hughes GJ, Reason AJ, Savoy L, Jaton J, Frutiger-Hughes S. 1999. Carbohydrate moieties in human secretory component. Biochim. Biophys. Acta 1434:86–93 [Google Scholar]
  163. Royle L, Roos A, Harvey DJ, Wormald MR, Van Gijlswijk-Janssen D et al. 2003. Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems. J. Biol. Chem. 278:20140–53 [Google Scholar]
  164. Mathias A, Corthesy B. 2011. Recognition of gram-positive intestinal bacteria by hybridoma- and colostrum-derived secretory immunoglobulin A is mediated by carbohydrates. J. Biol. Chem. 286:17239–47 [Google Scholar]
  165. Cravioto A, Tello A, Villafán H, Ruiz J, del Vedovo S, Neeser JR. 1991. Inhibition of localized adhesion of enteropathogenic Escherichia coli to HEp-2 cells by immunoglobulin and oligosaccharide fractions of human colostrum and breast milk. J. Infect. Dis. 163:1247–55 [Google Scholar]
  166. Falk P, Roth KA, Boren T, Westblom TU, Gordon JI, Normark S. 1993. An in vitro adherence assay reveals that Helicobacter pylori exhibits cell lineage-specific tropism in the human gastric epithelium. PNAS 90:2035–39 [Google Scholar]
  167. Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D et al. 1998. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science 279:373–77 [Google Scholar]
  168. Wold AE, Mestecky J, Tomana M, Kobata A, Ohbayashi H et al. 1990. Secretory immunoglobulin A carries oligosaccharide receptors for Escherichia coli type 1 fimbrial lectin. Infect. Immun. 58:3073–77 [Google Scholar]
  169. Connell I, Agace W, Klemm P, Schembri M, Marild S, Svanborg C. 1996. Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract. PNAS 93:9827–32 [Google Scholar]
  170. Aniansson G, Andersson B, Lindstedt R, Svanborg C. 1990. Anti-adhesive activity of human casein against Streptococcus pneumoniae and Haemophilus influenzae. Microb. Pathog. 8:315–23 [Google Scholar]
  171. Stromqvist M, Falk P, Bergstrom S, Hansson L, Lonnerdal B et al. 1995. Human milk kappa-casein and inhibition of Helicobacter pylori adhesion to human gastric mucosa. J. Pediatr. Gastroenterol. Nutr. 21:288–96 [Google Scholar]
  172. Rueda R. 2007. The role of dietary gangliosides on immunity and the prevention of infection. Br. J. Nutr. 98:Suppl. 1S68–73 [Google Scholar]
  173. Idota T, Kawakami H. 1995. Inhibitory effects of milk gangliosides on the adhesion of Escherichia coli to human intestinal carcinoma cells. Biosci. Biotechnol. Biochem. 59:69–72 [Google Scholar]
  174. Otnaess AB, Laegreid A, Ertresvag K. 1983. Inhibition of enterotoxin from Escherichia coli and Vibrio cholerae by gangliosides from human milk. Infect. Immun. 40:563–69 [Google Scholar]
  175. Laegreid A, Otnaess AB, Fuglesang J. 1986. Human and bovine milk: comparison of ganglioside composition and enterotoxin-inhibitory activity. Pediatr. Res. 20:416–21 [Google Scholar]
  176. Newburg DS, Ashkenazi S, Cleary TG. 1992. Human milk contains the Shiga toxin and Shiga-like toxin receptor glycolipid Gb3. J. Infect. Dis. 166:832–36 [Google Scholar]
  177. Pacheco AR, Sperandio V. 2012. Shiga toxin in enterohemorrhagic E. coli: regulation and novel anti-virulence strategies. Front. Cell. Infect. Microbiol. 2:81 [Google Scholar]
  178. Saeland E, de Jong MA, Nabatov AA, Kalay H, Geijtenbeek TB, van Kooyk Y. 2009. MUC1 in human milk blocks transmission of human immunodeficiency virus from dendritic cells to T cells. Mol. Immunol. 46:2309–16 [Google Scholar]
  179. Wu L, KewalRamani VN. 2006. Dendritic-cell interactions with HIV: infection and viral dissemination. Nat. Rev. Immunol. 6:859–68 [Google Scholar]
  180. Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC et al. 2000. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100:587–97 [Google Scholar]
  181. Hong PW, Flummerfelt KB, de Parseval A, Gurney K, Elder JH, Lee B. 2002. Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120-DC-SIGN binding. J. Virol. 76:12855–65 [Google Scholar]
  182. Hong PW, Nguyen S, Young S, Su SV, Lee B. 2007. Identification of the optimal DC-SIGN binding site on human immunodeficiency virus type 1 gp120. J. Virol. 81:8325–36 [Google Scholar]
  183. Requena M, Bouhlal H, Nasreddine N, Saidi H, Gody JC et al. 2008. Inhibition of HIV-1 transmission in trans from dendritic cells to CD4+ T lymphocytes by natural antibodies to the CRD domain of DC-SIGN purified from breast milk and intravenous immunoglobulins. Immunology 123:508–18 [Google Scholar]
  184. Yolken RH, Peterson JA, Vonderfecht SL, Fouts ET, Midthun K, Newburg DS. 1992. Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis. J. Clin. Investig. 90:1984–91 [Google Scholar]
  185. Schroten H, Hanisch FG, Plogmann R, Hacker J, Uhlenbruck G et al. 1992. Inhibition of adhesion of S-fimbriated Escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction. Infect. Immun. 60:2893–99 [Google Scholar]
  186. Liu B, Yu Z, Chen C, Kling DE, Newburg DS. 2012. Human milk mucin 1 and mucin 4 inhibit Salmonella enterica serovar Typhimurium invasion of human intestinal epithelial cells in vitro. J. Nutr. 142:1504–9 [Google Scholar]
  187. Dallas DC, Guerrero A, Khaldi N, Castillo PA, Martin WF et al. 2013. Extensive in vivo human milk peptidomics reveals specific proteolysis yielding protective antimicrobial peptides. J. Proteome Res. 12:2295–304 [Google Scholar]
  188. Hakansson AP, Roche-Hakansson H, Mossberg AK, Svanborg C. 2011. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex. PLOS ONE 6:e17717 [Google Scholar]
  189. Garrido D, Dallas DC, Mills DA. 2013. Consumption of human milk glycoconjugates by infant-associated bifidobacteria: mechanisms and implications. Microbiology 159:649–64 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error