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Human Milk Proteins

Key Components for the Biological Activity of Human Milk
  • Bo Lönnerdal
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 554)

Abstract

Human milk contains a wide array of proteins that provide biologic activities ranging from antimicrobial effects to immunostimulatory functions. Proteins like lactoferrin, secretory IgA, κ-casein, lactoperoxidase, haptocorrin, lactadherin and peptides formed from human milk proteins during digestion can inhibit the growth of pathogenic bacteria and viruses and therefore protect against infection. At the same time, proteins like lactoferrin, bile-salt stimulated lipase, haptocorrin, κ-casein, and folate-binding protein can facilitate the absorption of nutrients in the neonatal gut. However, the proteins in human milk themselves also provide adequate amounts of essential amino acids to the growing infant. This suggests a highly adapted digestive system, which allows the survival of some proteins and peptides in the upper gastrointestinal tract, while still allowing amino acid utilization from these proteins further down in the gut. It is now possible to produce recombinant human milk proteins in transgenic plants and animals, which makes it possible to further study the bioactivity of these proteins. Provided these proteins can be produced in large scale at low cost, that they show biologic activity and pose no safety concerns, it may be possible to add some human milk proteins to infant diets, such as formula and complementary foods. Human milk proteins produced in rice or potatoes, for example, could be added without much purification, because these staples commonly are used in weaning foods. Thus, some qualities provided by human milk may be included into other diets, although it is highly unlikely that all unique components of human milk can be copied this way.

Keywords

Human Milk Whey Protein Infant Formula Breastfed Infant Human Lactoferrin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. Adkins Y, Lönnerdal B. Mechanisms of vitamin B12 absorption in breast-fed infants. J Pediatr Gastroenterol Nutr 2002;35:192–198.PubMedCrossRefGoogle Scholar
  2. Adkins Y, Lönnerdal B. Potential host-defense role of a human milk vitamin B12-binding protein, haptocorrin, in the gastrointestinal tract of breast-fed infants assessed with porcine haptocorrin in vitro. Am J Clin Nutr 2003;77:1234–1240.PubMedGoogle Scholar
  3. Adkins Y, Lönnerdal B. Biotechnology Strategies to Produce Specific Food Ingredients: Proteins and Peptides. In: Eds. German B (in press)Google Scholar
  4. Andersson Y, Lindquist S, Lagerqvist C, Hernell O. Lactoferrin is responsible for the fungistatic effect of human milk. Early Hum Dev 2000;59:95–105.PubMedCrossRefGoogle Scholar
  5. Antony AC, Utley CS, Marceli PD, Kolhouse JF. Isolation, characterization, and comparison of the solubilized particulate and soluble folate binding proteins from human milk. J Biol Chem 1982;257:10081–10089.PubMedGoogle Scholar
  6. Arnold RR, Brewer M, Gauthier JJ. Bactericidal activity of human lactoferrin: sensitivity of a variety of microorganisms. Infect Immun 1980;28:893–898.PubMedGoogle Scholar
  7. Berseth CL, Lichtenberger LM, Morriss FH. Comparison of the gastrointestinal growth-promoting effects of rat colostrum and mature milk in newborn rats in vivo. Am J Clin Nutr 1983;37:52–60.PubMedGoogle Scholar
  8. Björck L, Rosen CG, Marshall V, Reiter B. Antibacterial activity of lactoperoxidase system in milk against Pseudomonas and other gram-negative bacteria. Appl Microbiol 1975;30:199–204.PubMedGoogle Scholar
  9. Brantl V. Novel opioid peptides derived from human β-casein. Eur J Pharmacol 1984;106:213–214.PubMedCrossRefGoogle Scholar
  10. Brignon G, Chtourou A, Ribadeau-Dumas B. Preparation and amino acid sequence of human k-casein. FEBS Lett 1985;188:48–54.PubMedCrossRefGoogle Scholar
  11. Bullen JJ, Rogers HJ, Leigh L. Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. Br Med J 1972;1:69–72.PubMedCrossRefGoogle Scholar
  12. Cavaletto M, Cantisani A, Giuffrida G, Napolitano L, Conti A. Human αS1-casein like protein: purification and N-terminal sequence determination. Biol Chem Hoppe-Seyler 1994;375:149–151.PubMedCrossRefGoogle Scholar
  13. Chierici R, Sawatzki G, Tamisari L, Volpato S, Vigi V. Supplementation of an adapted formula with bovine lactoferrin. 2. Effects on serum iron, ferritin and zinc levels. Acta Paediatr 1992;81:475–479.PubMedCrossRefGoogle Scholar
  14. Chipman DM, Sharon N. Mechanism of lysozyme action. Science 1969;165:454–465.PubMedCrossRefGoogle Scholar
  15. Chowanadisai W, Lönnerdal B. Alpha-1-antitrypsin and antichymotrypsin in human milk: origin, concentrations, and stability. Am J Clin Nutr 2002;76:828–833.PubMedGoogle Scholar
  16. Colman N, Hettiarachchy N, Herbert V. Detection of a milk factor that facilitates folate uptake by intestinal cells. Science 1981;211:1427–1428.PubMedCrossRefGoogle Scholar
  17. Corps AN, Brown KD. Stimulation of intestinal cell proliferation in culture by growth factors in human and ruminant mammary secretions. J Endocrinol 1987; 113:285–290.PubMedCrossRefGoogle Scholar
  18. Corps AN, Blakeley DM, Carr J, Rees LH, Brown KD. Synergistic stimulation of Swiss mouse 3T3 fibroblasts by epidermal growth factor and other factors in human milk. J Endocrinol 1987;112:151–159.PubMedCrossRefGoogle Scholar
  19. Davidson LA, Lönnerdal B. Persistence of human milk proteins in the breast-fed infant. Acta Paediatr Scand 1987;76:733–740.PubMedCrossRefGoogle Scholar
  20. Davidson LA, Lönnerdal B. Specific binding of lactoferrin to brush border membrane: ontogeny and effect of glycan chain. Am J Physiol 1988;254:G580–G585.PubMedGoogle Scholar
  21. Davidson LA, Lönnerdal B. Fecal alpha 1-antitrypsin in breast-fed infants is derived from human milk and is not indicative of enteric protein loss. Acta Paediatr Scand 1990;79:137–141.PubMedCrossRefGoogle Scholar
  22. Dewey KG, Lönnerdal B. Milk and nutrient intake of breastfed infants from 1 to 6 months: relation to growth and fatness. J Pediatr Gastroenterol Nutr 1983;2:497–506.PubMedCrossRefGoogle Scholar
  23. Dewey KG, Finley DA, Lönnerdal B. Breast milk volume and composition during late lactation (7–20 months). J Pediatr Gastroenterol Nutr 1984;3:713–720.PubMedCrossRefGoogle Scholar
  24. Dewey KG, Heinig MJ, Nommsen-Rivers LA. Differences in morbidity between breast-fed and formula-fed infants. J Pediatr 1995;126:696–702.PubMedCrossRefGoogle Scholar
  25. Donovan SM, Lönnerdal B. Isolation of the non-protein nitrogen fraction from human milk by gel-filtration chromatography and its separation by fast protein liquid chromatography. Am J Clin Nutr 1987;50:53–57.Google Scholar
  26. Donovan SM, Ogle J. Growth factors in milk as mediators of infant development. Annu Rev Nutr 1994; 14:147–167.PubMedCrossRefGoogle Scholar
  27. Donovan SM, Hintz RL, Rosenfeld RG. Insulin-like growth factors I and II and their binding proteins in human milk: effect of heat-treatment on IGF and IGF binding protein stability. J Pediatr Gastroenterol Nutr 1991;13:242–253.PubMedCrossRefGoogle Scholar
  28. Edde L, Hipolito RB, Hwang FF, Headon DR, Shalwitz RA, Sherman MP. Lactoferrin protects neonatal rats from gut-related systemic infection. Am J Physiol Gastrointest Liver Physiol 2001;281: G1140–G1150.PubMedGoogle Scholar
  29. Ellison RTJ, Giehl TJ. Killing of Gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 1991;88:1080–1091.PubMedCrossRefGoogle Scholar
  30. Fairweather-Tait SJ, Balmer SE, Scott PH, Ninski MJ. Lactoferrin and iron absorption in newborn infants. Pediatr Res 1987;22:651–654.PubMedCrossRefGoogle Scholar
  31. Fiat AM, Migliore-Samour D, Joliès P, Drouet L, Sollier CB, Caen J. Biologically active peptides from milk proteins with emphasis on two examples concerning antithrombotic and immunomodulating activities. J Dairy Sci 1993;76:301–310.PubMedCrossRefGoogle Scholar
  32. Fransson G-B, Lönnerdal B. Iron in human milk. J Pediatr 1980;96:380–384.PubMedCrossRefGoogle Scholar
  33. Fredrikzon B, Hernell O, Bläckberg L, Olivecrona T. Bile salt-stimulated lipase in human milk: evidence of activity in vivo and of a role in the digestion of milk retinol esters. Pediatr Res 1978;12:1048–1052.PubMedCrossRefGoogle Scholar
  34. Goldman AS. The immune system of human milk: antimicrobial, anti-inflammatory, and immunomodulating properties. Pediatr Infect Dis J 1993;12:664–672.PubMedCrossRefGoogle Scholar
  35. Greenberg R, Groves ML. Human ß-casein. Amino acid sequence and identification of phosphorylation sites. J Biol Chem 1984;259:5128–5132.Google Scholar
  36. Grosvenor CE, Picciano MF, Baumrucker CR. Hormones and growth factors in milk. Endocrinol Rev 1993;14:710–728.Google Scholar
  37. Gullberg R. Possible influence of vitamin B12-binding protein in milk on the intestinal flora in breast-fed infants. Scand J Gastroenterol 1973;8:497–503.PubMedCrossRefGoogle Scholar
  38. György P. The uniqueness of human milk. Biochemical aspects. Am J Clin Nutr 1971;24:970–975.PubMedGoogle Scholar
  39. Hamosh M. Enzymes in human milk. In: Jensen RG, editor. Handbook of Milk Composition. San Diego: Academic Press, 1995; pp 388–427.CrossRefGoogle Scholar
  40. Hansen M, Sandström B, Lönnerdal B. The effect of casein phosphopeptides on zinc and calcium absorption from high phytate diets assessed in rat pups and Caco-2 cells. Pediatr Res 1996;40:547–552.PubMedCrossRefGoogle Scholar
  41. Harmsen MC, Swart PJ, Debethune MP, Pauwels R, Declercq E, The TH, Meijer DKF. Antiviral effects of plasma and milk proteins: Lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. J Infect Dis 1995;172:380–388.PubMedCrossRefGoogle Scholar
  42. He J, Furmanski P. Sequence specificity and transcriptional activation in the binding of lactoferrin to DNA. Nature 1995;373:721–724.PubMedCrossRefGoogle Scholar
  43. Heird WC, Schwarz SM, Hansen IH. Colostrum-induced enteric mucosal growth in beagle puppies. Pediatr Res 1984;18:512–515.PubMedCrossRefGoogle Scholar
  44. Heitlinger LA, Lee PC, Dillon WP, Lebenthal E. Mammary amylase: a possible alternate pathway of carbohydrate digestion in infancy. Pediatr Res 1979;13:969–972.CrossRefGoogle Scholar
  45. Hernell O, Bläckberg L. Digestion of human milk lipids: physiologic significance of sn-2-monoacylglycerol hydrolysis by bile salt-stimulated lipase. Pediatr Res 1983;16:882–885.CrossRefGoogle Scholar
  46. Hernell O, Lönnerdal B. Iron status of infants fed low iron formula: no effect of added bovine lactoferrin or nucleotides. Am J Clin Nutr 2002;76:858–864.PubMedGoogle Scholar
  47. Hernell O, Bläckberg L, Lindberg T. Human milk enzymes with emphasis on the lipases. In: Lebenthal E, editor. Textbook of Gastroenterology and Nutrition in Infancy. New York: Raven Press, 1989; pp 209–217.Google Scholar
  48. Huang J, Wu L, Yalda D, Adkins Y, Kelleher SL, Crane M, Lönnerdal B, Rodriguez RL, Huang N. Expression of functional recombinant human lysozyme in transgenic rice culture. Transgenic Res 2002a; 11:229–230.CrossRefGoogle Scholar
  49. Huang J, Nandi S, Wu L, Yalda D, Bartley G, Rodriguez RL, Lönnerdal B, Huang N. Expression of natural antimicrobial human lysozyme in rice grains. Mol Breeding 2002b; 10:83–94.CrossRefGoogle Scholar
  50. Humphrey BD, Huang N, Klasing KC. Rice expressing lactoferrin and lysozyme has antibiotic-like properties when fed to chicks. J Nutr 2002;132:1214–1218.PubMedGoogle Scholar
  51. Kawakami H, Lönnerdal B. Isolation and function of a receptor for human lactoferrin in human fetal intestinal brush-border membranes. Am J Physiol 1991;261:G841–G846.PubMedGoogle Scholar
  52. Kelleher SL, Lönnerdal B. Immunological activities associated with milk. In: Woodward B, Draper HH, editors. Immunological Properties of Milk. New York: Plenum Publishers. Adv Nutr Res 2001;10:39–65.Google Scholar
  53. Kelleher SL, Chatterton D, Nielsen K, Lönnerdal B. Effects of glycomacropeptide and α-lactalbumin supplementation of infant formula on growth and nutritional status in infant rhesus monkeys. Am J Clin Nutr 2003;77:1261–1268.PubMedGoogle Scholar
  54. Kim Y-K, Yu D-Y, Lönnerdal B, Chung B-H. Novel angiotensin-I-converting enzyme inhibitory peptides derived from recombinant human αs1-casein expressed in Escherichia coli. J Dairy Res 1999;66:431–439.PubMedCrossRefGoogle Scholar
  55. Klagsburn M. Human milk stimulates DNA synthesis and cellular proliferation in cultured fibroblasts. Proc Natl Acad Sci USA 1978;75:5057–5061.CrossRefGoogle Scholar
  56. Kleesen B, Bunke H, Tovar K, Noack J, Sawatzki G. Influence of two infant formulas and human milk on the development of the fecal flora in newborn infants. Acta Paediatr 1995;84:1347–1356.CrossRefGoogle Scholar
  57. Kunz C, Lönnerdal B. Human-milk proteins: analysis of casein and casein subunits by anion-exchange chromatography, gel electrophoresis, and specific staining methods. Am J Clin Nutr 1987a;51:37–46.Google Scholar
  58. Kunz C, Lönnerdal B. Re-evaluation of the whey protein/casein ratio of human milk. Acta Paediatr 1987b;81:107–112.CrossRefGoogle Scholar
  59. Lee-Huang S, Huang PL, Sun Y, Kung HF, Blithe DL, Chen HC. Lysozyme and RNAses as anti-HIV components in beta-core preparations of human chorionic gonadotropin. Proc Natl Acad Sci USA 1999;96:2678–2681.PubMedCrossRefGoogle Scholar
  60. Liepke C, Adermann K, Raida M, Mägert H-J, Forssmann W-G, Zucht H-D. Human milk provides peptides highly stimulating the growth of bifidobacteria. Eur J Biochem 2002;269:712–718.PubMedCrossRefGoogle Scholar
  61. Lindberg T. Protease inhibitors in human milk. Pediatr Res 1979;13:969–972.PubMedCrossRefGoogle Scholar
  62. Lindberg T, Skude G. Amylase in human milk. Pediatrics 1982;70:235–238.PubMedGoogle Scholar
  63. Lindberg T, Ohlsson K, Weström B. Protease inhibitors and their relation to proteases in human milk. Pediatr Res 1982;16:479–483.PubMedCrossRefGoogle Scholar
  64. Lindh E. Increased resistance of immunoglobulin dimers to proteolytic degradation after binding of secretory component. J Immunol 1985;113:284–288.Google Scholar
  65. Lönnerdal, B. Recombinant human milk proteins—an opportunity and a challenge. Am J Clin Nutr 1996;63:622S–626S.Google Scholar
  66. Lönnerdal B. Expression of human milk proteins in plants. J Am Coll Nutr 2002;21(Suppl 3):218S–221S.Google Scholar
  67. Lönnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 2003;77:1537S–1543S.PubMedGoogle Scholar
  68. Lönnerdal B, Glazier C. Calcium binding by a-lactalbumin in human milk. J Nutr 1985; 115:1209–1216.PubMedGoogle Scholar
  69. Lönnerdal B, Iyer S. Lactoferrin: molecular structure and biological function. Annu Rev Nutr 1995;15:93–110.PubMedCrossRefGoogle Scholar
  70. Lönnerdal B, Forsum E, Hambraeus L. A longitudinal study of the protein, nitrogen and lactose contents of human milk from Swedish well-nourished mothers. Am J Clin Nutr 1976a;29:1 127–1133.Google Scholar
  71. Lönnerdal B, Forsum E, Hambraeus L. The protein content of human milk. I. A transversal study of Swedish normal material. Nutr Rep Int 1976b; 13:125–134.Google Scholar
  72. Ma L, Xu RJ. Oral insulin-like growth factor-I stimulates intestinal enzyme maturation in newborn rats. Life Sci 1997;61:51–58.PubMedCrossRefGoogle Scholar
  73. Menard D, Pothier P. Radioautographic localization of epidermal growth factor receptors in human fetal gut. Gastroenterology 1991;101:640–649.PubMedGoogle Scholar
  74. Morgan CH, Courts AGP, McFadyen MC, King TP, Kelly D. Characterization of IGF-I receptors in porcine small intestine during postnatal development. J Nutr Biochem 1996;7:339–347.CrossRefGoogle Scholar
  75. Nandi S, Suzuki YA, Huang J, Yalda D, Pham P, Wu L, Bartley G, Huang N, Lönnerdal B. Expression of human lactoferrin in transgenic rice grains for the application in infant formula. Plant Sci 163:713–722.Google Scholar
  76. Newburg DS. Do the binding properties of oligosaccharides in milk protect human infants from gastrointestinal bacteria? J Nutr 1997;127: 980S–984S.PubMedGoogle Scholar
  77. Nichols BL, McKee KS, Henry JF, Putman M. Human lactoferrin stimulates thymidine incorporation into DNA of rat crypt cells. Pediatr Res 1987;21:563–567.PubMedCrossRefGoogle Scholar
  78. Patton S, Houston GE. A method for isolation of milk fat globules. Lipids 1986;21:170–174.PubMedCrossRefGoogle Scholar
  79. Pellegrini A, Thomas U, Bramaz N, Hunziker P, Von Fellenberg R. Isolation and identification of three bactericidal domains in the bovine a-lactalbumin molecule. Biochim Biophys Acta 1999;1426:439–448.PubMedCrossRefGoogle Scholar
  80. Plaut AG, Qiu J, St Geme JW 3rd. Human lactoferrin proteolytic activity: analysis of the cleaved region in the IgA protease of Hemophilus influenzae. Vaccine 2000;19(Suppl 1):S148–S152.PubMedCrossRefGoogle Scholar
  81. Read LC, Upton FM, Francis GL, Wallace JC, Dahlenburg GW, Ballard FJ. Changes in the growth-promoting activity of human milk during lactation. Pediatr Res 1984;18:133–139.PubMedCrossRefGoogle Scholar
  82. Ren J. Alpha-lactalbumin possesses a distinct zinc binding site. J Biol Chem 1993;268:19292–19298.PubMedGoogle Scholar
  83. Said HM, Home DW, Wagner C. Effect of human milk folate binding protein on folate intestinal transport. Arch Biochem Biophys 1986;251:114–120.PubMedCrossRefGoogle Scholar
  84. Salter DN, Mowlem A. Neonatal role of folate-binding protein: studies on the course of digestion of goat’s milk folate binder in the 6-d old kid. Br J Nutr 1983;50:589–596.PubMedCrossRefGoogle Scholar
  85. Sandberg, DP, Begley JA, Hall CA. The content, binding, and forms of vitamin B12 in milk. Am J Clin Nutr 1981;34:1717–1724.PubMedGoogle Scholar
  86. Sato R, Noguchi T, Naito H. Casein phosphopeptide (CPP) enhances calcium absorption from the ligated segment of rat small intestine. J Nutr Sci Vit 1986;32:67–76.CrossRefGoogle Scholar
  87. Sato R, Shindo M, Gunshin H, Noguchi T, Naito H. Characterization of phosphopeptide derived from bovine beta-casein: an inhibitor to intra-intestinal precipitation of calcium phosphate. Biochim Biophys Acta 1991;1077:413–415.PubMedCrossRefGoogle Scholar
  88. Schlimme E, Meisel H. Bioactive peptides derived from milk proteins. Structural, physiological and analytical aspects. Nahrung 1995;39:1–20.PubMedCrossRefGoogle Scholar
  89. Shin K, Hayasawa H, Lönnerdal B. Purification and quantification of lactoperoxidase in human milk with use of immunoadsorbents with antibodies against recombinant human lactoperoxidase. Am J Clin Nutr 2001;73:984–989.PubMedGoogle Scholar
  90. Son K-N, Park J, Chung C-K, Chung DK, Yu D-Y, Lee K-K, Kim J. Human lactoferrin activates transcription of IL-1β gene in mammalian cells. Biochem Biophys Res Commun 2002;290:236–241.PubMedCrossRefGoogle Scholar
  91. Steele WF, Morrisons M. Antistreptococcal activity of lactoperoxidase. J Bacterid 1969;97:635–639.Google Scholar
  92. Strömquist M, Falk P, Bergström S, Hansson L, Lönnerdal B, Normark S, Hernell O. Human milk K-casein and inhibition of Helicobacter pylori adhesion to human gastric mucosa. J Pediatr Gastroenterol Nutr 1995;21:288–296.CrossRefGoogle Scholar
  93. Suzuki YA, Shin K, Lönnerdal B. Molecular cloning and functional expression of a human intestinal lactoferrin receptor. Biochemistry 2001;40:15771–15779.PubMedCrossRefGoogle Scholar
  94. Suzuki YA, Kelleher SL, Yalda D, Wu L, Huang J, Huang N, Lönnerdal B. Expression, characterization, and biologic activity of recombinant human lactoferrin in rice. J Pediatr Gastroenterol Nutr 2003;36:190–199.PubMedCrossRefGoogle Scholar
  95. Telemo E, Hanson LÅ. Antibodies in milk. J Mammary Gland Biol Neoplasia 1996;1:243–249.PubMedCrossRefGoogle Scholar
  96. Tornita M, Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K. Potent antibacterial peptides generated by pepsin digestion of bovine lactoferrin. J Dairy Sci 1991;74:4137–4142.CrossRefGoogle Scholar
  97. Young GP, Taranto TM, Jonas HA Cox AJ, Hogg A, Werther GA. Insulin-like growth factors and the developing and mature rat small intestine: receptors and biological actions. Digestion 1990;46:240–252.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Bo Lönnerdal
    • 1
  1. 1.Department of Nutrition & Program of International NutritionUniversity of CaliforniaDavisUSA

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