15,080
Views
51
CrossRef citations to date
0
Altmetric
Reviews

More than sugar in the milk: human milk oligosaccharides as essential bioactive molecules in breast milk and current insight in beneficial effects

ORCID Icon, , , &

References

  • Ackerman, D. L., K. M. Craft, R. S. Doster, J.-H. Weitkamp, D. M. Aronoff, J. A. Gaddy, and S. D. Townsend. 2018. Antimicrobial and antibiofilm activity of human milk oligosaccharides against Streptococcus agalactiae, Staphylococcus aureus, and Acinetobacter baumannii. ACS Infectious Diseases 4 (3):315–24. doi: 10.1021/acsinfecdis.7b00183.
  • Ackerman, D. L., R. S. Doster, J.-H. Weitkamp, D. M. Aronoff, J. A. Gaddy, and S. D. Townsend. 2017. Human milk oligosaccharides exhibit antimicrobial and antibiofilm properties against group B Streptococcus. ACS Infectious Diseases 3 (8):595–605. doi: 10.1021/acsinfecdis.7b00064.
  • Adamkin, D. H. 2012. Mother’s milk, feeding strategies, and lactoferrin to prevent necrotizing enterocolitis. Journal of Parenteral and Enteral Nutrition 36 (1_suppl):25S–9S. doi: 10.1177/0148607111420158.
  • Ahmad, T., M. Gogarty, E. G. Walsh, and D. J. Brayden. 2017. A comparison of three Peyer’s patch “M-like” cell culture models: Particle uptake, bacterial interaction, and epithelial histology. European Journal of Pharmaceutics and Biopharmaceutics 119:426–36. doi: 10.1016/j.ejpb.2017.07.013.
  • Akkerman, R., M. M. Faas, and P. de Vos. 2019. Non-digestible carbohydrates in infant formula as substitution for human milk oligosaccharide functions: Effects on microbiota and gut maturation. Critical Reviews in Food Science and Nutrition 59 (9):1486–12. doi: 10.1080/10408398.2017.1414030.
  • Allaire, J. M., S. M. Crowley, H. T. Law, S. Y. Chang, H. J. Ko, and B. A. Vallance. 2018. The intestinal epithelium: Central coordinator of mucosal immunity. Trends in Immunology 39 (9):677–96. doi: 10.1016/j.it.2018.04.002.
  • Aly, E., A. Ali Darwish, R. Lopez-Nicolas, C. Frontela-Saseta, and G. Ros-Berruezo. 2018. Bioactive components of human milk: Similarities and differences between human milk and infant formula. In Selected topics in breastfeeding. London: IntechOpen. doi: 10.5772/intechopen.73074.
  • Andreas, N. J., B. Kampmann, and K. Mehring Le-Doare. 2015. Human breast milk: A review on its composition and bioactivity. Early Human Development 91 (11):629–35. doi: 10.1016/j.earlhumdev.2015.08.013.
  • Angeloni, S., J. L. Ridet, N. Kusy, H. Gao, F. Crevoisier, S. Guinchard, S. Kochhar, H. Sigrist, and N. Sprenger. 2004. Glycoprofiling with micro-arrays of glycoconjugates and lectins. Glycobiology 15 (1):31–41. doi: 10.1093/glycob/cwh143.
  • Asakuma, S., E. Hatakeyama, T. Urashima, E. Yoshida, T. Katayama, K. Yamamoto, H. Kumagai, H. Ashida, J. Hirose, and M. Kitaoka. 2011. Physiology of consumption of human milk oligosaccharides by infant gut-associated bifidobacteria. Journal of Biological Chemistry 286 (40):34583–92. doi: 10.1074/jbc.M111.248138.
  • Asakuma, S., T. Yokoyama, K. Kimura, Y. Watanabe, T. Nakamura, K. Fukuda, and T. Urashima. 2010. Effect of Human milk oligosaccharides on messenger ribonucleic acid expression of toll-like receptor 2 and 4, and of MD2 in the intestinal cell line HT-29. Journal of Applied Glycoscience 57 (3):177–83. doi: 10.5458/jag.57.177.
  • Austin, S., D. Cuany, J. Michaud, B. Diehl, and B. Casado. 2018. Determination of 2’-fucosyllactose and lacto-N-neotetraose in infant formula. Molecules 23 (10):2650. doi: 10.3390/molecules23102650.
  • Aziz, M., L. W. Hansen, J. M. Prince, and P. Wang. 2017. Role of mfg-e8 in neonatal inflammation. In Dairy in human health and disease across the lifespan, 21–30. London: IntechOpen. doi:10.1016/B978-0-12-809868-4.00002-9.
  • Baregamian, N., J. Song, M. G. Jeschke, B. M. Evers, and D. H. Chung. 2006. IGF-1 protects intestinal epithelial cells from oxidative stress-induced apoptosis. Journal of Surgical Research 136 (1):31–7. doi: 10.1016/j.jss.2006.04.028.
  • Binns, C., M. Lee, and W. Y. Low. 2016. The long-term public health benefits of breastfeeding. Asia Pacific Journal of Public Health 28 (1):7–14. doi: 10.1177/1010539515624964.
  • Blum, J. W., and C. R. Baumrucker. 2002. Colostral and milk insulin-like growth factors and related substances: Mammary gland and neonatal (intestinal and systemic) targets. Domestic Animal Endocrinology 23 (1-2):101–10. (02)00149-2 doi: 10.1016/S0739-7240(02)00149-2.
  • Bode, L. 2012. Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology 22 (9):1147–62. doi: 10.1093/glycob/cws074.
  • Bode, L. 2019. Human milk oligosaccharides: Next-generation functions and questions. Nestle Nutrition Institute Workshop Series 90:191–201. doi: 10.1159/000490306.
  • Bode, L., N. Contractor, D. Barile, N. Pohl, A. R. Prudden, G. J. Boons, Y. S. Jin, and S. Jennewein. 2016. Overcoming the limited availability of human milk oligosaccharides: Challenges and opportunities for research and application. Nutrition Reviews 74 (10):635–44. doi: 10.1093/nutrit/nuw025.
  • Boedeker, E. C., and A. Allen. 2018. The structure and function of gastrointestinal mucus. In Attachment of organisms to the gut mucosa, 3–12. London: IntechOpen. doi: 10.1201/9781351069977-2.
  • Boix-Amorós, A., M. C. Collado, and A. Mira. 2016. Relationship between milk microbiota, bacterial load, macronutrients, and human cells during lactation. Frontiers in Microbiology 7 (APR):492. doi: 10.3389/fmicb.2016.00492.
  • Boyce, C., M. Watson, G. Lazidis, S. Reeve, K. Dods, K. Simmer, and G. McLeod. 2016. Preterm human milk composition: A systematic literature review. British Journal of Nutrition 116 (6):1033–45. doi: 10.1017/S0007114516003007.
  • Brandtzaeg, P. 2016. Immunity in the gut: Mechanisms and functions. In Viral gastroenteritis: molecular epidemiology and pathogenesis, 23–46. London: Academic Press. doi: 10.1016/B978-0-12-802241-2.00002-X.
  • Brenmoehl, J., D. Ohde, E. Wirthgen, and A. Hoeflich. 2018. Cytokines in milk and the role of TGF-beta. Best Practice & Research Clinical Endocrinology & Metabolism 32 (1):47–56. doi: 10.1016/j.beem.2018.01.006.
  • Briere, C. E., T. Jensen, J. M. McGrath, E. E. Young, and C. Finck. 2017. Stem-like cell characteristics from breast milk of mothers with preterm infants as compared to mothers with term infants. Breastfeeding Medicine 12 (3):174–9. doi: 10.1089/bfm.2017.0002.
  • Cabrera-Rubio, R.,. M. C. Collado, K. Laitinen, S. Salminen, E. Isolauri, and A. Mira. 2012. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. The American Journal of Clinical Nutrition 96 (3):544–51. doi: 10.3945/ajcn.112.037382.
  • Cacho, N. T., and R. M. Lawrence. 2017. Innate immunity and breast milk. Frontiers in Immunology 8 (May):584. doi: 10.3389/fimmu.2017.00584.
  • Cappelletti, M., S. D. Bella, E. Ferrazzi, D. Mavilio, and S. Divanovic. 2016. Inflammation and preterm birth. Journal of Leukocyte Biology 99 (1):67–78. doi: 10.1189/jlb.3MR0615-272RR.
  • Castanys-Muñoz, E., M. J. Martin, and E. Vazquez. 2016. Building a beneficial microbiome from birth. Advances in Nutrition 7 (2):323–30. doi: 10.3945/an.115.010694.
  • Chairatana, P., and E. M. Nolan. 2017. Defensins, lectins, mucins, and secretory immunoglobulin A: Microbe-binding biomolecules that contribute to mucosal immunity in the human gut. Critical Reviews in Biochemistry and Molecular Biology 52 (1):45–56. doi: 10.1080/10409238.2016.1243654.
  • Cheng, L., M. B. G. Kiewiet, A. Groeneveld, A. Nauta, and P. de Vos. 2019. Human milk oligosaccharides and its acid hydrolysate LNT2 show immunomodulatory effects via TLRs in a dose and structure-dependent way. Journal of Functional Foods 59 (March):174–84. doi: 10.1016/j.jff.2019.05.023.
  • Chichlowski, M., G. De Lartigue, J. Bruce German, H. E. Raybould, and D. A. Mills. 2012. Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function. Journal of Pediatric Gastroenterology and Nutrition 55 (3):321–7. doi: 10.1097/MPG.0b013e31824fb899.
  • Chong, C. Y. L., F. H. Bloomfield, and J. M. O’Sullivan. 2018. Factors affecting gastrointestinal microbiome development in neonates. Nutrients 10 (3):274. doi: 10.3390/nu10030274.
  • Cicero, A. F. G., F. Fogacci, and A. Colletti. 2017. Potential role of bioactive peptides in prevention and treatment of chronic diseases: A narrative review. British Journal of Pharmacology 174 (11):1378–94. doi: 10.1111/bph.13608.
  • Collado, M. C., M. Gueimonde, L. Ruiz, M. Aparicio, I. Castro, and J. M. Rodríguez. 2019. Baby’s first microbes: The microbiome of human milk. In How fermented foods feed a healthy gut microbiota, 3–33. Berlin: Springer. doi: 10.1007/978-3-030-28737-5_1.
  • Conlon, M. A., and A. R. Bird. 2014. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7 (1):17–44. doi: 10.3390/nu7010017.
  • Coppa, G. V., O. Gabrielli, P. Pierani, C. Catassi, A. Carlucci, and P. L. Giorgi. 1993. Changes in carbohydrate composition in human milk over 4 months of lactation. Pediatrics 91 (3):637–41. www.aappublications.org/news.
  • Cregan, M. D., Y. Fan, A. Appelbee, M. L. Brown, B. Klopcic, J. Koppen, L. R. Mitoulas, K. M. E. Piper, M. A. Choolani, Y.-S. Chong, et al. 2007. Identification of nestin-positive putative mammary stem cells in human breastmilk. Cell and Tissue Research 329 (1):129–36. doi: 10.1007/s00441-007-0390-x.
  • Dawod, B., and J. S. Marshall. 2019. Cytokines and soluble receptors in breast milk as enhancers of oral tolerance development. Frontiers in Immunology 10 (JAN):16. doi: 10.3389/fimmu.2019.00016.
  • Doare, K., Le, B. Holder, A. Bassett, and P. S. Pannaraj. 2018. Mother’s milk: A purposeful contribution to the development of the infant microbiota and immunity. Frontiers in Immunology 9 (Feb):361. doi: 10.3389/fimmu.2018.00361.
  • Dominguez-Bello, M. G., E. K. Costello, M. Contreras, M. Magris, G. Hidalgo, N. Fierer, and R. Knight. 2010. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proceedings of the National Academy of Sciences of United States of America 107 (26):11971–5. doi: 10.1073/pnas.1002601107.
  • Duska-McEwen, G., A. P. Senft, T. L. Ruetschilling, E. G. Barrett, and R. H. Buck. 2014. Human milk oligosaccharides enhance innate immunity to respiratory syncytial virus and influenza in vitro. Food and Nutrition Sciences 05 (14):1387–98. doi: 10.4236/fns.2014.514151.
  • Dvorak, B. 2010. Milk epidermal growth factor and gut protection. The Journal of Pediatrics 156 (2):S31–S5. doi: 10.1016/j.jpeds.2009.11.018.
  • Dvorak, B., C. C. Fituch, C. S. Williams, N. M. Hurst, and R. J. Schanler. 2003. Increased epidermal growth factor levels in human milk of mothers with extremely premature infants. Pediatric Research 54 (1):15–9. doi: 10.1203/01.PDR.0000065729.74325.71.
  • EFSA NDA Panel. 2015a. Safety of 2′‐O‐fucosyllactose as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA Journal 13 (7):4184. doi: 10.2903/j.efsa.2015.4184.
  • EFSA NDA Panel. 2015b. Statement on the safety of lacto‐N‐neotetraose and 2′‐O‐fucosyllactose as novel food ingredients in food supplements for children. EFSA Panel on Dietetic Products. Nutrition and Allergies 13 (11):4299. doi: 10.2903/j.efsa.2015.4299.
  • Egge, H., A. Dell, and H. Von Nicolai. 1983. Fucose containing oligosaccharides from human milk. I. Separation and identification of new constituents. Archives of Biochemistry and Biophysics 224 (1):235–53. (83)90207-2 doi: 10.1016/0003-9861(83)90207-2.
  • El-Hawiet, A., Y. Chen, K. Shams-Ud-Doha, E. N. Kitova, Y. St-Pierre, and J. S. Klassen. 2017. High-throughput label-and immobilization-free screening of human milk oligosaccharides against lectins. Analytical Chemistry 89:28. doi: 10.1021/acs.analchem.7b00542.
  • Elwakiel, M., J. A. Hageman, W. Wang, I. M. Szeto, J. B. Van Goudoever, K. A. Hettinga, and H. A. Schols. 2018. Human milk oligosaccharides in colostrum and mature milk of Chinese mothers: Lewis positive secretor subgroups. Journal of Agricultural and Food Chemistry 66 (27):7036–43. doi: 10.1021/acs.jafc.8b02021.
  • Ewald, D. R., and S. C. J. Sumner. 2018. Human microbiota, blood group antigens, and disease. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 10 (3):e1413. doi: 10.1002/wsbm.1413.
  • Fernández, L., S. Langa, V. Martín, A. Maldonado, E. Jiménez, R. Martín, and J. M. Rodríguez. 2013. The human milk microbiota: Origin and potential roles in health and disease. Pharmacological Research 69 (1):1–10. doi: 10.1016/j.phrs.2012.09.001.
  • Field, C. J. 2005. The immunological components of human milk and their effect on immune development in infants. The Journal of Nutrition 135 (1):1–4. doi: 10.1093/jn/135.1.1.
  • Figueroa-Lozano, S., and P. de Vos. 2019. Relationship between oligosaccharides and glycoconjugates content in human milk and the development of the gut barrier. Comprehensive Reviews in Food Science and Food Safety 18 (1):121–39. doi: 10.1111/1541-4337.12400.
  • Fukuda, S., H. Toh, K. Hase, K. Oshima, Y. Nakanishi, K. Yoshimura, T. Tobe, J. M. Clarke, D. L. Topping, T. Suzuki, et al. 2011. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469 (7331):543–9. doi: 10.1038/nature09646.
  • Gao, X., R. J. McMahon, J. G. Woo, B. S. Davidson, A. L. Morrow, and Q. Zhang. 2012. Temporal changes in milk proteomes reveal developing milk functions. Journal of Proteome Research 11 (7):3897–907. doi: 10.1021/pr3004002.
  • Garofalo, R., S. Chheda, F. Mei, K. H. Palkowetz, H. E. Rudloff, F. C. Schmalstieg, D. K. Rassin, and A. S. Goldman. 1995. Interleukin-10 in human milk. Pediatric Research 37 (4):444–9. doi: 10.1203/00006450-199504000-00010.
  • Garrido, D., J. H. Kim, J. B. German, H. E. Raybould, and D. A. Mills. 2011. Oligosaccharide binding proteins from Bifidobacterium longum subsp. infantis reveal a preference for host glycans. PLoS One. 6 (3):e17315. doi: 10.1371/journal.pone.0017315.
  • Garrido, D., S. Ruiz-Moyano, D. G. Lemay, D. A. Sela, J. B. German, and D. A. Mills. 2015. Comparative transcriptomics reveals key differences in the response to milk oligosaccharides of infant gut-associated bifidobacteria. Scientific Reports 5 (1):13517. doi: 10.1038/srep13517.
  • Gensollen, T., S. S. Iyer, D. L. Kasper, and R. S. Blumberg. 2016. How colonization by microbiota in early life shapes the immune system. Science 352 (6285):539–44. doi: 10.1126/science.aad9378.
  • Gila-Diaz, A., S. M. Arribas, A. Algara, M. A. Martín-Cabrejas, Á. L. López de Pablo, M. Sáenz de Pipaón, and D. Ramiro-Cortijo. 2019. A review of bioactive factors in human breastmilk: A focus on prematurity. Nutrients 11 (6):1307. doi: 10.3390/nu11061307.
  • Goldman, A. S., C. Garza, B. L. Nichols, and R. M. Goldblum. 1982. Immunologic factors in human milk during the first year of lactation. The Journal of Pediatrics 100 (4):563–7. (82)80753-1 doi: 10.1016/S0022-3476(82)80753-1.
  • Gotoh, A., T. Katoh, M. Sakanaka, Y. Ling, C. Yamada, S. Asakuma, T. Urashima, Y. Tomabechi, A. Katayama-Ikegami, S. Kurihara, et al. 2018. Sharing of human milk oligosaccharides degradants within bifidobacterial communities in faecal cultures supplemented with Bifidobacterium bifidum. Scientific Reports 8 (1):13958. doi: 10.1038/s41598-018-32080-3.
  • Guo, S., T. Gillingham, Y. Guo, D. Meng, W. Zhu, W. A. Walker, and K. Ganguli. 2017. Secretions of Bifidobacterium infantis and Lactobacillus acidophilus protect intestinal epithelial barrier function. Journal of Pediatric Gastroenterology and Nutrition 64 (3):404–12. doi: 10.1097/MPG.0000000000001310.
  • Hamosh, M., J. A. Peterson, T. R. Henderson, C. D. Scallan, R. Kiwan, R. L. Ceriani, M. Armand, N. R. Mehta, and P. Hamosh. 1999. Protective function of human milk: The milk fat globule. Seminars in Perinatology 23 (3):242–9. (99)80069-X doi: 10.1016/S0146-0005(99)80069-X.
  • Hassiotou, F., and D. T. Geddes. 2015. Immune cell–mediated protection of the mammary gland and the infant during breastfeeding. Advances in Nutrition 6 (3):267–75. doi: 10.3945/an.114.007377.
  • He, Y., S. Liu, S. Leone, and D. S. Newburg. 2014. Human colostrum oligosaccharides modulate major immunologic pathways of immature human intestine. Mucosal Immunology 7 (6):1326–39. doi: 10.1038/mi.2014.20.
  • He, Y. Y., S. B. Liu, D. E. Kling, S. Leone, N. T. Lawlor, Y. Huang, S. B. Feinberg, D. R. Hill, and D. S. Newburg. 2016. The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 65 (1):33–46. doi: 10.1136/gutjnl-2014-307544.
  • Hill, C. J., D. B. Lynch, K. Murphy, M. Ulaszewska, I. B. Jeffery, C. A. O’Shea, C. Watkins, E. Dempsey, F. Mattivi, K. Tuohy, et al. 2017. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort. Microbiome 5 (1):4. doi: 10.1186/s40168-016-0213-y.
  • Hill, D. R., and D. S. Newburg. 2015. Clinical applications of bioactive milk components. Nutrition Reviews 73 (7):463–76. doi: 10.1093/nutrit/nuv009.
  • Hillman, E. T., H. Lu, T. Yao, and C. H. Nakatsu. 2017. Microbial ecology along the gastrointestinal tract. Microbes and Environments 32 (4):300–13. doi: 10.1264/jsme2.ME17017.
  • Hoeflich, A., and Z. Meyer. 2017. Functional analysis of the IGF-system in milk. Best Practice & Research Clinical Endocrinology & Metabolism 31 (4):409–18. doi: 10.1016/j.beem.2017.10.002.
  • Holscher, H. D., L. Bode, and K. A. Tappenden. 2017. Human Milk oligosaccharides influence intestinal epithelial cell maturation in vitro. Journal of Pediatric Gastroenterology and Nutrition 64 (2):296–301. doi: 10.1097/MPG.0000000000001274.
  • Hosseini, S. M., T. Talaei-Khozani, M. Sani, and B. Owrangi. 2014. Differentiation of human breast-milk stem cells to neural stem cells and neurons. Neurology Research International 2014:1–8. doi: 10.1155/2014/807896.
  • Hossny, E. M., D. H. El-Ghoneimy, R. H. El-Owaidy, M. G. Mansour, M. T. Hamza, and A. F. El-Said. 2020. Breast milk interleukin-7 and thymic gland development in infancy. European Journal of Nutrition 59 (1):111–8. doi: 10.1007/s00394-018-01891-5.
  • Jansen, M. 2019. Marching out of the crypt. Science 365 (6454):642–3. doi: 10.1126/science.aay5861.
  • Jantscher-Krenn, E., T. Lauwaet, L. A. Bliss, S. L. Reed, F. D. Gillin, and L. Bode. 2012. Human milk oligosaccharides reduce Entamoeba histolytica attachment and cytotoxicity in vitro. British Journal of Nutrition 108 (10):1839–46. doi: 10.1017/S0007114511007392.
  • Jantscher-Krenn, E., M. Zherebtsov, C. Nissan, K. Goth, Y. S. Guner, N. Naidu, B. Choudhury, A. V. Grishin, H. R. Ford, and L. Bode. 2012. The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut 61 (10):1417–25. doi: 10.1136/gutjnl-2011-301404.
  • Jeurink, P. V., J. van Bergenhenegouwen, E. Jiménez, L. M. J. Knippels, L. Fernández, J. Garssen, J. Knol, J. M. Rodríguez, and R. Martín. 2013. Human milk: A source of more life than we imagine. Beneficial Microbes 4 (1):17–30. doi: 10.3920/BM2012.0040.
  • Johansson, M. E. V., and G. C. Hansson. 2016. Immunological aspects of intestinal mucus and mucins. Nature Reviews Immunology 16 (10):639–49. doi: 10.1038/nri.2016.88.
  • Johnson, P. H., and W. M. Watkins. 1992. Purification of the Lewis blood-group gene associated α-3/4-fucosyltransferase from human milk: An enzyme transferring fucose primarily to Type 1 and lactose-based oligosaccharide chains. Glycoconjugate Journal 9 (5):241–9. doi: 10.1007/BF00731136.
  • Jost, T., C. Lacroix, C. Braegger, and C. Chassard. 2015. Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health. Nutrition Reviews 73 (7):426–37. doi: 10.1093/nutrit/nuu016.
  • Kavanaugh, D., J. O'Callaghan, M. Kilcoyne, M. Kane, L. Joshi, and R. M. Hickey. 2015. The intestinal glycome and its modulation by diet and nutrition. Nutrition Reviews 73 (6):359–75. doi: 10.1093/nutrit/nuu019.
  • Kavanaugh, D. W., J. O’Callaghan, L. F. Buttó, H. Slattery, J. Lane, M. Clyne, M. Kane, L. Joshi, and R. M. Hickey. 2013. Exposure of Bifidobacterium longum subsp. infantis to milk oligosaccharides increases adhesion to epithelial cells and induces a substantial transcriptional response. PLoS One 8 (6):e67224. doi: 10.1371/journal.pone.0067224.
  • Khodayar-Pardo, P., L. Mira-Pascual, M. C. Collado, and C. Martínez-Costa. 2014. Impact of lactation stage, gestational age and mode of delivery on breast milk microbiota. Journal of Perinatology 34 (8):599–605. doi: 10.1038/jp.2014.47.
  • Kirmiz, N., R. C. Robinson, I. M. Shah, D. Barile, and D. A. Mills. 2018. Milk glycans and their interaction with the infant-gut microbiota. Annual Review of Food Science and Technology 9 (1):429–50. doi: 10.1146/annurev-food-030216-030207.
  • Kitaoka, M. 2012. Bifidobacterial enzymes involved in the metabolism of human milk oligosaccharides. Advances in Nutrition 3 (3):422S–9S. doi: 10.3945/an.111.001420.
  • Kling, P. J., T. M. Sullivan, R. A. Roberts, A. F. Philipps, and O. Koldovský. 1998. Human milk as a potential enteral source of erythropoietin. Pediatric Research 43 (2):216–21. doi: 10.1203/00006450-199802000-00010.
  • Knoop, K. A., and R. D. Newberry. 2018. Goblet cells: Multifaceted players in immunity at mucosal surfaces. Mucosal Immunology 11 (6):1551–7. doi: 10.1038/s41385-018-0039-y.
  • Kong, C., M. Elderman, L. Cheng, B. J. de Haan, A. Nauta, and P. de Vos. 2019. Modulation of intestinal epithelial glycocalyx development by human milk oligosaccharides and non-digestible carbohydrates. Molecular Nutrition & Food Research 63 (17):1900303. doi: 10.1002/mnfr.201900303.
  • Kulinich, A., and L. Liu. 2016. Human milk oligosaccharides: The role in the fine-tuning of innate immune responses. Carbohydrate Research 432:62–70. doi: 10.1016/j.carres.2016.07.009.
  • Kuntz, S., S. Rudloff, and C. Kunz. 2008. Oligosaccharides from human milk influence growth-related characteristics of intestinally transformed and non-transformed intestinal cells. British Journal of Nutrition 99 (3):462–71. doi: 10.1017/S0007114507824068.
  • Kurakevich, E., T. Hennet, M. Hausmann, G. Rogler, and L. Borsig. 2013. Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c + cells through TLR4. Proceedings of the National Academy of Sciences of Sciences 110 (43):17444–9. America, doi: 10.1073/pnas.1306322110.
  • Ladirat, S. E. 2014. Galacto-oligosasaccharides to counter the side effects of antibiotic treatments. https://library.wur.nl/WebQuery/wda/2050554
  • Lawrence, R. M., and R. A. Lawrence. 2004. Breast milk and infection. Clinics in Perinatology 31 (3):501–28. doi: 10.1016/j.clp.2004.03.019.
  • Le Doare, K., and B. Kampmann. 2014. Breast milk and group B streptococcal infection: Vector of transmission or vehicle for protection? Vaccine 32 (26):3128–32. doi: 10.1016/j.vaccine.2014.04.020.
  • Lenoir, D., D. Ruggiero-Lopez, P. Louisot, and M. C. Biol. 1995. Developmental changes in intestinal glycosylation: Nutrition-dependent multi-factor regulation of the fucosylation pathway at weaning time. Biochimica et Biophysica Acta (Bba) - Biomembranes 1234 (1):29–36. doi: 10.1016/0005-2736(94)00254-M.
  • Lewis, D. E., and S. E. Blutt. 2019. Organization of the immune system. In Clinical immunology. doi: 10.1016/B978-0-7020-6896-6.00002-8.
  • Lewis, E. D., C. Richard, B. M. Larsen, and C. J. Field. 2017. The importance of human milk for immunity in preterm infants. Clinics in Perinatology 44 (1):23–47. doi: 10.1016/j.clp.2016.11.008.
  • Lin, A. E., C. A. Autran, S. D. Espanola, L. Bode, and V. Nizet. 2014. Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. Journal of Infectious Diseases 209 (3):389–98. doi: 10.1093/infdis/jit464.
  • Lin, A. E., C. A. Autran, A. Szyszka, T. Escajadillo, M. Huang, K. Godula, A. R. Prudden, G.-J. Boons, A. L. Lewis, K. S. Doran, et al. 2017. Human milk oligosaccharides inhibit growth of group B Streptococcus. Journal of Biological Chemistry 292 (27):11243–9. doi: 10.1074/jbc.M117.789974.
  • Liu, B., Z. Yu, C. Chen, D. E. Kling, and D. S. Newburg. 2012. Human milk mucin 1 and mucin 4 inhibit Salmonella enterica Serovar Typhimurium invasion of human intestinal epithelial cells in vitro. The Journal of Nutrition 142 (8):1504–9. doi: 10.3945/jn.111.155614.
  • Lodge, C., D. Tan, M. Lau, X. Dai, R. Tham, A. Lowe, G. Bowatte, K. Allen, and S. Dharmage. 2015. Breastfeeding and asthma and allergies: A systematic review and meta-analysis. Acta Paediatrica 104:38–53. doi: 10.1111/apa.13132.
  • Lönnerdal, B. 2014. Infant formula and infant nutrition: Bioactive proteins of human milk and implications for composition of infant formulas. American Journal of Clinical Nutrition 99 (3):712S–717S. doi: 10.3945/ajcn.113.071993.
  • Lönnerdal, B. 2016. Human milk: Bioactive proteins/peptides and functional properties. Nestle Nutrition Institute Workshop Series 86:97–107. doi: 10.1159/000442729.
  • Loui, A., E. Eilers, E. Strauss, A. Pohl-Schickinger, M. Obladen, and P. Koehne. 2012. Vascular endothelial growth factor (VEGF) and soluble VEGF receptor 1 (sFlt-1) levels in early and mature human milk from mothers of preterm versus term infants. Journal of Human Lactation 28 (4):522–8. doi: 10.1177/0890334412447686.
  • Macpherson, A. J., M. G. de Agüero, and S. C. Ganal-Vonarburg. 2017. How nutrition and the maternal microbiota shape the neonatal immune system. Nature Reviews Immunology 17 (8):508–17. doi: 10.1038/nri.2017.58.
  • Mäkivuokko, H., S. J. Lahtinen, P. Wacklin, E. Tuovinen, H. Tenkanen, J. Nikkilä, M. Björklund, K. Aranko, A. C. Ouwehand, and J. Mättö. 2012. Association between the ABO blood group and the human intestinal microbiota composition. BMC Microbiology 12 (1):94. doi: 10.1186/1471-2180-12-94.
  • Martens, E. C., M. Neumann, and M. S. Desai. 2018. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nature Reviews Microbiology 16 (8):457–70. doi: 10.1038/s41579-018-0036-x.
  • Martin, C. R., P. R. Ling, and G. L. Blackburn. 2016. Review of infant feeding: Key features of breast milk and infant formula. Nutrients 8 (5):279. doi: 10.3390/nu8050279.
  • Martín, R., M. Olivares, M. L. Marín, L. Fernández, J. Xaus, and J. M. Rodríguez. 2005. Probiotic potential of 3 lactobacilli strains isolated from breast milk. Journal of Human Lactation 21 (1):8–17. doi: 10.1177/0890334404272393.
  • Martini, M.,. F. Salari, and I. Altomonte. 2016. The macrostructure of milk lipids: The fat globules. Critical Reviews in Food Science and Nutrition 56 (7):1209–21. doi: 10.1080/10408398.2012.758626.
  • McGuire, M. K., and M. A. McGuire. 2017. Got bacteria? The astounding, yet not-so-surprising, microbiome of human milk. Current Opinion in Biotechnology 44:63–8. doi: 10.1016/j.copbio.2016.11.013.
  • McLeod, K. H., J. L. Richards, Y. A. Yap, and E. Mariño. 2019. Dietary short chain fatty acids: How the gut microbiota fight against autoimmune and inflammatory diseases. In. Bioactive food as dietary interventions for arthritis and related inflammatory diseases, 139–59. London: Academic Press. doi: 10.1016/b978-0-12-813820-5.00007-6.
  • Meki, A. R. M. A., T. H. Saleem, M. H. Al-Ghazali, and A. A. Sayed. 2003. Interleukins -6, -8 and -10 and tumor necrosis factor-alpha and its soluble receptor I in human milk at different periods of lactation. Nutrition Research 23 (7):845–55. (03)00035-6 doi: 10.1016/S0271-5317(03)00035-6.
  • Molès, J. P., E. Tuaillon, C. Kankasa, A. S. Bedin, N. Nagot, A. Marchant, J. M. McDermid, and P. Van de Perre. 2018. Breastmilk cell trafficking induces microchimerism-mediated immune system maturation in the infant. Pediatric Allergy and Immunology 29 (2):133–43. doi: 10.1111/pai.12841.
  • Mountzouris, K. C., A. L. McCartney, and G. R. Gibson. 2002. Intestinal microflora of human infants and current trends for its nutritional modulation. British Journal of Nutrition 87 (5):405–20. doi: 10.1079/BJN2002563.
  • Mowat, A. M., and W. W. Agace. 2014. Regional specialization within the intestinal immune system. Nature Reviews Immunology 14 (10):667–85. doi: 10.1038/nri3738.
  • Mueller, N. T., E. Bakacs, J. Combellick, Z. Grigoryan, and M. G. Dominguez-Bello. 2015. The infant microbiome development: Mom matters. Trends in Molecular Medicine 21 (2):109–17. doi: 10.1016/j.molmed.2014.12.002.
  • Neu, J., B. Poindexter, A. L. Morrow, and D. S. Newburg. 2019. Human milk oligosaccharide. In Gastroenterology and nutrition, 43–57. doi: 10.1016/B978-0-323-54502-0.00004-9.
  • Newton, R., B. Priyadharshini, and L. A. Turka. 2016. Immunometabolism of regulatory T cells. Nature Immunology 17 (6):618–25. doi: 10.1038/ni.3466.
  • Nijman, R. M., Y. Liu, A. Bunyatratchata, J. T. Smilowitz, B. Stahl, and D. Barile. 2018. Characterization and quantification of oligosaccharides in human milk and infant formula. Journal of Agricultural and Food Chemistry 66 (26):6851–9. doi: 10.1021/acs.jafc.8b01515.
  • Ninkina, N.,. M. S. Kukharsky, M. V. Hewitt, E. A. Lysikova, L. N. Skuratovska, A. V. Deykin, and V. L. Buchman. 2019. Stem cells in human breast milk. Human Cell 32 (3):223–30. doi: 10.1007/s13577-019-00251-7.
  • Okumura, R., and K. Takeda. 2017. Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Experimental & Molecular Medicine 49 (5):e338–e338. doi: 10.1038/emm.2017.20.
  • Palmeira, P., and M. Carneiro-Sampaio. 2016. Immunology of breast milk. Revista da Associação Médica Brasileira 62 (6):584–93. doi: 10.1590/1806-9282.62.06.584.
  • Parigi, S. M., M. Eldh, P. Larssen, S. Gabrielsson, and E. J. Villablanca. 2015. Breast milk and solid food shaping intestinal immunity. Frontiers in Immunology 6 (Jul):415. doi: 10.3389/fimmu.2015.00415.
  • Patel, A. L., and J. H. Kim. 2018. Human milk and necrotizing enterocolitis. Seminars in Pediatric Surgery 27 (1):34–8. doi: 10.1053/j.sempedsurg.2017.11.007.
  • Patki, S., S. Kadam, V. Chandra, and R. Bhonde. 2010. Human breast milk is a rich source of multipotent mesenchymal stem cells. Human Cell 23 (2):35–40. doi: 10.1111/j.1749-0774.2010.00083.x.
  • Pitt, J., M. Chan, C. Gibson, O. Hasselwander, A. Lim, P. Mukerji, R. Mukherjea, A. Myhre, P. Sarela, P. Tenning, et al. 2019. Safety assessment of the biotechnologically produced human-identical milk oligosaccharide 3-Fucosyllactose (3-FL). Food and Chemical Toxicology 134:110818. doi: 10.1016/j.fct.2019.110818.
  • Plaza-Díaz, J., L. Fontana, and A. Gil. 2018. Human milk oligosaccharides and immune system development. Nutrients 10 (8):1038. doi: 10.3390/nu10081038.
  • Puccio, G., P. Alliet, C. Cajozzo, E. Janssens, G. Corsello, N. Sprenger, S. Wernimont, D. Egli, L. Gosoniu, and P. Steenhout. 2017. Effects of infant formula with human milk oligosaccharides on growth and morbidity: A randomized multicenter trial. Journal of Pediatric Gastroenterology and Nutrition 64 (4):624–31. doi: 10.1097/MPG.0000000000001520.
  • Reboldi, A., and J. G. Cyster. 2016. Peyer’s patches: Organizing B-cell responses at the intestinal frontier. Immunological Reviews 271 (1):230–45. doi: 10.1111/imr.12400.
  • Rodríguez-Camejo, C.,. A. Puyol, L. Fazio, A. Rodríguez, E. Villamil, E. Andina, V. Cordobez, H. Díaz, M. Lemos, G. Siré, et al. 2018. Antibody profile of colostrum and the effect of processing in human milk banks: Implications in immunoregulatory properties. Journal of Human Lactation 34 (1):137–47. doi: 10.1177/0890334417706359.
  • Ruiz-Palacios, G. M., L. E. Cervantes, P. Ramos, B. Chavez-Munguia, and D. S. Newburg. 2003. Campylobacter jejuni binds intestinal H(O) antigen (Fucα1, 2Galβ1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. Journal of Biological Chemistry 278 (16):14112–20. doi: 10.1074/jbc.M207744200.
  • Sabha, B. H., F. Alzahrani, H. A. Almehdar, V. N. Uversky, and E. M. Redwan. 2018. Disorder in milk proteins: Lactadherin multifunctionality and structure. Current Protein & Peptide Science 19 (10):983–97. doi: 10.2174/1389203719666180608091849.
  • Salli, K., H. Anglenius, J. Hirvonen, A. A. Hibberd, I. Ahonen, M. T. Saarinen, K. Tiihonen, J. Maukonen, and A. C. Ouwehand. 2019. The effect of 2′-fucosyllactose on simulated infant gut microbiome and metabolites; A pilot study in comparison to GOS and lactose. Scientific Reports 9 (1):13232. doi: 10.1038/s41598-019-49497-z.
  • Santajit, S., and N. Indrawattana. 2016. Mechanisms of antimicrobial resistance in ESKAPE pathogens. BioMed Research International 2016:1–8. doi: 10.1155/2016/2475067.
  • Savel'ev, A. N., T. G. Kanyshkova, A. A. Kulminskaya, V. N. Buneva, E. V. Eneyskaya, M. V. Filatov, G. A. Nevinsky, and K. N. Neustroev. 2001. Amylolytic activity of IgG and sIgA immunoglobulins from human milk. Clinica Chimica Acta 314 (1-2):141–52. (01)00691-X doi: 10.1016/S0009-8981(01)00691-X.
  • Schrezenmeir, J., H. Korhonen, C. Williams, H. S. Gill, and N. Shah. 2000. Foreword. British Journal of Nutrition 84 (S1):1. doi: 10.1017/S0007114500002178.
  • Schwab, C., H. J. Ruscheweyh, V. Bunesova, V. T. Pham, N. Beerenwinkel, and C. Lacroix. 2017. Trophic interactions of infant bifidobacteria and Eubacterium hallii during L-fucose and fucosyllactose degradation. Frontiers in Microbiology 8 (Jan):95. doi: 10.3389/fmicb.2017.00095.
  • Secker, G. A., and N. L. Harvey. 2015. VEGFR signaling during lymphatic vascular development: From progenitor cells to functional vessels. Developmental Dynamics 244 (3):323–331. doi: 10.1002/dvdy.24227.
  • Semba, R. D., and S. E. Juul. 2002. Erythropoietin in human milk: Physiology and role in infant health. Journal of Human Lactation 18 (3):252–261. doi: 10.1177/089033440201800307.
  • Shiou, S. R., Y. Yu, S. Chen, M. J. Ciancio, E. O. Petrof, J. Sun, and E. C. Claud. 2011. Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis. Journal of Biological Chemistry 286 (14):12123–12132. doi: 10.1074/jbc.M110.154625.
  • Siafakas, C. G., F. Anatolitou, R. D. Fusunyan, W. A. Walker, and I. R. Sanderson. 1999. Vascular endothelial growth factor (VEGF) is present in human breast milk and its receptor is present on intestinal epithelial cells. Pediatric Research 45 (5):652–657. doi: 10.1203/00006450-199905010-00007.
  • Sitarik, A. R., K. R. Bobbitt, S. L. Havstad, K. E. Fujimura, A. M. Levin, E. M. Zoratti, H. Kim, K. J. Woodcroft, G. Wegienka, D. R. Ownby, et al. 2017. Breast milk transforming growth factor β is associated with neonatal gut microbial composition. Journal of Pediatric Gastroenterology and Nutrition 65 (3):e60–e67. doi: 10.1097/MPG.0000000000001585.
  • Sprenger, G. A., F. Baumgärtner, and C. Albermann. 2017. Production of human milk oligosaccharides by enzymatic and whole-cell microbial biotransformations. Journal of Biotechnology 258:79–91. doi: 10.1016/j.jbiotec.2017.07.030.
  • Tailford, L. E., E. H. Crost, D. Kavanaugh, and N. Juge. 2015. Mucin glycan foraging in the human gut microbiome. Frontiers in Genetics 6 (Feb):81. doi: 10.3389/fgene.2015.00081.
  • Tamburini, S., N. Shen, H. C. Wu, and J. C. Clemente. 2016. The microbiome in early life: Implications for health outcomes. Nature Medicine 22 (7):713–722. doi: 10.1038/nm.4142.
  • Telang, S. 2018. Lactoferrin: A critical player in neonatal host defense. Nutrients 10 (9):1228. doi: 10.3390/nu10091228.
  • Tezuka, H., and T. Ohteki. 2019. Regulation of IgA production by intestinal dendritic cells and related cells. Frontiers in Immunology 10:1891. doi: 10.3389/fimmu.2019.01891.
  • Thomas, P. G., M. R. Carter, O. Atochina, A. A. Da’Dara, D. Piskorska, E. McGuire, and D. A. Harn. 2003. Maturation of dendritic cell 2 phenotype by a helminth glycan uses a toll-like receptor 4-dependent mechanism. The Journal of Immunology 171 (11):5837–5841. doi: 10.4049/jimmunol.171.11.5837.
  • Thomson, P., D. A. Medina, and D. Garrido. 2018. Human milk oligosaccharides and infant gut bifidobacteria: Molecular strategies for their utilization. Food Microbiology 75:37–46. doi: 10.1016/j.fm.2017.09.001.
  • Thurl, S., M. Munzert, G. Boehm, C. Matthews, and B. Stahl. 2017. Systematic review of the concentrations of oligosaccharides in human milk. Nutrition Reviews 75 (11):920–933. doi: 10.1093/nutrit/nux044.
  • Thurl, S., M. Munzert, J. Henker, G. Boehm, B. Müller-Werner, J. Jelinek, and B. Stahl. 2010. Variation of human milk oligosaccharides in relation to milk groups and lactational periods. British Journal of Nutrition 104 (9):1261–1271. doi: 10.1017/S0007114510002072.
  • Torow, N., B. J. Marsland, M. W. Hornef, and E. S. Gollwitzer. 2017. Neonatal mucosal immunology. Mucosal Immunology 10 (1):5–17. doi: 10.1038/mi.2016.81.
  • Toscano, M., R. De Grandi, E. Grossi, and L. Drago. 2017. Role of the human breast milk-associated microbiota on the newborns’ immune system: A mini review. Frontiers in Microbiology 8 (Oct):2100. doi: 10.3389/fmicb.2017.02100.
  • Townsend, S. D. 2019. Human milk oligosaccharides: Defense against pathogens. Breastfeeding Medicine 14 (S1):S-5–S6. doi: 10.1089/bfm.2019.0039.
  • Triantis, V., L. Bode, and J. R. J. van Neerven. 2018. Immunological effects of human milk oligosaccharides. Frontiers in Pediatrics 6:190. doi: 10.3389/fped.2018.00190.
  • Turfkruyer, M., and V. Verhasselt. 2015. Breast milk and its impact on maturation of the neonatal immune system. Current Opinion in Infectious Diseases 28 (3):199–206. doi: 10.1097/QCO.0000000000000165.
  • Urbaniak, C., M. Angelini, G. B. Gloor, and G. Reid. 2016. Human milk microbiota profiles in relation to birthing method, gestation and infant gender. Microbiome 4 (1):1. doi: 10.1186/s40168-015-0145-y.
  • Van De Perre, P. 2003. Transfer of antibody via mother’s milk. Vaccine 21 (24):3374–3376. (03)00336-0 doi: 10.1016/S0264-410X(03)00336-0.
  • van den Elsen, L. W. J., J. Garssen, R. Burcelin, and V. Verhasselt. 2019. Shaping the gut microbiota by breastfeeding: The gateway to allergy prevention? Frontiers in Pediatrics 7 (FEB):47. doi: 10.3389/fped.2019.00047.
  • Vandenplas, Y., B. Berger, V. Carnielli, J. Ksiazyk, H. Lagström, M. Sanchez Luna, N. Migacheva, J.-M. Mosselmans, J.-C. Picaud, M. Possner, et al. 2018. Human milk oligosaccharides: 2’-fucosyllactose (2’-FL) and lacto-n-neotetraose (LNnT) in infant formula. Nutrients 10 (9):1161. doi: 10.3390/nu10091161.
  • Vass, R. A., A. Kemeny, T. Dergez, T. Ertl, D. Reglodi, A. Jungling, and A. Tamas. 2019. Distribution of bioactive factors in human milk samples. International Breastfeeding Journal 14 (1):9. doi: 10.1186/s13006-019-0203-3.
  • Vasta, G. R. 2012. Galectins as pattern recognition receptors: Structure, function, and evolution. Advances in Experimental Medicine and Biology 946:21–36. doi: 10.1007/978-1-4614-0106-3_2.
  • Victora, C. G., R. Bahl, A. J. D. Barros, G. V. A. França, S. Horton, J. Krasevec, S. Murch, M. J. Sankar, N. Walker, and N. C. Rollins. 2016. Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. The Lancet 387 (10017):475–490. (15)01024-7 doi: 10.1016/S0140-6736(15)01024-7.
  • Vieira Borba, V., K. Sharif, and Y. Shoenfeld. 2018. Breastfeeding and autoimmunity: Programing health from the beginning. American Journal of Reproductive Immunology 79 (1):e12778. doi: 10.1111/aji.12778.
  • Vojdani, A. 2015. Oral tolerance and its relationship to food immunoreactivities. Alternative Therapies in Health and Medicine 21:23–32. http://www.ncbi.nlm.nih.gov/pubmed/25599183.
  • Wagner, C. L., S. N. Taylor, and D. Johnson. 2008. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clinical Reviews in Allergy & Immunology 34 (2):191–204. doi: 10.1007/s12016-007-8032-3.
  • Wang, C., M. Zhang, H. Guo, J. Yan, F. Liu, J. Chen, Y. Li, and F. Ren. 2019. Human milk oligosaccharides protect against necrotizing enterocolitis by inhibiting intestinal damage via increasing the proliferation of crypt cells. Molecular Nutrition & Food Research 63 (18):1900262. doi: 10.1002/mnfr.201900262.
  • Wickramasinghe, S., A. R. Pacheco, D. G. Lemay, and D. A. Mills. 2015. Bifidobacteria grown on human milk oligosaccharides downregulate the expression of inflammation-related genes in Caco-2 cells. BMC Microbiology 15 (1):172. doi: 10.1186/s12866-015-0508-3.
  • Witkowska-Zimny, M., and E. Kaminska-El-Hassan. 2017. Cells of human breast milk. Cellular & Molecular Biology Letters 22 (1):11. doi: 10.1186/s11658-017-0042-4.
  • Wu, R. Y., B. Li, Y. Koike, P. Määttänen, H. Miyake, M. Cadete, K. C. Johnson-Henry, S. R. Botts, C. Lee, T. R. Abrahamsson, et al. 2018. Human milk oligosaccharides increase mucin expression in experimental necrotizing enterocolitis. Molecular Nutrition & Food Research 63 (3):1800658–11. doi: 10.1002/mnfr.201800658.