Immune factors of human breast milk and their role in infant protection

Breastfeeding exerts a positive long-term impact on child health, reducing the risk of both infectious and non-infectious diseases. Human milk contains a range of bioactive components that determine its overall immunological activity. Immunoglobulins are unique constituents of breast milk and exert multifaceted effects that promote the development of local mucosal protection as well as an adequate systemic immune response. Immunoglobulins play a key role in infant immune defense, substantially influencing susceptibility to infectious diseases. This effect is mediated by their ability to neutralize pathogens and prevent their penetration, thereby forming the newborn’s first line of defense. Human breast milk stem cells possess self-renewal capacity and multilineage differentiation potential. Numerous studies indicate that stem cells can enter the infant’s body during breastfeeding, playing a crucial role in the development of various organs, tissues, and the nervous system. The role of breast milk exosomes in immune cell activation and differentiation, the development of antigen tolerance, and the establishment of immunological mechanisms is being investigated. Of particular interest is the biologically active breast milk component lactopontin, which has immunoregulatory, antimicrobial, anti-inflammatory, and proliferative effects, thereby supporting neonatal immunogenesis. The protein-lipid complex HAMLET, with specific and broad bactericidal and oncolytic activity, is a promising biological agent for the development of novel approaches to combating infections and cancer. Further research should focus on detailed investigation of the mechanisms of action of each breast milk component. This will enable the development of optimal strategies for the prevention and treatment of various diseases.

1. Zaharova I.N., Sugyan N.G., Orobinskaya Ya.V. Lactation dominant: How does a woman make her choice? Pediatriya. Consilium Medicum. 2025; 2:114–119 (in Russ.). DOI:10.26442/26586630.2025.2.203341.

2. Hauck F.R, Thompson J.M., Tanabe K.O., Moon R.Y., Vennemann M.M. Breastfeeding and reduced risk of sudden infant death syndrome: a meta-analysis. Pediatrics. 2011; 128(1): 103–10. DOI: 10.1542/peds.2010-3000

3. Rudant J., Lightfoot T., Urayama K.Y., Petridou E., Dockerty J.D., Magnani C. et al. Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a Childhood Leukemia International Consortium study. Am J Epidemiol. 2015;181(8):549–62. DOI: 10.1093/aje/kwu298

4. Su Q., Sun X., Zhu L., Yan Q., Zheng P., Mao Y. et al. Breastfeeding and the risk of childhood cancer: a systematic review and dose-response meta-analysis. BMC Med. 2021; 19(1): 90. DOI: 10.1186/s12916-021-01950-5

5. Zaharova I.N., Sugyan N.G., Orobinskaya Ya.V. The mysterious bifidus factor. Pediatriya. Consilium Medicum. 2025; 2: 125–130 (in Russ.). DOI: 10.26442/26586630.2025.2.203333

6. Roopenian D.C., Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007; 7(9): 715–25. DOI: 10.1038/nri2155

7. Laouar A. Maternal Leukocytes and Infant Immune Programming during Breastfeeding. Trends Immunol. 2020; 41(3): 225–239. DOI: 10.1016/j.it.2020.01.005

8. Campo J.J., Seppo A.E., Randall A.Z., Pablo J., Hung C., Teng A. et al. Human milk antibodies to global pathogens reveal geographic and interindividual variations in IgA and IgG. J Clin Invest. 2024; 134(15): e168789. DOI: 10.1172/JCI168789

9. Rio-Aige K., Azagra-Boronat I., Castell M., Selma-Royo M., Collado M.C., Rodríguez-Lagunas M.J. et al. The Breast Milk Immunoglobulinome. Nutrients. 2021; 13(6): 1810. DOI: 10.3390/nu13061810

10. Divakara N., Dempsey Z., Saraswati C., Garssen J., Silva D., Keelan J.A. et al. Effect of maternal prebiotic supplementation on human milk immunological composition: Insights from the SYMBA study. Pediatr Allergy Immunol. 2024; 35(9): e14226. DOI: 10.1111/pai.14226

11. Perruzza L., Rezzonico Jost T., Raneri M., Gargari G., Palatella M., De Ponte Conti B. et al. Protection from environmental enteric dysfunction and growth improvement in malnourished newborns by amplification of secretory IgA. Cell Rep Med. 2024; 5(7): 101639. DOI: 10.1016/j.xcrm.2024.101639

12. Verhasselt V., Tellier J., Carsetti R., Tepekule B. Antibodies in breast milk: Pro-bodies designed for healthy newborn development. Immunol Rev. 2024; 328(1): 192–204. DOI: 10.1111/imr.13411

13. Cregan M.D., Fan Y., Appelbee A., Brown M.L., Klopcic B., Koppen J. et al. Identification of nestin-positive putative mammary stem cells in human breastmilk. Cell Tissue Res. 2007; 329(1): 129–36. DOI: 10.1007/s00441-007-0390-x

14. Hassiotou F., Geddes D.T. Immune cell-mediated protection of the mammary gland and the infant during breastfeeding. Adv Nutr. 2015; 6(3): 267–75. DOI: 10.3945/an.114.007377

15. Faa G., Pichiri G., Coni P., Dessì A., Fraschini M., Fanos V. They will be famous: Multipotent stem cells in breast milk. World J Clin Pediatr. 2025; 14(2): 101080. DOI: 10.5409/wjcp.v14.i2.101080

16. Thomas E., Zeps N., Rigby P., Hartmann P. Reactive oxygen species initiate luminal but not basal cell death in cultured human mammary alveolar structures: a potential regulator of involution. Cell Death Dis. 2011; 2(8): e189. DOI: 10.1038/cddis.2011.69

17. Goudarzi N., Shabani R., Ebrahimi M., Baghestani A., Dehdashtian E., Vahabzadeh G. et al. Comparative phenotypic characterization of human colostrum and breast milk-derived stem cells. Hum Cell. 2020; 33(2): 308–317. DOI: 10.1007/s13577-019-00320-x

18. Hassiotou F., Beltran A., Chetwynd E., Stuebe A.M., Twigger A.J., Metzger P. et al. Breastmilk is a novel source of stem cells with multilineage differentiation potential. Stem Cells. 2012; 30(10): 2164–74. DOI: 10.1002/stem.1188

19. Cabinian A., Sinsimer D., Tang M., Zumba O., Mehta H., Toma A. et al. Transfer of Maternal Immune Cells by Breastfeeding: Maternal Cytotoxic T Lymphocytes Present in Breast Milk Localize in the Peyer’s Patches of the Nursed Infant. PLoS One. 2016; 11(6): e0156762. DOI: 10.1371/journal.pone.0156762

20. Alsaweed M., Lai C.T., Hartmann P.E., Geddes D.T., Kakulas F. Human Milk Cells Contain Numerous miRNAs that May Change with Milk Removal and Regulate Multiple Physiological Processes. Int J Mol Sci. 2016; 17(6): 956. DOI: 10.3390/ijms17060956

21. Aydın M.Ş, Yiğit E.N., Vatandaşlar E., Erdoğan E., Öztürk G. Transfer and Integration of Breast Milk Stem Cells to the Brain of Suckling Pups. Sci Rep. 2018; 8(1): 14289. DOI: 10.1038/s41598-018-32715-5

22. He L., Sun Z., Zhao C., Sun H. Breast Milk Stem Cells in the Treatment of Neonatal Diseases. Curr Stem Cell Res Ther. 2025; 20(5): 538–545. DOI: 10.2174/011574888X304788240526190336

23. Keller T., Körber F., Oberthuer A., Schafmeyer L., Mehler K., Kuhr K. et al. Intranasal breast milk for premature infants with severe intraventricular hemorrhage-an observation. Eur J Pediatr. 2019; 178(2): 199–206. DOI: 10.1007/s00431-018-3279-7

24. Ahn S.Y., Chang Y.S., Sung S.I., Park W.S. Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial. Stem Cells Transl Med. 2018; 7(12): 847–856. DOI: 10.1002/sctm.17-0219

25. Chutipongtanate S., Morrow A.L., Newburg D.S. Human Milk Extracellular Vesicles: A Biological System with Clinical Implications. Cells. 2022; 11(15): 2345. DOI: 10.3390/cells11152345

26. Golan-Gerstl R., Reif S. Extracellular vesicles in human milk. Curr Opin Clin Nutr Metab Care. 2022; 25(3): 209–215. DOI: 10.1097/MCO.0000000000000834

27. Manca S., Upadhyaya B., Mutai E., Desaulniers A.T., Cederberg R.A, White B.R. et al. Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns. Sci Rep. 2018; 8(1): 11321. DOI: 10.1038/s41598-018-29780-1

28. Kim E.B., Song J.H., Le L.N., Kim H., Koh J.W., Seo Y. et al. Characterization of exosomal microRNAs in preterm infants fed with breast milk and infant formula. Front Nutr. 2024;11:1339919. DOI: 10.3389/fnut.2024.1339919

29. Kim K.M., Choi J.W. Associations between breastfeeding and cognitive function in children from early childhood to school age: a prospective birth cohort study. Int Breastfeed J. 2020 Sep 29;15(1):83. DOI: 10.1186/s13006-020-00326-4

30. Farpour-Lambert N.J., Ells L.J., Martinez de Tejada B., Scott C. Obesity and Weight Gain in Pregnancy and Postpartum: an Evidence Review of Lifestyle Interventions to Inform Maternal and Child Health Policies. Front Endocrinol (Lausanne). 2018; 9: 546. DOI: 10.3389/fendo.2018.00546

31. Elliott R.O., He M. Unlocking the Power of Exosomes for Crossing Biological Barriers in Drug Delivery. Pharmaceutics. 2021; 13(1): 122. DOI: 10.3390/pharmaceutics13010122

32. Cristóbal-Cañadas D., Parrón-Carrillo R., Parrón-Carreño T. Exosomes in Breast Milk: Their Impact on the Intestinal Microbiota of the Newborn and Therapeutic Perspectives for High-Risk Neonates. Int J Mol Sci. 2025; 26(7): 3421. DOI: 10.3390/ijms26073421

33. Melnik B.C., Stremmel W., Weiskirchen R., John S.M., Schmitz G. Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development. Biomolecules. 2021; 11(6): 851. DOI: 10.3390/biom11060851

34. Pantazi A.C., Balasa A.L., Mihai C.M., Chisnoiu T., Lupu V.V., Kassim M.A.K. et al. Development of Gut Microbiota in the First 1000 Days after Birth and Potential Interventions. Nutrients. 2023 Aug 20;15(16):3647. DOI: 10.3390/nu15163647

35. Peng W., Han J., Li S., Zhang L., Yang C., Guo J. et al. The Association of Human Milk Feeding With Short-Term Health Outcomes Among Chinese Very/Extremely Low Birth Weight Infants. J Hum Lact. 2022; 38(4): 670–677. DOI: 10.1177/08903344221078237

36. Rezai T., Fell-Hakai S., Guleria S., Toldi G. The Role of Breast Milk Cell-Free DNA in the Regulation of the Neonatal Immune Response. Nutrients. 2024; 16(24): 4373. DOI: 10.3390/nu16244373

37. Tong L., Zhang S., Liu Q., Huang C., Hao H., Tan M.S. et al. Milk-derived extracellular vesicles protect intestinal barrier integrity in the gut-liver axis. Sci Adv. 2023; 9(15): eade5041. DOI: 10.1126/sciadv.ade5041

38. Di S.J., Cui X.W., Liu T.J., Shi Y.Y. Therapeutic potential of human breast milk-derived exosomes in necrotizing enterocolitis. Mol Med. 2024; 30(1): 243. DOI: 10.1186/s10020-024-01010-7

39. Zhu J., Yu X., Wang Y., Bai S., Lai J., Tong X. et al. Longitudinal changes of lactopontin (milk osteopontin) in term and preterm human milk. Front Nutr. 2022; 9: 962802. DOI: 10.3389/fnut.2022.962802

40. West C.E., Kvistgaard A.S., Peerson J.M., Donovan S.M., Peng Y.M., Lönnerdal B. Effects of osteopontin-enriched formula on lymphocyte subsets in the first 6 months of life: a randomized controlled trial. Pediatr Res. 2017; 82(1): 63– 71. DOI: 10.1038/pr.2017.77

41. Lyu Y., Wen X., Hu J., Huang Y., Qiao Y., Zhang J. Compendium of lactopontin: Molecular structure, manufacturing process and biological functions. Food Bioscience. 2025; 65(8): 106155. DOI: /10.1016/j.fbio.2025.106155

42. Ren S., Hui Y., Goericke-Pesch S., Pankratova S., Kot W., Pan X. et al. Gut and immune effects of bioactive milk factors in preterm pigs exposed to prenatal inflammation. Am J Physiol Gastrointest Liver Physiol. 2019; 317(1): G67-G77. DOI: 10.1152/ajpgi.00042.2019

43. Vansarla G., Håkansson A.P., Bergenfelz C. HAMLET a human milk protein-lipid complex induces a pro-inflammatory phenotype of myeloid cells. Eur J Immunol. 2021; 51(4): 965–977. DOI: 10.1002/eji.202048813

44. Chetta K.E., Newton D.A., Wagner C.L., Baatz J.E. Free Fatty Acid and α-Lactalbumin-Oleic Acid Complexes in Preterm Human Milk Are Cytotoxic to Fetal Intestinal Cells in vitro. Front Nutr. 2022; 9: 918872. DOI:10.3389/fnut.2022.918872

45. Chetta K.E., Forconi M., Newton D.A., Wagner C.L., Baatz J.E. Corrigendum to “HAMLET in human milk is resistant to digestion and carries essential free long chain polyunsaturated fatty acids and oleic acid”. Food Chem. 2024; 438: 138126. DOI: 10.1016/j.foodchem.2023.138126

46. Svanborg, C., Aits S., Brest P., Gustafsson L., Mok K., Moreillhon C. et al. HAMLET, a tumoricidal molecular complex from human milk. BMC Proc. 2009; 3(5): S11. DOI: 10.1186/1753-6561-3-S5-S11