Human Breast Milk: Bioactive Components, from Stem Cells to Health Outcomes
Purpose of Review
Breast milk (BM) is a peculiar fluid owing unique properties and resulting the ideal food during early neonatal period. As widely known, it can improve the outcome of both neonate and lactating mother, influencing their whole life. BM is characterized by several beneficial components; among these, a great role is played by BM own and specific microbiome, deeply investigated in many studies. Moreover, the use of metabolomics in BM analysis allowed a better characterization of its metabolic pathways that vary according to lactation stage and neonatal gestational age. The aim of this review is to describe growth factors, cytokines, immunity mediators, and stem cells (SCs) contained in BM and investigate their functions and effects on neonatal outcome, especially focusing on immuno- and neurodevelopment.
We evaluated recent and updated literature on this field. The article that we analyzed to write this review have been found in MEDLINE using breast milk-derived stem cells, biofactors, growth factors, breastfeeding-related outcomes, neurodevelopment, and neonatal immunological system as keywords. Discovering and characterizing BM components could result very useful to clarify the pathophysiology of their influence on neonatal growth and even to improve artificial formulations’ composition. Moreover, since SCs abilities and their involvement in the development of several diseases, they could help to discover specific targets for new therapies.
It could be useful to characterize BM-derived SC markers, properties, and variations during lactation stages, to understand their potential role in therapeutic applications, since they could be noninvasively isolated from BM. More studies will help to describe more in detail the characteristics of mother-to-child communication through breastfeeding and its potential role in the next future.
KeywordsBreastfeeding Colostrum Growth factors Stem cells Neonatal outcome Regenerative medicine
Brain-derived neurotrophic factor
Breast milk-derived stem cells
Body mass index
Chronic lung disease
Cluster of differentiation
Central nervous system
Epidermal growth factor
Epidermal growth factor
Extremely low birth weight
Fibroblast growth factors
Granulocyte-colony stimulating factor
Glial cell line-derived neurotrophic factor
Heparin-binding epidermal growth factor
Hepatocyte growth factor
Human milk oligosaccharides
Insulin growth factors
Milk fat globule membrane
Mesenteric lymph nodes
Mesenchymal stem cells
Neonatal intensive care unit
Octamer-binding transcription factor 4
Retinopathy of prematurity
Small for GA
Sex determining region Y-box
tdTomato + cells
Transforming growth factor
Tumor necrosis factors
Vascular endothelial growth factor
Very low birth weight
- XDH/XO or XOR
VF, DGP, and FB conceptualized the structure of the review. FB provided the literature update and wrote the initial version of the manuscript. VF and DGB critically revised, modified, and approved the work. Finally, all authors approved the final version of the manuscript.
Compliance with Ethical Standards
Conflict of Interest
Flaminia Bardanzellu, Diego Giampietro Peroni, and Vassilios Fanos declare they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 2.Hassiotou F, Heath B, Ocal O, Filgueira L, Geddes D, Hartmann P, et al. Breastmilk stem cell transfer from mother to neonatal organs. FASEB J. 2014;28:216.4.Google Scholar
- 10.German BJ, Smilowitz JT, Lebrilla CB. Metabolomics and milk: the development of the microbiota in breastfed infants. In: Kochhar S, Martin F-P, editors. Metabonomics and gut microbiota in nutrition and disease (Molecular and integrative toxicology). London: Humana press (Springer); 2015. p. 147–67.CrossRefGoogle Scholar
- 13.•• Bardanzellu F, Fanos V, Strigini FAL, Artini PG, Peroni DG. Human breast milk: exploring the linking ring among emerging components. Front Pediatr. 2018;6:215. https://doi.org/10.3389/fped.2018.00215Paper summarizing the last evidence regarding metabolomics and microbiomics in human breast milk.
- 41.Ruiz L, Espinosa-Martos I, García-Carral C, Manzano S, McGuire MK, Meehan CL, et al. What’s normal? Immune profiling of human milk from healthy women living in different geographical and socioeconomic settings. Front Immunol. 2017;8:696. https://doi.org/10.3389/fimmu.2017.00696.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Moles L, Manzano S, Fernández L, Montilla A, Corzo N, Ares S, et al. Bacteriological, biochemical and immunological properties of colostrum and mature milk from mothers extremely preterm infants. J Pediatr Gastroenterol Nutr. 2015;60:120–6. https://doi.org/10.1097/MPG.0000000000000560.CrossRefPubMedGoogle Scholar
- 43.Schack-Nielsen L, Michaelsen KF. Breastfeeding and future health. Curr Opin Clin Nutr Metab Care. 2006;9:289–96. https://doi.org/10.1097/01.mco.0000222114.84159.79.CrossRefPubMedGoogle Scholar
- 46.Siafakas C, Anatolitou F, Fusunyan RD, Walker WA, Sanderson IR. Vascular endothelial growth factor (VEGF) is present in human breast milk and its receptor is present on intestinal epithelial cells. Pediatr Res. 1999;45:652–7. https://doi.org/10.1203/00006450-199905010-00007.CrossRefPubMedGoogle Scholar
- 48.Collado MC, Santaella M, Mira-Pascual L, Martinez-Arias E, Khodayar-Pardo P, Ros G, et al. Longitudinal study of cytokine expression, lipid profile and neuronal growth factors in human breast milk from term and preterm. Nutrients. 2015;19:8577–91. https://doi.org/10.3390/nu7105415.CrossRefGoogle Scholar
- 50.Torres-Castro P, Abril-Gil M, Rodríguez-Lagunas MJ, Castell M, Perez-Cano FJ, Franch A. TGF-Beta 2, EGF, and FGF21 growth factors present in breast milk promote mesenteric lymph node lymphocytes maturation in suckling rats. Nutrients. 2018;10:E1171. https://doi.org/10.3390/nu10091171.CrossRefPubMedGoogle Scholar
- 51.Young BE, Levek C, Reynolds RM, Rudolph MC, MacLean P, Hernandez PL, et al. Bioactive components in human milk are differentially associated with rates of lean and fat mass deposition in infants of mothers with normal vs. elevated BMI. Pediatr Obes. 2018;13:598–606. https://doi.org/10.1111/ijpo.12394.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Murphy J, Pfeiffer RM, Lynn BCD, Caballero AI, Browne EP, Punska EC, et al. Pro-inflammatory cytokines and growth factors in human milk: an exploratory analysis of racial differences to inform breast cancer etiology. Breast Cancer Res Treat. 2018;172:209–19. https://doi.org/10.1007/s10549-018-4907-7.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.• Sitarik AR, Bobbitt KR, Havstad SL, Fujimura KE, Levin AM, Zoratti EM, et al. Breast milk TGF beta is associated with neonatal gut microbial composition. J Pediatr Gastroenterol Nutr. 2018;65:e60–7. https://doi.org/10.1097/MPG.0000000000001585Interesting study investigating the role of BM TGFβ1, TGFβ2, and IL-10 in shaping the neonatal gut microbiome in 52 mother-child couples, modulating neonatal outcome and including neonatal immune system development. CrossRefGoogle Scholar
- 54.Abstract from the Academy of breastfeeding medicine 20th Annual international meeting Los Angeles California. Breastfeed Med. 2015;10:1–20. https://doi.org/10.1089/bfm.2015.29009.Abstracts.
- 60.Nunes M, da Silva CH, Bosa VL, Rombaldi Bernardi J, Ribas Werlang IC, Zubaran GM, et al. Could a remarkable decrease in leptin and insulin levels from colostrums to mature milk contribute to early growth catch-up of SGA infants? BMC Pregnancy Childbirth. 2017;17:410. https://doi.org/10.1186/s12884-017-1593-0.CrossRefPubMedPubMedCentralGoogle Scholar
- 83.• Briere CE, McGrath JM, Jensen T. Breast milk stem cells. Paper presented at Pediatric Academic Society Baltimora. 2016. This article summarizes the current evidence regarding breast milk derived stem cells (BMDSCs), especially in relation to different stage of lactation, expressed markers and lineages. Google Scholar
- 86.•• Briere CE, Jensen T, Young EE MGJM, Finck C. Stem-like cell characteristics from breast milk of mothers with preterm infants as compared to mothers with term infants. Breast Feed Med. 2017;12:174–9. https://doi.org/10.1089/bfm.2017.0002Study demonstrating that SCs content differs in BM from mothers delivering term and preterm neonates. Comparing samples from preterm neonates (born before than 37 weeks of GA) with full term samples, a different percentage and a variable expression of SCs ‘markers was highlighted. CrossRefGoogle Scholar
- 90.Li CY, Wu XY, Tong JB, Yang XX, Zhao JL, Zheng QF, et al. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther. 2015;6:55. https://doi.org/10.1186/s13287-015-0066-5.CrossRefPubMedPubMedCentralGoogle Scholar
- 100.•• Jimènez BC, Parada YA, Marin AV, de Pipaon Marcos MS. Beneficios a corto, medio y largo plazo de la ingesta de leche humana en recien nacidos de muy bajo peso. Short, medium and long term benefits of human milk intake in very low birth weight infants. Nutr Hosp. 2017;34:5. https://doi.org/10.20960/nh.1014Study demonstrating a better neurodevelopmental outcome at two years and a better score in the global and verbal cognitive area at five years of age in a population of 152 very low birth weight (VLBW) neonates assuming BM since the first weeks of life.
- 103.Roze JC, Darmaun D, Boquien CY, Flamant C, Picaud JC, Savagner C, et al. The apparent breastfeeding paradox in very preterm infants: relationship between breast feeding, early weight gain and neurodevelopment based on results from two cohorts. EPIPAGE and LIFT. BMJ Open. 2012;2:e000834. https://doi.org/10.1136/bmjopen-2012-000834.CrossRefPubMedPubMedCentralGoogle Scholar
- 105.Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC, et al. Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007;120:e953–9. https://doi.org/10.1542/peds.2006-3227.CrossRefPubMedGoogle Scholar
- 107.Belfort MB, Anderson PJ, Nowak V, Lee KJ, Molesworth C, Thompson DK, et al. A breast milk feeding, brain development, and neurocognitive outcomes: a 7-year longitudinal study in infants born at less than 30 weeks' gestation. J Pediatr. 2016;177:133–139e1. https://doi.org/10.1016/j.jpeds.2016.06.045.CrossRefPubMedPubMedCentralGoogle Scholar
- 113.Wang Q, Cui Q, Yan C. The effect of supplementation of long-chain polyunsaturated fatty acids during lactation on neurodevelopmental outcomes of preterm infant from infancy to school age: a systematic review and meta-analysis. Pediatr Neurol. 2016;59:54–61. https://doi.org/10.1016/j.pediatrneurol.2016.02.017.CrossRefPubMedGoogle Scholar
- 116.O’Connor DL, Jacobs J, Hall R, Adamkin D, Auestad N, Castillo M, et al. Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. J Pediatr Gastroenterol Nutr. 2003;37:437–46.CrossRefGoogle Scholar
- 126.Alsaweed M, Hartmann P, Geddes D, Foteini K. MicroRNAs in breastmilk and the lactating breast: potential immunoprotectors and developmental regulators for the infant and the mother. Int J Environ Res Public Health. 2015;12:13981–4020. https://doi.org/10.3390/ijerph12111398.CrossRefPubMedPubMedCentralGoogle Scholar