How Human Milk Helps Build Baby Brains

How Human Milk Helps Build Baby Brains

Categories: Leader Today

The bioactive role of extra-nutritive components of human milk on cognitive development

Audrey Humphries(1), Nneoma Edokobi(1), Catherine Lavallee(1), and Brittany Howell Ph.D.(2,3)

(1) Virginia Tech Carilion School of Medicine (VTCSOM), Roanoke, Virginia
(2) Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia
(3) Department of Human Development and Family Science, Virginia Tech, Blacksburg, Virginia

Milk is a major contributor to optimal brain development and improved cognitive performance later in life (Shafai et al. 2018), but it is still unclear which components are responsible. Human milk not only contains the ideal nutrient composition (water, fat, carbohydrates, and protein) to support an infant’s basic nutritional needs, but it also contains extra-nutritive components that may play additional indirect, yet still active, roles in an infant’s growth (Hamosh 2001), including brain development (Petryk, Harris, and Jongbloed 2007).
There is currently little research that directly assesses the relationships between breastmilk’s extra-nutritive bioactive components and infant neurodevelopment. However, several studies present evidence that these factors influence infant gut maturation, especially with respect to the gut’s immunologic properties and microbiome (bacteria and other microorganisms in the infant gut) colonization (Thai and Gregory 2020; McElroy and Weitkamp 2011; Palmeira et al. 2016). At first, it may seem odd to think that an infant’s intestinal health may give us insight to an infant’s brain development. Yet in the last twenty years, there has been increasing support for the microbiota-gut-brain axis hypothesis. This theory, backed by an impressive amount of research, supports the idea that the human gut’s commensal (beneficial) bacteria, epithelial cells, nerve cells, immune cells, and other important local mediators in the intestinal tract can communicate with and influence the brain (Montiel-Castro et al. 2013). With this amount of supporting literature on the gut-brain axis hypothesis (Niemarkt et al. 2019; Anderson et al. 2017; Gao et al. 2019; Jena et al. 2020), we find it reasonable to consider that some types of extra-nutritive components in human milk have the potential to indirectly and/or directly impact infant brain development by influencing the infant gut.

Extra-nutritive agents in human milk

Three extra-nutritive agents in human milk of particular interest in neurodevelopmental research are cortisol, oligosaccharides, and growth factors.

The role of cortisol

Cortisol is a vital glucocorticoid hormone (a type of steroid hormone) that is produced by the adrenal gland. Physiologically, cortisol acts on almost every organ system in the body, helping to regulate the body’s immune responses and healing capability, appetite and glucose metabolism, blood pressure, and, most notably, the stress response. Although a significant fraction of a mother’s serum (found in blood) cortisol ends up in her breastmilk (Patacchioli et al. 1992; Hollanders et al. 2017), its defined function in milk is still not fully understood. Cortisol’s biochemical structure allows it to cross both the intestinal barrier to enter the bloodstream (Angelucci et al. 1985; Yeh, Yeh, and Holt 1989) and the blood-brain barrier (Pariante et al. 2004; Angelucci et al. 1985), making it an ideal candidate as a biochemical messenger during critical periods of infant brain development.

Currently, there are studies demonstrating that breastmilk cortisol may influence an infant’s temperament (Hinde et al. 2015; Sullivan et al. 2011; Grey et al. 2013), social behavior, and cognitive functioning (Dettmer et al. 2018). This is not surprising, as the hippocampus, an important center in the brain for learning, memory development, and memory retrieval, has a high concentration of glucocorticoid receptors (Koning et al. 2019; de Kloet, Joëls, and Holsboer 2005). Additionally, high cortisol levels are thought to impact not only human behavior and cognitive functioning, but also the volume of the hippocampus in various pathological states (Lupien et al. 1998; Brown, Varghese, and McEwen 2004; Sheline et al. 1999). While it is likely that milk cortisol may travel directly to the brain, it is also possible that it may exert its action indirectly through various proposed pathways of the gut-brain axis. Not only has cortisol been found to be necessary for the development of the hypothalamic-pituitary-adrenal axis (Finken et al. 2016), but cortisol has also been linked to favorable gut microbiome compositions (de Punder and Pruimboom 2015; Kelly et al. 2015; Farzi, Fröhlich, and Holzer 2018). With the current state of research, we can appreciate that cortisol has the potential to be very influential on infant brain development, specifically on behavior, temperament, and memory processing. However, more definitive research is needed to conclude any causal relationship.

Human milk oligosaccharides help with the gut-brain connection

Other extra-nutritive agents that may influence the neurodevelopment of infants are human milk oligosaccharides (HMOs), a class of prebiotic (something that supports growth of microbes) in milk. Oligosaccharides are sugar molecules that are nutritive agents for commensal bacteria that colonize the human gut (McKeen et al. 2019; Pruss et al. 2021; Luo et al. 2021); however they are indigestible to humans. A study in 2016 also found HMOs to have antimicrobial effects against pathogenic (disease causing) microorganisms in the infant gut by lining the intestinal wall (Kulinich and Liu 2016), giving further support that HMOs help support a diverse commensal gut microbiome. Researchers have found that by supporting the diversity of gut microbes, HMOs end up playing a significant role in infant gut maturation and innate (nonspecific) immune system development (Cacho and Lawrence 2017). As the majority of all human immune cells reside in the gut, this is not a surprising finding.

So, how could HMOs ultimately impact infant brain development? While HMOs support the infant gut microbiota, the gut microbiota help activate the peripheral immune cells in the gut, and interestingly, these immune cells may play a role in regulating the body’s response to neurogenesis (production of nerve cells) (Fung et al. 2020). In preclinical and clinical studies, researchers have demonstrated that through their impact on the gut and immune system, HMOs may indirectly support cognitive development (Fleming et al. 2020b; Docq et al. 2020), facilitate hippocampal development and memory formation (Vázquez et al. 2015; Fleming et al. 2020b; 2020a), and contribute to the long-term strengthening of synapses, which are the connections between neurons (Vázquez et al. 2015). Moreover, the gut microbiota are also thought to impact the production of neurotransmitters (chemicals that transmit messages between neurons in the brain), providing additional support that HMOs may influence the growth of protective commensal bacteria in the infant gut during critical periods of development and may thereby influence brain growth and function (Jj and J 2019).

Growth factors influence brain development

Lastly, growth factors are well known to trigger cell growth and differentiation in the body (Rodrigues 2013). While more than 50 different kinds of growth factors are present in human milk, one in particular called nerve growth factor (NGF) may be specifically important for infant brain development (Ballard and Morrow 2013). Although NGF is responsible for some of the growth and proliferation of neurons, NGF’s reach is not isolated to the brain. It has also been found to positively influence the growth and survival of cells in the reproductive system (Rocco et al. 2018), as well as demonstrating anti-inflammatory properties (Minnone, De Benedetti, and Bracci-Laudiero 2017). NGF’s role in the developing body has been well-documented, but there are currently no studies that directly correlate human milk NGF with neurodevelopment. Another growth factor present in human milk is brain-derived neurotrophic factor (BDNF), which has been hypothesized to be necessary for specific kinds of neuron growth and differentiation (Hård et al. 2019).
Growth factors, and many other extra nutritive factors in human milk, may travel to the brain through a type of extracellular transport vesicle (tiny spherical sac) called an exosome. These are known to be present in human milk (Galley and Besner 2020); they contain a variety of molecules, including small proteins, that can be transported to cells locally or to distant sites in the body (Qin et al. 2016). Exosomes are not digested in the infant gut and are capable of incorporating themselves into the intestinal cells and immune cells lining the infant intestinal tract (Sauter and Reidy 2017). It is possible that exosomes might allow many kinds of extra-nutritive factors, including growth factors, to influence different aspects of infant growth, including neurological development and gut maturation. While NGF, BDNF, or other growth factors may be critical chemical messengers in the link between the infant gut microbiome and brain development, more research is needed to truly ascertain their precise role in infant gut-brain maturation.

Extra-nutritive components in human milk may play critical roles, both directly and indirectly through the gut microbiome, on infant brain development. Although several additional factors have been studied in the context of neurodevelopmental biology, it is clear that human milk oligosaccharides, growth factors, and cortisol are notable candidates for several reasons. First, the biochemical structure of each compound makes it possible for it to communicate with the gut microbiota, intestinal tissue, and/or brain tissue. Second, growth factors, oligosaccharides, and cortisol, even when not coming from human milk, have physiological roles in our bodies that correlate to brain health and functioning. Lastly, studies have found associations between these bioactive molecules and healthy gut development, neuronal growth and differentiation, and changes in behavior, temperament, and cognitive performance. Although the wealth of correlational information on this connection offers insight into the potential for human milk to hold the key to optimal brain and behavioral development, more prospective, longitudinal research is needed to establish causal relationships.


Anderson, George, Cathy Vaillancourt, Michael Maes, and Russel J. Reiter. 2017. “Breastfeeding and the Gut-Brain Axis: Is There a Role for Melatonin?” Biomolecular Concepts 8 (3–4): 185–95.

Angelucci, L., F. R. Patacchioli, S. Scaccianoce, A. Di Sciullo, A. Cardillo, and S. Maccari. 1985. “A Model for Later-Life Effects of Perinatal Drug Exposure: Maternal Hormone Mediation.” Neurobehavioral Toxicology and Teratology 7 (5): 511–17.

Ballard, Olivia, and Ardythe L. Morrow. 2013. “Human Milk Composition: Nutrients and Bioactive Factors.” Pediatric Clinics of North America 60 (1): 49–74.

Brown, E. Sherwood, Femina P. Varghese, and Bruce S. McEwen. 2004. “Association of Depression with Medical Illness: Does Cortisol Play a Role?” Biological Psychiatry 55 (1): 1–9.

Cacho, Nicole Theresa, and Robert M. Lawrence. 2017. “Innate Immunity and Breast Milk.” Frontiers in Immunology 8: 584.

Dettmer, Amanda M., Ashley M. Murphy, Denisse Guitarra, Emily Slonecker, Stephen J. Suomi, Kendra L. Rosenberg, Melinda A. Novak, Jerrold S. Meyer, and Katie Hinde. 2018. “Cortisol in Neonatal Mother’s Milk Predicts Later Infant Social and Cognitive Functioning in Rhesus Monkeys.” Child Development 89 (2): 525–38.

Docq, Sylvia, Marcia Spoelder, Wendan Wang, and Judith R. Homberg. 2020. “The Protective and Long-Lasting Effects of Human Milk Oligosaccharides on Cognition in Mammals.” Nutrients 12 (11).

Farzi, Aitak, Esther E. Fröhlich, and Peter Holzer. 2018. “Gut Microbiota and the Neuroendocrine System.” Neurotherapeutics 15 (1): 5–22.

Finken, Martijn J. J., Bibian van der Voorn, Annemieke C. Heijboer, Marita de Waard, Johannes B. van Goudoever, and Joost Rotteveel. 2016. “Glucocorticoid Programming in Very Preterm Birth.” Hormone Research in Paediatrics 85 (4): 221–31.

Fleming, Stephen A., Austin T. Mudd, Jonas Hauser, Jian Yan, Sylviane Metairon, Pascal Steiner, Sharon M. Donovan, and Ryan N. Dilger. 2020a. “Human and Bovine Milk Oligosaccharides Elicit Improved Recognition Memory Concurrent With Alterations in Regional Brain Volumes and Hippocampal MRNA Expression.” Frontiers in Neuroscience 14: 770.

Fleming, Stephen A., Austin T. Mudd, Jonas Hauser, Jian Yan, Sylviane Metairon, Pascal Steiner, Sharon M. Donovan, and Ryan N. Dilger.. 2020b. “Dietary Oligofructose Alone or in Combination with 2’-Fucosyllactose Differentially Improves Recognition Memory and Hippocampal MRNA Expression.” Nutrients 12 (7).

Fung TC, Olson CA, Hsiao EY. 2017. “Interactions between the microbiota, immune and nervous systems in health and disease.” Nat Neuroscience 20(2):145-155. doi:10.1038/nn.4476.

Galley, Jeffrey D., and Gail E. Besner. 2020. “The Therapeutic Potential of Breast Milk-Derived Extracellular Vesicles.” Nutrients 12 (3).

Gao, Wei, Andrew P. Salzwedel, Alexander L. Carlson, Kai Xia, M. Andrea Azcarate-Peril, Martin A. Styner, Amanda L. Thompson, et al. 2019. “Gut Microbiome and Brain Functional Connectivity in Infants-a Preliminary Study Focusing on the Amygdala.” Psychopharmacology 236 (5): 1641–51.

Grey, Katherine R., Elysia Poggi Davis, Curt A. Sandman, and Laura M. Glynn. 2013. “Human Milk Cortisol Is Associated With Infant Temperament.” Psychoneuroendocrinology 38 (7): 1178–85.

Hamosh, Margit. 2001. “Bioactive Factors in Human Milk.” Pediatric Clinics of North America, Breastfeeding 2001, Part 1: The Evidence for Breastfeeding, 48 (1): 69–86.

Hård, Anna-Lena, Anders K. Nilsson, Anna-My Lund, Ingrid Hansen‐Pupp, Lois E. H. Smith, and Ann Hellström. 2019. “Review Shows That Donor Milk Does Not Promote the Growth and Development of Preterm Infants as Well as Maternal Milk.” Acta Paediatrica 108 (6): 998–1007.

Hinde, Katie, Amy L. Skibiel, Alison B. Foster, Laura Del Rosso, Sally P. Mendoza, and John P. Capitanio. 2015. “Cortisol in Mother’s Milk across Lactation Reflects Maternal Life History and Predicts Infant Temperament.” Behavioral Ecology 26 (1): 269–81.

Hollanders, Jonneke J., Annemieke C. Heijboer, Bibian van der Voorn, Joost Rotteveel, and Martijn J. J. Finken. 2017. “Nutritional Programming by Glucocorticoids in Breast Milk: Targets, Mechanisms and Possible Implications.” Best Practice & Research. Clinical Endocrinology & Metabolism 31 (4): 397–408.

Jena, Ankita, Carlos A. Montoya, Jane A. Mullaney, Ryan N. Dilger, Wayne Young, Warren C. McNabb, and Nicole C. Roy. 2020. “Gut-Brain Axis in the Early Postnatal Years of Life: A Developmental Perspective.” Frontiers in Integrative Neuroscience 14: 44.

Jj, Pei, and Tang J. 2019. “[A Review on the Relationship between Breast Milk Nutrients and Brain Development in Preterm Infants].” Zhongguo Dang Dai Er Ke Za Zhi = Chinese Journal of Contemporary Pediatrics 21 (6): 607–12.

Kelly, John R., Paul J. Kennedy, John F. Cryan, Timothy G. Dinan, Gerard Clarke, and Niall P. Hyland. 2015. “Breaking down the Barriers: The Gut Microbiome, Intestinal Permeability and Stress-Related Psychiatric Disorders.” Frontiers in Cellular Neuroscience 9: 392.

Kloet, E. Ron de, Marian Joëls, and Florian Holsboer. 2005. “Stress and the Brain: From Adaptation to Disease.” Nature Reviews. Neuroscience 6 (6): 463–75.

Koning, Anne-Sophie C A M, Jacobus C Buurstede, Lisa T C M van Weert, and Onno C Meijer. 2019. “Glucocorticoid and Mineralocorticoid Receptors in the Brain: A Transcriptional Perspective.” Journal of the Endocrine Society 3 (10): 1917–30.

Kulinich, Anna, and Li Liu. 2016. “Human Milk Oligosaccharides: The Role in the Fine-Tuning of Innate Immune Responses.” Carbohydrate Research 432 (September): 62–70.

Luo, Yanhong, Yue Xiao, Jianxin Zhao, Hao Zhang, Wei Chen, and Qixiao Zhai. 2021. “The Role of Mucin and Oligosaccharides via Cross-Feeding Activities by Bifidobacterium: A Review.” International Journal of Biological Macromolecules 167 (January): 1329–37.

Lupien, S. J., M. de Leon, S. de Santi, A. Convit, C. Tarshish, N. P. Nair, M. Thakur, B. S. McEwen, R. L. Hauger, and M. J. Meaney. 1998. “Cortisol Levels during Human Aging Predict Hippocampal Atrophy and Memory Deficits.” Nature Neuroscience 1 (1): 69–73.

McElroy, Steven J., and Jörn-Hendrik Weitkamp. 2011. “Innate Immunity in the Small Intestine of the Preterm Infant.” NeoReviews 12 (9): e517–26.

McKeen, Starin, Wayne Young, Jane Mullaney, Karl Fraser, Warren C. McNabb, and Nicole C. Roy. 2019. “Infant Complementary Feeding of Prebiotics for TheMicrobiome and Immunity.” Nutrients 11 (2).

Minnone, Gaetana, Fabrizio De Benedetti, and Luisa Bracci-Laudiero. 2017. “NGF and Its Receptors in the Regulation of Inflammatory Response.” International Journal of Molecular Sciences 18 (5).

Montiel-Castro, Augusto Jacobo, Rina María González-Cervantes, Gabriela Bravo-Ruiseco, and Gustavo Pacheco-Lopez. 2013. “The Microbiota-Gut-Brain Axis: Neurobehavioral Correlates, Health and Sociality.” Frontiers in Integrative Neuroscience 7.

Niemarkt, Hendrik J., Tim G. De Meij, Christ-Jan van Ganzewinkel, Nanne K. H. de Boer, Peter Andriessen, Matthias C. Hütten, and Boris W. Kramer. 2019. “Necrotizing Enterocolitis, Gut Microbiota, and Brain Development: Role of the Brain-Gut Axis.” Neonatology 115 (4): 423–31.

Palmeira, Patricia, Magda Carneiro-Sampaio, Patricia Palmeira, and Magda Carneiro-Sampaio. 2016. “Immunology of Breast Milk.” Revista Da Associação Médica Brasileira 62 (6): 584–93.

Pariante, Carmine M., Sarah A. Thomas, Simon Lovestone, Andrew Makoff, and Robert W. Kerwin. 2004. “Do Antidepressants Regulate How Cortisol Affects the Brain?” Psychoneuroendocrinology 29 (4): 423–47.

Patacchioli, Francesca R., Giovanni Cigliana, Antonietta Cilumbriello, Giuseppina Perrone, Oriana Capri, Sebastiano Alemà, Lucio Zichella, and Luciano Angelucci. 1992. “Maternal Plasma and Milk Free Cortisol during the First 3 Days of Breast-Feeding Following Spontaneous Delivery or Elective Cesarean Section.” Gynecologic and Obstetric Investigation 34 (3): 159–63.

Petryk, Andrea, Susan R. Harris, and Lynette Jongbloed. 2007. “Breastfeeding and Neurodevelopment: A Literature Review.” Infants & Young Children 20 (2): 120–34.

Pruss, K. M., A. Marcobal, A. M. Southwick, D. Dahan, S. A. Smits, J. A. Ferreyra, S. K. Higginbottom, et al. 2021. “Mucin-Derived O-Glycans Supplemented to Diet Mitigate Diverse Microbiota Perturbations.” The ISME Journal 15 (2): 577–91.

Punder, Karin de, and Leo Pruimboom. 2015. “Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability.” Frontiers in Immunology 6: 223.

Qin, Wenyi, Yoshikazu Tsukasaki, Santanu Dasgupta, Nitai Mukhopadhyay, Mitsuo Ikebe, and Edward R. Sauter. 2016. “Exosomes in Human Breast Milk Promote EMT.” Clinical Cancer Research 22 (17): 4517–24.

Rocco, Maria Luisa, Marzia Soligo, Luigi Manni, and Luigi Aloe. 2018. “Nerve Growth Factor: Early Studies and Recent Clinical Trials.” Current Neuropharmacology 16 (10): 1455–65.

Rodrigues, Lígia R. 2013. “Milk Minor Constituents, Enzymes, Hormones, Growth Factors, and Organic Acids.” In Milk and Dairy Products in Human Nutrition, 220–45. John Wiley & Sons, Ltd.

Sauter, Edward R., and Deirdre Reidy. 2017. “How Exosomes in Human Breast Milk May Influence Breast Cancer Risk.” Translational Cancer Research 6 (8).

Shafai, Touraj, Monika Mustafa, Sandra Compsos, and Lida Niake. 2018. “The Influence of Breastfeeding and the Infant’s Social Environment on Neuroplasticity and Brain Development: The First 1000 Days.” Selected Topics in Breastfeeding, February.

Sheline, Y. I., M. Sanghavi, M. A. Mintun, and M. H. Gado. 1999. “Depression Duration but Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 19 (12): 5034–43.

Sullivan, Erin C., Katie Hinde, Sally P. Mendoza, and John P. Capitanio. 2011. “Cortisol Concentrations in the Milk of Rhesus Monkey Mothers Are Associated with Confident Temperament in Sons, but Not Daughters.” Developmental Psychobiology 53 (1): 96–104.

Thai, Julie D., and Katherine E. Gregory. 2020. “Bioactive Factors in Human Breast Milk Attenuate Intestinal Inflammation during Early Life.” Nutrients 12 (2).

Vázquez, Enrique, Alejandro Barranco, Maria Ramírez, Agnes Gruart, José M. Delgado-García, Esther Martínez-Lara, Santos Blanco, et al. 2015. “Effects of a Human Milk Oligosaccharide, 2’-Fucosyllactose, on Hippocampal Long-Term Potentiation and Learning Capabilities in Rodents.” The Journal of Nutritional Biochemistry 26 (5): 455–65.

Yeh, Kwo-Yih, Mary Yeh, and Peter R. Holt. 1989. “Induction of Intestinal Differentiation by Systemic and Not by Luminal Corticosterone in Adrenalectomized Rat Pups*.” Endocrinology 124 (4): 1898–1904.

Audrey Humphries is originally from California, USA. Audrey graduated with a B.S. degree in biology from University of California (UC) Santa Barbara in 2016.  After working as a senior clinical research coordinator at UC San Francisco’s Cancer Center for over three years in cutaneous and head and neck oncology, Audrey joined the Virginia Tech Carilion School of Medicine’s class of 2024 MD program.  Audrey joined the Howell lab at the Fralin Biomedical Research Institute at Virginia Tech Carilion in 2020.

Nneoma Edokobi was born in Lagos, Nigeria but was predominantly raised in Rockville, Maryland, USA. She graduated with a B.A in biological science from the University of Maryland, Baltimore County in 2016. Afterwards she worked in the biotechnology industry for four years developing electrochemiluminescence immunoassays. She then received an Advanced Biomedical Sciences graduate certificate from George Mason University, Fairfax County, Virginia in 2019. In 2020 she relocated to Roanoke, Virginia, USA, as part of Virginia Tech Carilion School of Medicine’s class of 2024.

Catherine Lavallee is a second-year medical student at Virginia Tech Carilion School of Medicine in Roanoke, Virginia. Catherine was born and raised in Rockville, Maryland. She earned her BS in biology from the Catholic University of America in Washington, DC. She then moved to Boston, Massachusetts, USA, USA, to work in a food allergy lab that studies how breastmilk protects infants from developing food allergies. She joined the Howell lab in 2020.

Brittany Howell, PhD is an assistant professor in neuroscience of human development at the Fralin Biomedical Research Institute at Virginia Tech Carilion School of Medicine, and the Department of Human Development and Family Science at Virginia Tech. She grew up in rural New Hampshire, USA, then moved to New Orleans, Louisiana, USA, where she earned a B.S. in neuroscience, and cell and molecular biology. She completed her PhD in neuroscience at Emory University, Atlanta, Georgia followed by postdoctoral training in developmental science at the Institute of Child Development, at the University of Minnesota, USA. Her lab, lovingly called the Maternal Influence on Neurodevelopment (MIND) Lab, was established in 2019 and looks at the complex biobehavioral pathways through which mothers shape their baby’s brains and behavioral development.

Erin VandeLinde is a Leader and IBCLC who provides lactation consultation to MIND Lab – the authors wrote this article at her request.