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.
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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.