It is well-known that breastfeeding is the gold standard of infant nutrition, as breast milk contains protective nutrients for the growth and development of infants and may have a protective effect against long-term diseases including obesity, asthma, celiac disease, and allergies. A recent review, published by Dr. Thierry Hennet and Dr. Lubor Borsig from the Department of Physiology and Centre for Integrative Human Physiology at University of Zürich (Switzerland), describes the up-to-date data regarding the unique biology of human breast milk as a multifunctional fluid.
Humans may have the most complex breast milk of all mammals. It comprises close to 200 different oligosaccharides, far above the average 30-50 found in other mammals. Not only do human milk oligosaccharides act as prebiotics, but they also exert antimicrobial functions by acting as soluble receptors for harmful bacteria and viruses, which inhibit them to infect the host. Researchers still don’t know the role of each of these sugars and the reason why their composition changes during breastfeeding, but authors of the review suggest that oligosaccharides are likely linked to the development of the gut microbiota and the training of the mucosal immune system.
Breast milk acts as a fertilizer for bacteria, favouring the colonization of the newborn gut by specific bacterial groups that can digest breast milk oligosaccharides. In fact, complex milk oligosaccharides -which are higher in colostrum than in mature milk- cannot be digested by the suckling infant and reach the large intestine, where they are assimilated by selected bacterial taxa including Bifidobacterium spp. and Bacteroides spp. Gut bacteria have preferences for specific milk oligosaccharides and, therefore, interindividual variability in maternal milk oligosaccharides may affect the pattern of bacterial colonization in the neonatal gut.
A recent study, led by Prof. David A. Mills from the Department of Food Science and Technology at the University of California at Davis, has found that oligosaccharide structures released from mother’s milk and cow’s milk can serve as a sole source for the selective growth of Bifidobacterium species. The researchers have demonstrated previously that glycoproteins from human milk (i.e. compounds with both protein and oligosaccharides) may be a source of nourishment for the beneficial microbes in the infant gut. They have also showed that Bifidobacterium longum subsp. infantis (B. infantis) expressed constitutively an enzyme called EndoBI-1 (a kind of N-acetylglucosaminidase) that could split the oligosaccharides away from the glycoproteins. However, there was no definitive answer as to which component of the glycoproteins (either protein or sugar molecules) was supporting growth of B. infantis, which is a key infant gut microbe. In the new study, the researchers showed that B. infantis-produced EndoBI-1 enzyme is able to harvest specific sugar compounds that are obtained from human breast milk and bovine colostrum. These sugar molecules, named EndoBI-1-released N-glycans, supported the rapid growth of Bifidobacterium longum subsp. longum, B. infantis, B. breve and B. bifidum, which consumes these released N-glycans as a sole carbon source. However, the oligosaccharides from the cow’s milk did not support growth of Bifidobacterium animalis subsp. lactis, which is found in the human gut. Noticeably, released N-glycans enable more rapid bifidobacteria growth than the conjugated form. Prof. Mills noted that B. infantis has many genes involved in breaking down glycoproteins in mother’s milk in order to release the oligosaccharides. The study also showed that B. infantis does not grow on the deglycosylated milk protein fraction, clearly indicating that the oligosaccharides provide the key substrate for growth. On the whole, this study points out that oligosaccharides from milk may serve as selective substrate for the enrichment of infant bifidobacteria. Also, the findings suggest that N-glycans released from bovine milk glycoproteins may serve as a novel prebiotic substrate for infants.
Human breast milk also delivers immune-active compounds (such as immunoglobulins, cytokines, defensins, and lactoferrin, among others) to the infant gut. These bioactive proteins help establish the baby’s immune system by contributing to innate immune protection and maturation of mucosal immunity, preventing pathogenic bacterial overgrowth and inducing tolerogenic responses towards structurally related mucosal glycans. As an infant’s immune system matures further, there is a decrease in the levels of maternal antibodies of up to 90%, and a decrease in the diversity of breast milk sugars, whereas mature milk has proportionally high levels of lipids and caseins.
Several hormones in breast milk (e.g., leptin, adiponectin) affect metabolic pathways and support the growth and development of the suckling infant. Beyond providing protective compounds as discussed above, breast milk also may transmit environmental lipophilic contaminants and a few pathogens, such as human immunodeficiency virus (HIV) and cytomegalovirus (CMV), to the suckling infant. Newborns from CMV-positive mothers are protected prenatally, whereas in the case of HIV, transmission of the virus has been reported in up to 40% of mother-infant pairs.
Regarding the role of the newborn’s immune system in tolerating gut microbes, until now it has been thought that IgA antibodies supplied by breast milk are primarily responsible for it in early life. A recent study, led by Dr. Gregory Barton from the Department of Molecular and Cell Biology at University of California, Berkeley (USA), has demonstrated in mice that IgG antibodies acquired from breast milk help limit immune responses to newly encountered microbes early in life to a greater extent than do IgA antibodies. Maternal transmission of microbiota-specific IgG antibodies starts as early as 2 weeks of age and they are acquired from mothers after birth. Besides this, maternal transmission of IgG coordinates with IgA to limit mucosal T cell responses against commensals and reinforce intestinal immunity in neonates. As abnormal immune responses against beneficial gut microbes may lead to disease, the researchers mention that characterizing the immune response to gut microbes may offer new insights for assessing an individual’s risk for inflammatory intestinal disorders and implementing early therapeutic interventions.
Additional health benefits of breast milk are often overlooked: those that extend to the nursing mother. Recent data presented in the Hennet, et al. review demonstrate the functional complexity of breast milk bioactive components, including immunoglobulins, cytokines, antimicrobial proteins, hormones, and oligosaccharides, which work together to fortify mucosal immunity, shape the gut microbiota, stimulate body growth, and even regulate birth spacing in mothers.
Researchers are careful to note that these findings do not translate directly into specific breastfeeding recommendations. “Despite the many functions of breast milk, children can grow up healthy with limited supplies or without ever being exposed, raising controversial questions about what is normal when it comes to the length of breastfeeding,” stated a press release related to the study by Hennet, et al. “Breast milk is the product of millions of years of evolution and certainly possesses the optimal nutrients for a newborn, but the question is how long does the newborn really need this supply? We feel families should make that decision, and not scientists,” said study co-author Lubor Borsig.
In conclusion, human breast milk comprises a complex composition of protective compounds for the infant. Although a few of them have been characterized and well studied, further research is needed to depict a clear picture of the role of protective factors provided by breast milk in influencing the mucosal immune system and the intestinal microbiota.
Hennet T, Borsig L. Breastfed at Tiffany’s. Trends Biochem Sci. 2016. doi:10.1016/j.tibs.2016.02.008.
Karav S, Le Parc A, Maria Leite Nobrega de Moura Bell J, et al. Oligosaccharides released from milk glycoproteins are selective growth substrates for infant-associated bifidobacteria. Appl Environ Microbiol. 2016. doi:10.1128/AEM.00547-16.
Koch MA, Reiner GL, Lugo KA, et al. Maternal IgG and IgA antibodies dampen mucosal T helper cell responses in early life. Cell. 2016; 165(4):827-41. doi: http://dx.doi.org/10.1016/j.cell.2016.04.055