Human Milk Bioactives in Breastfeeding: Understanding the Complex Biology of Mother-Child Interactions

The human infant’s transition from a placental to mammary supply line for nutrients, and then from breastmilk to specialised complementary foods, and then on to the adult diet, needs to be well managed to achieve the most successful outcomes. Likewise, the transition from an aseptic environment in utero to a sudden exposure to thousands of antigens and living organisms, some of which are pathogenic, also requires an exquisitely orchestrated series of immunological adaptations. Breastmilk plays a central role in all of these, as does the baby’s gut microbiome and there is a powerful interaction between the two.In this supplement, we have 4 papers that address different aspects of this complex biology of mother-child interactions by examining the role of human milk bioactives and the optimal timing at which they are introduced and then gradually withdrawn as the infant matures.Although perhaps not generally thought of in the category of “bio-actives” nutrients are, of course, highly bioactive. In this first paper, Andrew Prentice [1] examines the relationship between a mother’s diet and her nutritional status (body stores of nutrients) and the composition of the milk that she produces.On account of a series of evolutionary “choices” human milk composition is very different from other species, even from other primates. The primary determinant is the growth rate of young humans that has evolved to be very slow in order to give plenty of time for the construction and training of a very large brain. This slow maturation means that, although energy needs are high (much of which is supplied by high lactose levels compared to other species), the nutrient needs for deposition as new tissue (protein, fatty acids, calcium, and all the other micronutrients) are very low; so human milk is very dilute. This in turn means that the strain on the mother’s resources is modest and thus milk composition is usually satisfactory across a wide range of maternal nutritional status and diets.The paper first reviews the longitudinal changes in milk composition as lactation progresses aided by the recent publication of the MILQ study results; a multicountry comparison of the nutrient content of milks produced by well-nourished mothers in Bangladesh, Brazil, Denmark, and Gambia. Patterns vary considerably, some nutrients start low and increase whilst others show a reverse pattern and some remain quite constant. These different patterns are illustrated in the paper using MILQ data for thiamine (increasing to a plateau), vitamin A (rapidly decreasing early post-partum), and calcium (rather steady throughout lactation).Combining the recent MILQ results with a review of the older literature allows certain general principles to be drawn up which describe how breastmilk nutrient levels relate to the mother’s diet and nutritional status. First, the proximate composition of milk (protein, fat and carbohydrate) is relatively independent of the mother’s nutrition, although the fatty acid composition of milk does vary with the fatty acid profile of the mother’s diet. Second, the levels of most water-soluble vitamins in milk closely follow maternal intake and status, and are readily increased by supplementing the mother; folate is an exception. Third, the fat-soluble vitamins (A, D, K) are moderately sensitive to diet and can be altered by high-dose supplements; vitamin E is an exception. Lastly, milk iodine and selenium levels are sensitive to diet and hence show large geographical variations according to soil levels; the other minerals are virtually unaffected by diet or supplements.In summary, human lactation is robust and, in most circumstances, provides infants with a high quality and safe source of their required nutrients. The one major exception to this is iron for which levels are extremely low in human milk and babies draw heavily from their birth endowment of liver iron during the period of exclusive breastfeeding. This liver iron is laid down in the last trimester of pregnancy so premature and low-birthweight babies are recommended to receive iron supplements.Helen Nabwera and Makena Mwaniki [2] start their paper with a strong emphasis on why breastmilk is the preferred food for babies, and a reminder of the WHO advice that, ideally, babies would be put to the breast as soon as possible after delivery, be fed exclusively on breastmilk for the first 6 months, and continue to receive mother’s milk alongside their complementary foods up to 2 years or beyond. But they also discuss the interplay of cultural attitudes across the world and the challenge faced by mothers who find it hard to maintain exclusive breastfeeding due to the pressures of working in the informal sector and unsupportive maternity leave laws and conditions (short maternity leave, limited workplace lactation spaces) in many countries. They emphasise that this inevitably has an influence on family’s decisions as to when and how to start introducing complementary foods. The title of their paper is careful not to state “transitioning away from breastfeeding” though in many cases this is the intention of mothers, especially those in high-income settings or those facing the employment constraints just mentioned.The ideal timing for the introduction of complementary foods is determined not by chronological age but rather by neuromuscular and behavioural cues such as an ability to maintain a stable head and trunk, disappearance of the tongue-thrust reflex, and an active interest in food. The timing of these transitions varies greatly between infants and may be delayed in those born prematurely and at low birthweight or suffering neurological disorders.They discuss the intersection between the ideal time for introduction of weaning foods and allergy prevention. Some evidence from randomised controlled trials suggests that introduction of commonly allergenic foods at around 4 months rather than 6 months can reduce the incidence of IgE-mediated allergy particularly among babies with severe eczema. This has led to contradictory recommendations from WHO (6 months) and ESPGHAN (17–23 weeks) and the American Academy of Pediatrics that advise around 4–6 months.The paper provides generic advice on the matter of what kinds of foods should be introduced and emphasises the special need to provide iron- and protein-rich foods. They point out that the mode of feeding (cup and spoon, finger foods, etc.) is highly dependent on culture, but always requires a gradual transition from finely pureed foods towards lumpier, more textured foods.The paper contains a thoughtful section about mothers who choose not to breastfeed and the many medical, cultural, legislative, and commercial reasons why this might be the case. The authors emphasise that even if mothers want or need to use commercial formulas partial breastfeeding is still strongly recommended in the light of its many protective properties and its ability to modulate immunity and the infant’s microbiome (for which, see below).The paper by Wendy Oddy [3] provides an overview of the many pathways by which breastmilk and breastfeeding help the baby’s immune system to develop. She divides the evidence into three overlapping generic areas: (1) human milk accelerates gut barrier function maturation in the immature neonatal mucosa; (2) the innate and adaptive immune bioactive components of human milk offer protection from pathogenic damage; and (3) components of human milk actively attenuate inflammatory reactions.A key factor orchestrating immune support via breastmilk is a constant communication and traffic of cellular and acellular components of immune defences between three beds of lymphoid tissue in the mother: the gut-associated and bronchial-associated lymphoid tissues send immune signals, molecules, vesicles and whole immune cells (activated innate and trained cognate cells) to the mammary-associated lymphoid tissue from whence they are exported to the baby via mother’s milk. There is also evidence of a retrograde flow within this system by which organisms from the baby can travel up the milk duct and activate the mother’s (more mature) immune system against specific pathogens in the infant.Innate immune defence compounds such as lactoferrin and lysozyme are abundant in early milk and levels are upregulated in the face of an infectious threat. Immunoglobulins are also present, especially IgA which is dimerised to form secretory IgA with a longer half-life. Colostrum has an exceptionally high concentration of sIgA which hence forms a key element in lining the neonatal gut. The paper dwells quite extensively on the more recent evidence that exosomes also flow through the mammary-associated lymphoid tissue and can putatively aid immunity by carrying small molecules including mRNAs.The final paper by Sharon Donovan [4] also covers immune development supported by human milk but narrows the aperture to look at HMOs. Following a description of the complex structures of HMOs and notes on their very high concentration in breastmilk, the paper describes a range of evidence (observational, pre-clinical, interventional) supporting the view that HMOs have evolved to provide a multi-layered system for modulating and enhancing the infant’s emerging immune defences. The modes of action are classified under six headings: strengthening of the intestinal barrier; anti-adhesive (decoy) effects; modulation of innate immune responses; regulation of adaptive immunity; anti-inflammatory and tolerogenic properties; and through modulation of the gut microbiota.In a final, important, section Donovan reviews the current evidence on whether the addition of so-called human identical milk oligosaccharides (HiMOs) to formula milks has clinical benefit. Of 38 human trials available to date, all showed HiMOs to be safe and well tolerated, and some trials showed evidence of benefit on a range of proxy markers of immunity as well as on stool consistency. In general milks with higher amounts and a more varied selection of HiMOs showed greater benefits. Further trials with meaningful clinical outcomes are required and these would necessarily require larger sample sizes than hitherto.The author has no conflict of interest to declare.The author is funded by UKRI Medical Research Council and the Wellcome Trust. The funders played no role in the content of this paper.The author was the sole contributor.