Human Milk Science The Variability In Composition And Consistency In Benefits

A recent statement by WHO 2011 recommends exclusive breastfeeding for the first six months, and continued breastfeeding up to two years and beyond.¹ After exclusive breastfeeding, safe, appropriate and adequate complementary foods are recommended.

Breastfeeding has numerous beneficial effects for the newborn infant and his mother, both shortand long term, including consequences for public health. Human milk has optimal nutritional value and beneficially influences absorption and metabolism, development of the gut microbiota, gut maturation, risk of infections and allergies, and brain and eye development.² Exclusive breastfeeding for at least 3 months is associated with a lower incidence and severity of diarrhoea, respiratory infection and otitis media. Exclusive breastfeeding for at least 6 months is associated with a lower incidence of allergic disease in at-risk infants. Breastfeeding is also associated with a lower incidence of obesity during childhood and adolescence, as well as with a lower incidence of hypertension and hypercholesterolemia in adulthood.

The composition of breast milk is influenced by gestational and postnatal age. Premature infants can be breastfed and/or receive mother's milk and/or bank milk, provided they receive energy, protein and mineral supplements. In a large review by Ip et al. it was concluded that the history of breastfeeding was associated with a reduction in the risk of acute otitis media, non-specific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, asthma (young children), obesity, type 1 and 2 diabetes, childhood leukemia, sudden infant death syndrome (SIDS), and necrotizing enterocolitis.³ Neonatal innate immune responses are differentially modulated by environmental exposure in the first month of life. The protective effect of breastfeeding against subsequent infections and atopy might be explained by its innate immune modulatory effects in the first month of life.⁴

There are also benefits for the breastfeeding mother. Return to pre-pregnancy weight occurs earlier in breastfeeding mothers. Breastfeeding is also associated with a decreased risk of breast and ovarian cancer in the premenopausal period and of hip fractures and osteoporosis in the postmenopausal period. Furthermore, very few medications contraindicate breastfeeding practice.⁵ In addition to macronutrients, which provide energy and building blocks to the newborn infant (such as lactose, triglycerides and proteins, respectively), human milk also contains a large number of compounds that modulate functional aspects of metabolism.

The key to unravelling the health benefits of human milk is an understanding of the causes and consequences of the variation in its composition. The development and the maturation of the gastro-intestinal tract and it's specific and digestive functions are of utmost importance. Maturation is a continuous process from foetal development until early childhood.⁶ A crucial phase starts after birth with enteral feeding. Human milk is essential not only from a nutritional point of view, but many of the non-digestible factors contribute to epithelial cell growth, mucosal barrier and immunity. Thus, support is needed for selective absorption of nutrients and protection from allergens and pathogens. Intestinal epithelial cells play an integral role in maintaining the intestinal barrier function and as such, form the first line of defence against infectious agents or allergens. At least for preterm infants it could be shown that intestinal permeability is improved by breastfeeding in a dose-related manner in the first postnatal month.⁷ It can be assumed that the different factors in human milk interfere in a concerted action to allow for an optimal maturation process and thus for the protection from birth onwards.

Human milk contains low amounts of protein (8-10 g/l). The ratio of caseins and whey proteins is tailored to cover functional and nutritional needs reflected by a specific postprandial response of the infant.⁸ There are many (whey) proteins with functional benefits, such as anti-infective lactoferrin, and customised antibodies to fight infections. 90% of all pathogens use the mucosa as a point of entry and represent a major killer of children below five years of age.⁹ Secretory immune globulin A (sIgA) is a main protecting factor against microbial infections but may further contribute to oral tolerance against indigenous microbiota and also against dietary antigens.¹⁰ Ovalbumin, gliadin, beta-lactoglobulin and other dietary proteins can pass naturally from mother to infant via breast milk. In the case of proven food allergy in a breastfed infant, the potential food allergen should be detected before dietary manipulation in mothers is initiated.¹² In addition, human milk contains further functional proteins such as growth hormones and interleukins inducing cell growth and cell differentiation.⁶

Human milk contains large amounts (10-12 g/l) of neutral and acidic human milk oligosaccharides (HMOS) with complex molecular structures affecting the gut microbiota and the developing immune system including allergy and infection structures.^{13, 14} Individually, the complex pattern of these HMOS vary on the basis of different gene expression and longitudinally within a specific group.¹⁵ These variations based on specific glycosylation enzymes are also relevant to the function of specific glycoproteins such as lactoferrin.¹⁶

Thus, together with these findings and the recent detection of gut microbiota entero-types,⁵⁹ we can speculate that the latter are possibly imprinted at early infancy.¹⁷ So far only limited structure-function-relations of the complex glycans and glycoconjugates have been deciphered such as the relation between Lewis-status and secretor status of mothers and the preventive effects of specific HMOS against viral and bacterial diarrhoea.¹⁸ However it is proven that all HMOS exhibit a clear prebiotic effect. This part of HMOS function could be translated into a concept for prebiotic nutrition for preterm and term infants.¹⁹ Increase of Bifidus-dominant microbiota, a reduction of pathogens in preterm-born infants, and reduced incidence of infections and allergic symptoms in term infants have been reported by applying specific mixtures of non-HMOS prebiotics.^20,21,22

A significant contribution of digestive comfort derives from establishing the microbiota typically for breastfed children and characterised further by stool characteristics such as low pH, pattern of short chain fatty acids, higher stool frequency and low consistency. Feeding tolerance in preterm infants was improved by specific prebiotics which shows that maturation of the GI tract is positively influenced.²³ The scientific concept of prebiotics -as originally derived from human milk- has recently been reviewed.²⁴ The additional function of glycans and glycoconjugates of human milk is in receptor mediated signalling and adhesion. These glycans interact in a key-lock principle with selected carbohydrate recognising receptors (lectins) such as with selectins²⁵ and also galectins²⁶ and thereby modulating the infant immune response.²⁷ Further more, they are able to inhibit binding of pathogens e.g. binding of ETEC to enteric cells,²⁸ as well as of other pathogens causing diarrhoea by a similar direct interaction.²⁹ The protection also occurs extra-intestinal i.e. in the urogenital compartment and is caused by uptake and excretion of HMOS.³⁰ The main effect of human milk on the gut microbiota may be derived from the prebiotic and anti-adhesive poperties of HMOS.^{14 , 24}

However, bacteria including beneficial genera are detected in low amounts in human milk samples. The relevance and physiological effect of their presence is currently being explored.³¹ They might also contribute to the colonisation of indigenous bacteria occurring in the first weeks after birth. In comparison to term infants, the intestinal bacterial colonisation in preterm is delayed.³² The intestinal microbiota influences the early development of the immune system including cellular and humoral responses, induction of toll-like receptor responses and shift from TH2 to TH1/TH17 state.³³ Commensal bacteria produces SCFA, bacteriocins and vitamins. They contribute to the mucosal and epithelial barriers, balance microbial ecology, and interfere with adherence to intestinal mucosa, thus, impede invasive pathogens.³⁴ Competitive exclusion of B breve to E coli and S typhimurium has been reported.³⁵

Depending on the diet, the lipid fraction of human milk of healthy mothers usually contains the optimal ratio of n-3 and n-6 long-chain polyunsaturated fatty acids (PUFAs). These are constituents of triglycerides and phospholipids, forming complex structures important for metabolism and brain development. These lipids vary over the course of lactation.^{36, 37} Furthermore, lipids in human milk vary based on the diet of the mother.38 More recently, a clear association between genotypes of lipid metabolising enzyme and fatty acid levels in diverse human tissues shows that these gene cluster polymorphisms are, in addition to nutritional regulation of fatty acid synthesis, a very important regulator of LC-PUFA synthesis.^{39, 40, 41}

In humans, the uptake of lipids from the diet is e.g. related to genetic polymorphisms of apolipoproteins within the early steps of lipid uptake from diet into chylomicrons.⁴² Typically, the lipid fraction of human milk (3–5 wt%) contains about 13– 15 wt% PUFA.⁴³ PUFAs are incorporated into cellular membrane phospholipids, contribute to membrane fluidity and serve as precursor for eicosanoid synthesis.⁴⁴ Moreover, PUFAs are known to stimulate differentiation, support gut maturation, reduce transcellular permeability and may also improve tight junction formation.⁴⁵ A fat blend similar to human milk lipids was tested in an experimental model with human intestinal epithelial cells. Interleukin 4 mediated barrier permeability was reduced by those complex lipids. The barrier integrity was determined by transepithelial electrical resistance and the macromolecular permeability was determined by fluorescent labelled dextran.⁴⁶ The experiments allowed insight into the mechanism of barrier integrity including alteration of the membrane phospholipids of the epithelial cells.⁴⁷

LCPUFAs are absorbed and systemicly available which exhibit also extra-intestinal effects as shown in an experimental model on lung infection. The synthesis of mucin48 as well as the balance of pro and anti-inflammatory effects⁴⁹ are influenced by lipids. With emerging analytical techniques, further complex functional lipids such as sphingolipids have been described recently.⁵⁰ These complex lipids compounds represent the dominant fraction of human milk.⁵⁰ Sphingomyelin has been shown to accelerate enzymic and morphologic maturation in experimental studies.⁵¹ Another functional lipid class are short chain fatty acids (SCFAs). Those compounds are produced by selective fermentation of non-digestible carbohydrates by the commensal saccharolytic microbiota of the intestine. SCFAs can induce specific mucin expression and prostaglandin ratios in an experimental model. Thus, SCFAs were found to improve the extrinsic barrier by enhancing epithelial mucus expression.⁵²

Human milk is a source of anti-oxidative compounds. Anti-oxidative vitamins and their concentrations decrease throughout the lactation, while their total anti-oxidative properties increase.⁵³ Also, proteins like lactoferrin can inhibit anti-oxidative effects.⁵⁴ Besides macro-,micronutrients and bacteria, human milk also contains living cells derived from the maternal system. Colostrum has nearly equal ratio of macrophages and neutrophils, with the latter disappearing rapidly in mature milk. Here, 90% of the milk leucocytes are phagocytic cells that kill bacteria and fungi. The highest concentrations of leukocytes in human milk occur in the first few days of lactation.⁵⁵

Human milk may contain some contaminants deriving from the environment. Those compounds and their effect have been reviewed elsewhere.⁵⁶ Recently this has been discussed in context with epigenetics. The authors concluded that due to the complexity and importance of motherinfant interactions, future research on developmental toxicology must consider the effects of contaminants not only on the offspring, but also on the mother and on the interactions and social bond between mother and infant.⁵⁷

Conclusion:

here is an ongoing need to better understand the contribution of specific human milk composition on digestion and absorption; the development of the gut and its microbiota; the immune system and the brain. There is an increased scientific interest to gain more insights into the complex interplay of macronutrients and trace compounds in human milk, which appears necessary to understand futher health benefits.

The key to unravelling the health benefits of human milk is an understanding of the causes and consequences of the variation in its composition. A promising topic is the influence of the dietary habits of the mother on macronutrient, micronutrient and trace element composition of her milk, in addition to environmental and life-style factors.

Even within a region the dietary habits may have consequences for the overall composition of breast milk as shown in a recent study comparing human milk from urban to suburban women in China. The level of macronutrients (protein, lipids, and carbohydrates) and micronutrients (copper, sodium, potassium, chlorine, zinc, manganese, phosphorus and iron) were all significantly lower in milk obtained from suburban women.⁵⁸

Further exploration into the many benefits of human milk must continue, in order to help support breastfeeding but also to help in understanding the nutritional needs of mothers and their infants in their early phase of life.