Human breast milk provides immunological protection for newborns and infants against common childhood diseases in addition to its well-documented nutritional value. During the last few decades there is increasing evidence of a possible relationship between high risk of developing autoimmune diseases and allergies and decreased rates and/or duration of breastfeeding. This review summarizes evidence in relation to the effects of breastfeeding on the development of the neonatal immune system and compares compositions of gut microflora and the development of the thymus between breastfed and non-breastfed infants. It also discusses protective mechanisms of those cells in HBM survival, such as high stomach pH and gut permeability of the newborn and the presence of antiproteases and fat globules in HBM.
*Abbreviations: HBM, human breast milk; sIgA, secretory IgA; NEC, necrotizing enterocolitis; GIT, gastrointestinal tract; IL-7, interleukin-7; TH2, T helper 2 cell; TNF-Î±, tumour necrosis factor- Î±; LOS, late-onset septicaemia; G-CSF, granulocyte colony-stimulating factor; MFGs, milk fat globules; MFGM, milk fat globule membrane.
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Although formula milk attempts to duplicate the composition of HBM, HBM is a highly complex secretion and undergoes dynamic changes over the lactation period. It provides optimal nutrition and various immunological components including living immune cells and bioactive proteins for neonates and infants in the vulnerable early months of life. The cellular components in HBM are around 14,000 cells/ml, mostly epithelial and immune cells, and the bioactive proteins include hormones, enzymes, growth factors, anticancer, anti-inflammatory, immunomodulating and anti-infectious factors. A high proportion of specific and non-specific immunological components are passively transferred through HBM to compensate for the synthesis deficiency of the infant during the first year of life such as secretory IgA (sIgA). Such cells and bioactive proteins are not available in formula milk.
There are convincing arguments relating to infants who receive exclusive breastfeeding in the first 6 months of life that show they have better development and more protection against common childhood infectious and gastrointestinal diseases including sepsis, pneumonia, otitis media, diarrhoea and necrotizing enterocolitis (NEC), than non-breastfed infants. Kramer and Kakuma found in a total of 22 countries, that infants who were exclusively breastfed for up to 6 months had no deficits in their growth and development. Another Norwegian cohort of preterm infants showed that infants who had early establishment of enteral feeding with HBM within the second week of life remarkably reduced relative risk of 3.7 for late-onset septicaemia (LOS).
There are substantial arguments for the potential benefits of HBM, not only in infancy but also in later life. A largely inconclusive argument exists related to the benefits of exclusive breastfeeding as providing better protection for allergy and autoimmune diseases. In other words, infants who do receive enough HBM during infancy have less chance of developing these diseases in the future. Recently, another finding was that of multiple lines of undifferentiated stem cells identified in human lactating mammary glands and acquired via HBM, which indicates potential for positive health outcomes through the lifespan.
However, the question arises as to how viable cells and proteins from HBM survive digestion and reach the intestine of the infant. Do immunological components from HBM enhance the development of the immune system for the offspring? The migration pattern of cells in HBM from the mother to the infant is largely unknown. One concern in regard to this topic is the difficulty of providing solid evidence using human infants, due to practical and ethical considerations. Therefore, most information contributing to answering this question comes from experiments from animals and comparisons between exclusively breast-fed infants and formula-fed infants. This brief review focuses on the evidence of cell survival after digestion and hypothesizes the support mechanisms for survival of milk proteins and cellular components in the gastrointestinal tract (GIT).
Evidence of cell survival in the breastfed infant
There are animal studies to suggest that immunological cells from HBM can attach to and traverse the neonatal GIT, and can be transported via the lymph ducts to the mesenteric lymph nodes. Using an autoradiographic study of intestinal tissue in rats and lambs, Sheldrake and Husband found that radiolabelled milk lymphocytes are absorbed into the gut mucosa and taken up into the circulation. A similar result was also observed by Tuboly et al in pigs. Further, labelled lymphoid cells are effectively taken up into a newborn lamb's lymph circulation regardless of the route, including injection or consumption via the digestive tract.
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It is not clear whether cells from breast milk provide protection locally at the GIT level or whether they have an ability to confer systemic immune protection. Evidence from animal studies has suggested that cells from breast milk reach other organs of the offspring after absorption from the GIT. Jain et al confirmed in their study that labelled human milk leukocytes in premature neonatal baboons were found primarily in the stomach and intestinal lumen followed by lower levels in the spleen and liver, and the lowest levels in bone marrow. There was a similar result repeated by Liebler-Tenorio and colleagues from newborn calves. Labelled macrophages, after having been fed to newborn mice, remained alive for at least 4 hours in the GIT and localized in the mucosal tissue and in some cases in the spleen. These macrophages in HBM were hypothesized to perform an immunological supportive function as antigen-presenting cells in the local immune response of the gut.
The neonatal immune system is naive because it has not been exposed to antigens and as a result, has deficiencies in memory T cells. However, convincing studies demonstrate that the memory T cells from the mother may be transferred to the offspring via HBM to compensate passively immunological memory T cells of the offspring. Wirt et al found that activated T cells are the primary population of lymphocytes in HBM, including CD4+ and CD8+ T cells, that have a higher population in the HBM than in human blood. The authors speculate that activation of T cells is due to being stimulated by tumour necrosis factor (TNF)-Î± and other cytokines and it is conversely possible that these activated T cells may produce cytokines, including TNF-Î±, found in HBM. These memory T cells pass through the stomach and intestine of the infant, particularly prior to the development of high gastric acidity which occurs after the first several days of life.
Composition of microflora
The gut-associated lymphoid tissue (GALT) in the intestine is thought the largest immune organ in the body, homing about 80% of the body's immune cells such as the majority of lymphocytes and other immune effector cells. The neonatal immune system is immature, therefore the lining of the gut which is the first barrier against the entry of exogenous pathogens and allergens is ineffective. HBM can enhance the immune system by the inoculation of the gut with microbiota, a complex microbial ecosystem composed of various strains of bacteria, protozoa and fungi. HBM helps the normal intestinal flora get settled and it counteracts potential pathogens.
There is increasing evidence to show striking differences in the composition of gut microflora between breast-fed and formula-fed infants. The intestine of breastfed infants is primarily colonized by higher numbers of Bifidobacteria which are considered beneficial bacteria. This bacterium seems to be found in children's microbiota, with both breast-fed and formula-fed infants. However, research suggests that in breastfed infants over 95% of the flora are Lactobacillus bifidus and Bifidobacterium spp., compared to formula-fed infants where only 40 to 60% of the flora is Bifidobacteria. Instead, formula-fed infants acquire a higher percentage of Gram-negative coliform bacteria, Bacteroides and others including Enterobacter, Enterococcus, Escherichia coli, and Clostridia than do breastfed infants.
Lactic acid bacteria and Bifidobacteria, which are predominately in the gut of breastfed infants, are thought to reduce the pathogenic potential of other bacteria in the gut by changing pH, producing certain antibiotic-like substances and/or reducing the invasive ability of pathogens. Breastfeeding confers several other positive effects including the inactivation of carcinogens as Lactobacillus and Bifido bacteria reduce tumour development and mucosal inflammatory activity, whereas Bacteroides and Clostridium increase the incidence and growth rate of colon tumours in animals. Lactobacillus provides benefits in reducing the numbers of infections by stimulating the production of antibodies. These probiotic bacteria are thought to be established by breastfeeding.
A large study of 957 infants in the Netherlands found an association between colonization with gut bacteria and the development of atopy within the first 2 years of life. Infants colonized with Escherichia coli had high risk of eczema. The high risk of developing recurrent wheeze, eczema, and allergic sensitization presented in infants colonized with Clostridium difficile compared with uncolonised infants. On the other hand, there is no association between these atopic outcomes and colonisation with Bifidobacteria, Bacteroides fragilis and Lactobacilli. Another prospective study of children from birth to 17 years found that exclusive breastfeeding provides significant protection, but the mechanism is unknown, against food allergies and eczema for the first 1 to 3 years and later against respiratory tract allergies. The prevalence of respiratory allergy increased to 65% at 17 year of age in infants who breastfed for less than 1 month of age. Recent clinical trials, but no conclusive studies, support the possibility of benefits from live microflora such as Lactobacilli and Bifidobacteria, suggesting they could be beneficial for allergy prevention or treatment in the future.
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The thymus is a special organ for maturation of T lymphocytes and its differentiation is completed by 18 to 20 weeks of fetal life. In general, less than 10% of T lymphocytes can be permitted from the thymus to the circulation. For the last several decades, there is substantial evidence to suggest that breastfeeding increases the size of the thymus. A longitudinal study by Hasselbalch et al found that the thymus of exclusively breastfed infants was twice as large as the size of formula-fed infants at age 4 months when the thymus is growing. An additional finding was the correlation between birth weight and the size of the thymus. Low birth weight could decrease the relative size index of the thymus, which may cause infectious disease in infancy. Further, they found not only a strong connection between thymus sizes with breastfeeding, but also found a correlation between increased number of CD8+ cells in peripheral blood and the size of thymus at 10 months of age. The result clearly indicates that breastfed infants who have large thymuses obtain a high percentage of T lymphocytes in the blood circulation, more so than non-breastfed infants. While our knowledge regarding the possible role of an enlarge thymus has grown, it still remains incomplete.
The size of the thymus is significant for infants at 6 months of age because a small thymic size could be related to a higher risk of mortality. A study in Guinea-Bissau in West Africa has shown that the strong association between the small thymic size and the high rate of mortality during the last 6 months of the first year of life. The authors speculate that thymus size has an influence on immunocompetence during the first year of life. Another African study in Gambia suggests that the rates of mortality in young adulthood in the region could be predicted by season of birth. Infants born during the "hungry" season presented with smaller thymuses, with the risk of mortality being ten times higher than infants born in the "harvest" season. In relation to the immune system in the Gambian study, those born in the hungry season had lower T cell receptor-rearrangement excision counts, and HBM from their mothers had significantly lower cytokine interleukin-7 (IL-7) compared with those mothers whose infants were born in the harvest season. However, the relationship between increased neonatal mortality and breastfeeding is unclear in developed countries.
IL-7 is essential for lymphocyte homeostasis and development, particularly in the very first stage of Th2 subset development and the primary activation of naive CD4+ cells. IL-7 sends crucial signals to lymphoid cells at early stages of development which is required for lymphopoiesis, as IL-7 knockout mice became significantly lymphopenic into its peripheral blood and lymphoid organs. The total T cell population decreased about 10 to 20 fold and thymic cellularity reduced 20 fold. In addition, Aspinall et al found that IL-7 knock-out mice presented higher thymocyte subsets and peripheral T cell populations when they were fostered onto normal mothers compared to IL-7 knock-out mothers. IL-7 labelled in IL-7 knock-out mice milk shows that it not only crosses the intestinal mucosa but also enters the lymphoid tissues of the offspring. The permeability of the neonatal gut can allow bioactive proteins, even large peptides such as insulin or epidermal growth factor, to transfer to internal tissues.