Breast milk contains various bioactive substances including hormones, immunoglobulins, enzymes and growth factors, in addition to its macro and micronutrients.1
It has been suggested that breast milk is a vehicle of communication between the maternal and infant immune systems,2 providing not only passive protection but also direct active immunomodulation.3
Breast milk protects newborns against pathogens through direct action on multiple physiological systems. Bioactive and immunological factors regulate the baby’s immune, metabolic and microbiological systems.4
Evidence shows that breastfeeding protects infants from all socioeconomic groups in a dose/duration-response pattern of protective effects.4,5,6 This review summarizes the immune components and immunological properties of breast milk and provides an update on its possible implications in the neonatal population.
> Postnatal immunological adaptation
In utero , the fetus shows tolerance to endotoxins and has privileged immunity.7 During labor, the fetus’ predominantly T-helper 2 response adapts to a more "adult" immune pattern with an increased proinflammatory response.7, 8
As enteral microbial antigens are encountered during milk feeding, the infant’s intestinal immune system develops rapidly.2 Effective activation of the immune system is carefully balanced with the tolerance necessary to allow colonization of the commensal microbiota in the newborn. 8
There remains an increased susceptibility to infection, partly due to the immature neonatal immune system and also due to the need to avoid an excessive inflammatory response to the postnatal environment. This dysregulated inflammation is even more pronounced in premature babies. 7
A sustained inflammatory response has been implicated in abnormal neurodevelopmental outcomes in premature infants.7,9 Examples of this include adverse neurologic outcomes following sepsis, necrotizing enterocolitis (NEC), and even coagulase-negative staphylococcal (NEC) infections (previously thought that they were skin commensals that caused contamination of the blood sample).7
Breast milk has been found to protect against late-onset sepsis caused by CoNS10 The incidence of periventricular leukomalacia, a cause of neurodevelopmental impairment, is potentially lower in breast-fed infants than in formula-fed infants. eleven
> Immunological properties
The immune and non-immune ingredients in breast milk promote the development of the infant’s immune system while regulating the balance between tolerance and inflammatory response.
All immunological components of breast milk, except immunoglobulin (Ig) G, are present in higher concentrations in colostrum than in mature milk.12
The interaction between these bioactive components with the intestinal microbiome attenuates inflammatory responses in babies and improves intestinal health. 13
> Immunoglobulins
In the early postnatal period, the neonatal intestinal immune system is immature and relies on passively acquired maternal antibodies, in particular secretory immunoglobulin A (sIgA). 13 In premature infants, breast milk is the predominant source of sIgA in the first month after birth.14
IgG and IgM antibodies are also present in breast milk and provide protection to the infant, but are present at much lower concentrations.12 The production of sIgA by the infant’s intestine is gradually stimulated by the intestinal microbiota, coinciding with a reduction in sIgA in breast milk.2 sIgA contributes to the regulation of tolerance to the immune response in the infant’s intestine. 2
> Cytokines
Cytokines are pluripotent polypeptides that modulate the immune system by binding to specific cellular receptors.3 Although the mammary gland is the main source of these cytokines, leukocytes in breast milk are capable of producing cytokines independently.2, 3
They can be divided into 2 groups, those that protect against infection by promoting inflammation and those that decrease it.15 They are believed to overcome the delay in maturation of the neonatal immune system by stimulating immune activity as they cross the intestinal barrier of the infant.15
The cytokine content of breast milk is influenced by different stages of breastfeeding, gestational age, infections, ethnicity, diet, and smoking.16 Adipocyte-derived cytokines, adipokines, exert metabolic programming effects through long-term by modifying weight and lean body mass in infants.17
> Growth factors and hormones
Breast milk contains many hormones and growth factors including lactoferrin, epidermal growth factor, nucleotides, insulin, prolactin, cortisol, thyroid hormones, leptin and erythropoietin.1,2,13,15.18
Breast milk is the main source of epidermal growth factor (EGF) and heparin-binding EGF-like growth factor, which are crucial in the regeneration and repair of the intestinal epithelium.19
Premature milk contains higher levels of EGF than term milk, which may partly explain why breast milk has a protective effect against NEC in this population.19 Human milk stem cells release growth factor of hepatocytes, which promotes organogenesis in the infant.20
> Lactoferrin
Lactoferrin is the major whey protein in all mammalian milk and is a key component of the mammalian innate response to infection.
Lactoferrin has broad antimicrobial and anti-inflammatory actions and has prebiotic properties, creating an enteric environment for the growth of beneficial bacteria and reducing colonization by pathogenic species.21
It is not known why endogenous lactoferrin in breast milk exerts different effects than exogenous lactoferrin supplementation in infants. However, bovine lactoferrin supplementation does not reduce mortality or significant morbidity in premature infants.22,23
Lactoferrin works together with lysozyme to exert an antibacterial effect by degrading the outer walls of bacteria. 13
> Nucleotides and fatty acids
Although these constitute relatively small fractions of breast milk, both nucleotides and fatty acids are reported to contribute to neonatal immune development.
Nucleotides have beneficial effects on mucosal immunity in animal models and may allow activation of macrophages through the production of immunomodulatory factors.2
> Extracellular cells and vesicles
Breast milk contains live cells including human breast milk-derived stem cells (hBSCs), epithelial progenitors, mature epithelial cells, and leukocytes.24, 25
The main cellular component of mature milk comprises cells of an epithelial nature derived from the mammary gland, especially lactocytes and myoepithelial cells.24
In mature milk, leukocytes represent approximately 2% of the cellular component. In contrast, leukocytes comprise up to 70% of the cellular component in colostrum24 and up to 94% in response to an infection of the infant or mother.12, 26 The composition of leukocytes by subtype varies, but macrophages and Neutrophils make up a larger proportion than lymphocytes.2
Leukocytes are believed to mediate active immunity and develop immunocompetence in the infant by phagocytosis, secretion of cytokines and immunoglobulins, and presentation of antigens, in addition to protecting the mammary gland from infection.2, 12, 27
Leukocyte immunomodulation occurs within the infant’s gastrointestinal tract and remotely in other tissues after transfer into the infant’s systemic circulation.12,26 It is unclear why the rates of symptomatic human immunodeficiency virus infections and cytomegalovirus are very low in exclusively breastfed infants, even with infected mothers.12
One hypothesis is that the presence of antiviral delivery agents in breast milk provides protection and virological control.28 It is unclear how childhood infections lead to an increase in the leukocyte content of breast milk.
A local immune response may result from a reversed milk flow during feeding, containing infant saliva.12,29 This may lead to dynamic cycling of bacteria within the mother-infant dyad, influencing the dynamic bacterial population and diverse found in breast milk and the infant microbiome.1, 29
In animal models, breast milk stem cells were detected in the blood and brain of lactating offspring, and differentiated into neuronal and glial cell types within the brain.30 During pregnancy and lactation, hBScs actively regenerate the mammary gland.12 In addition to cells, extracellular vesicles are detectable in breast milk and carry exosomes and proteins that play a role in cell signaling.1
> Human milk glycobiome
Milk glycans comprise human milk oligosaccharides (HMOs), glycoproteins and glycolipids, 31 together forming the milk glycobiome.
HMOs actively modulate the gut microbiota and confer protection against infectious diseases by acting as prebiotics that select for the growth of beneficial bacteria.31 One such genus is Bifidobacterium, which is commonly observed in breastfed infants.32 HMOs of small mass, they are abundant at the beginning of the lactation cycle and are preferentially consumed by strains of Bifidobacterium longum subsp Infantis. 32
Soluble milk oligosaccharides are present in large quantities in breast milk (5 to 23 g/L) and are the third largest solid component after lactose and lipids.33 The composition of HMO varies between mothers and is partially determined by the genotype of the maternal secretor (FUT2) 34 It is estimated that between 20% and 25% of the population is homozygous for the non-secretory allele; the remaining 75% to 80% are secretors.35
The breast milk of secretory mothers contains fucosylated α1-2, which are almost completely absent in the milk of non-secreting mothers.34, 35 The maternal secretory state is thought to influence the infant’s immune system through the gut microbiota. .4, 32 Furthermore, the secretory status of preterm infants themselves is associated with survival. 36
A portion of HMOs is absorbed from the infant’s intestine into the circulation and excreted in the urine. 37 HMOs are thought to directly influence the infant’s gut microbiome by reducing the adhesion of pathogenic bacteria and serving as a nutritional source, like prebiotics, for the microbiome itself because they remain largely undigested by the infant.1, 34
Sialylated oligosaccharides are known to improve intestinal barrier function and potentially improve nutrient absorption.38
In 6-month-old very short infants, corresponding breast milk samples were found to have lower amounts of sialylated HMOs.38 Preclinical models have indicated a microbiota-dependent causal relationship between bovine milk sialylated oligosaccharide and beneficial effects on growth, because no such effects on growth were observed in a germ-free animal model. 38
| Establishment of the gut microbiome |
The earliest source of infant intestinal colonizers is the maternal microbiota, transferred during birth, breastfeeding, and skin contact.39 Breastfed babies are estimated to ingest about 800,000 bacteria per day through breast milk. 1
The neonatal gut microbiome, the entire population of gut microorganisms including bacteria, viruses, and parasites, is thought to be influenced by the synergistic interaction between the infant gut microbiome, human milk microbes, and HMOs. 1, 39
The intestinal microbiota can be considered a metabolic organ, whose activity is modulated by bioactive components of breast milk. It is responsible for modulating the infant immune system through this metabolic activity.4
An immature gut microbiome, called dysbiosis , is associated with antibiotic exposure, cesarean delivery, formula feeding, and diarrheal diseases.39
In the first weeks after birth, Enterobaceria comprise the largest proportion of the microbiome, followed by a period of dynamic change in the microbiota, which is sensitive to the source of nutrition.39 Breast milk leads to greater diversity in both the microbiome as in the glycobiome.32, 39
Beneficial Bifidobacterium species dominate as a result of multiple mechanisms: HMOs function as decoy receptors at epithelial attachment sites to prevent pathogen colonization and promote Bifidobacterium; Proteolysis of the milk protein K-casein produces another decoy receptor, glycomacropeptide; proteolysis of lactoferrin produces antimicrobial lactoferricin; and cytokines and Igs A mediate the death of pathogens.4 At 2 years of age, the intestinal microbiome is very diverse and similar to that of an adult.39
| Healthy immune brain axis |
The stress-microbiome-immunity pathway remains poorly understood. In murine models, stressful events during pregnancy and milk feeding lead to altered gut microbiota in the offspring.
Babies born to mothers with depression have lower fecal IgAs, despite breastfeeding.40
The cause of this is unknown. However, infants exposed to high maternal distress during pregnancy show a reduction in lactic acid bacteria in early life.41 Such bacteria stimulate intestinal IgA production and improve the integrity of the intestinal lining. 42
| Clinical implications |
> Intestinal inflammation
NEC is an example of extreme intestinal inflammation. Current evidence suggests that NEC is a multifactorial process consisting of an immature neonatal immune system, alteration of the microbiome with subsequent overgrowth of pathogenic bacteria, and an exaggerated inflammatory response leading to necrosis of the intestine.43, 44, 45, 46 NEC mainly affects very premature infants.47
Although rates vary internationally, it is estimated that NEC occurs in up to 7% of newborns before 32 weeks of full gestation and in up to 22% of extremely low birth weight babies.48
Although not fully understood, the NEC pathway in premature infants is believed to be the result of increased intestinal immaturity, microbial dysbiosis, an immature immune system, and an uncontrolled inflammatory cascade.43, 45, 46
Some authors have suggested that NEC in full-term newborns has a different underlying pathophysiological mechanism.49 Altered mesenteric blood flow with possible hypoxic-ischemic reperfusion injury along with feeding with non-human milk are possible predisposing factors in the development of NEC. in term newborns.50, 51
The term NEC is associated with congenital heart disease, perinatal hypoxia, hypotension, sepsis, respiratory disease, and neonatal abstinence syndrome. 50, 51, 52 NEC is associated with adverse outcomes, including mortality, infection, poor growth, intestinal failure, and neurodevelopmental delay.53 More babies survive extreme preterm birth, leading to an increase in the number of babies at risk of developing NEC.53
It is not understood why breastfed infants have a reduced risk of NEC, 54, 55, 56, 57 with a dose-related association of breastmilk feeding and reduced risk of NEC. 55, 58, 59
Higher proportions of breast milk intake are associated with reduced intestinal inflammation. 60 A reduction in the rate of sepsis was observed in very low birth weight infants, in infants who received at least 50 ml/kg per day of breast milk in the first month after birth.59
Compared to bovine milk formula, breast milk is thought to reduce the risk of NEC by lowering gastric pH and improving intestinal motility.14 Immune maturation is thought to be increased by IgAs, lactoferrin, and HMOs, leading to reduced microbial dysbiosis. 14
IgA in breast milk has been shown to protect against the development of NEC in preterm infants.14 Overall, this protection is likely the result of multiple bioactive components that attenuate inflammation, particularly in preterm infants.13, 14 , 46, 61
Several Cochrane reviews of infant feeding methods and their association with NEC included infants who received breast milk. The use of formula versus donor breast milk for feeding preterm or low-birth-weight infants was evaluated in 12 completed trials involving 1,871 infants.
The authors suggested that formula feeding nearly doubles the risk of developing NEC.56 The incidence of NEC in full-term newborns can be reduced by identifying infants at highest risk and using breast milk feeding when possible. 51
> Atopic disease
Breastfeeding appears to protect infants against the development of atopic diseases, particularly in infants with a family history of atopy.62 Breastfeeding offers protection against atopic dermatitis, wheezing/asthma, allergic rhinitis, and cow’s milk protein allergy. . 2, 16, 62
Exclusive breastfeeding is recommended until 4 months of age to reduce allergic diseases. 63 Although the mechanism is unclear, high levels of IgA, certain cytokines, and HMO are associated with anti-allergy protection in infants, possibly through microbiome development.2, 16
Protection against allergic diseases may also be boosted by these immunostimulating bioactive components in breast milk. (sixteen)
| Conclusion |
Breast milk is an extremely complex mixture of interacting components, the composition of which varies between nursing mothers and during the lactation period. Our understanding of the effects of each component is still in its infancy.
The interrelationship between human milk composition and subsequent neonatal immunomodulation and microbiota remains elusive. Breastfeeding has wide-ranging clinical implications, many of which are not yet fully understood.
Education of the neonatal immune system through breast milk is increasingly thought to have critical lifelong implications on adult disease patterns.
