Human milk immunity

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A microscopy image of a sample of human breast milk A microscopy image of a sample of human breast milk.JPG
A microscopy image of a sample of human breast milk

Human milk immunity is the protection provided to the immune system of an infant via the biologically active components in human milk. Human milk was previously thought to only provide passive immunity primarily through Secretory IgA, but advances in technology have led to the identification of various immune-modulating components. [1] [2] [3] Human milk constituents provide nutrition and protect the immunologically naive infant as well as regulate the infant's own immune development and growth. [4]

Contents

Immune factors and immune-modulating components in human milk include cytokines, growth factors, proteins, microbes, and human milk oligosaccharides. [5] [6] Immune factors in human milk are categorized mainly as anti-inflammatory [2] primarily working without inducing inflammation or activating the complement system. [7]

Immune factors

Bio-active constituents of human milk that have been cataloged to possess immune-modulating capabilities include immunoglobulins, Lactoferrin, Lysozyme, oligosaccharides, lipids, cytokines, hormones, and growth factors. [7] [8] Some of the roles of bio-actives in human milk are theorized based on their function in other parts of the body, but the mechanisms and function of their activities remain to be discovered. [9]

IgA

Immunoglobulin A is the most well known immune factor in human milk. [2] In its secretory form, SIgA, it is the most plentiful antibody in human milk. [2] [8] It constitutes between 80-90% of all immunoglobulins present in milk. [8] SIgA provides adaptive immunity by directly targeting specific pathogens that both infant and mother have been exposed to in their environments. [2] [10]

Lactoferrin

Lactoferrin is an immune protein with strong anti-microbial function in human milk. [11] Lactoferrin protects the infant intestine by binding to iron to prevent pathogens from utilizing it as a resource. It also modulates immunity by blocking inflammatory signaling cytokines. [7]

Cytokines

Cytokines are pluripotent signaling molecules with the ability to bind to specific receptors. [3] They can cross the intestinal barrier and mediate immune activity. [12] Their presence in human milk may stimulate lymphocytes responsible for the development of the infant's specific immunity. [7] Cytokines present in human milk include IL-1β, IL-6, IL-8, IL-10, TNFα, and IFN-γ. [3]

Origin and establishment

Bio-active components in human milk are speculated to colonize in human milk in several ways including secretion by the mammary gland, epithelium cells, and by milk cells. [3] [12] Maternal immune factors are transferred by lymphocytes traveling from the mother's gut to the mammary gland [8] where the secretory cells of the breast produce antibodies. [10]

The origin of the human milk microbiota, including those with immune-modulating functions, are not well established. However, several theories including skin-to-skin contact, [2] the entero-mammary pathway, [13] and retrograde back-flow hypothesis [14] [15] have been put forth to explain the microbial composition of human milk.

Known factors of influence

From Colostrum to Breastmilk in days From Colostrum to Breastmilk - 4241.jpg
From Colostrum to Breastmilk in days

Lactation stage

Human milk immune composition is known to change over the course of lactation. [12] Most notably, antibody levels are lower in mature milk than in colostrum, [7] with SIgA measuring at up to 12 grams per liter in colostrum and decreasing to 1 gram per liter in mature milk. [8] Studies find time postpartum to be most influential on the presence of immune factors, including growth factors [16] and lactoferrin. [11]

Human milk microbiome

The exposure to microbiota through mother's milk is the primary stimulus for immune development in infants. [8] Microbiota interacts with the infant's immune system by stimulating the mucous layer, down-regulating the inflammatory response, producing antibodies and helping initiate oral tolerance. [17] Mucosal layers protection comes from their ability to limit pathogens from attaching to the infant intestinal tract. [8]

Human milk oligosaccharides

Human milk oligosaccharides (HMOs) are carbohydrate components in human milk. [12] They are mostly indigestible and work as a prebiotic to feed commensal bacteria in the infant gut. [9] [18] Studies show that HMOs also function as immune-modulators by blocking receptors that allow pathogenic bacteria to attach to the infant intestinal epithelium. [19]

Delivery mode

There are observed differences in immune factor composition in the milk of mothers who delivered cesarean versus vaginally. [20] A study of 82 women saw an increase in the levels of IgA in the colostrum of women who had cesarean births after experiencing labor when compared to women who delivered vaginally or had elected cesareans. [21]

Maternal Characteristics

Parity

Milk immunity levels are observably lower in women with higher parity. [22] A study among the Ariaal women of Kenya saw that milk IgA decreased drastically only in women who had given birth to eight or more children. [23]

Diet

Human milk composition remains relatively stable despite maternal dietary changes, except in cases of extreme maternal depletion. Seasonal changes and malnutrition influence the concentration of immune factors. [22]

In addition, intervention studies have confirmed that both fish oil [24] and fish consumption during pregnancy can alter immune-modulating components in human milk. [25]

Environmental factors

Differences in the maternal environment such as rural and urban environments, [26] including exposure to farming, [27] and exposure to pathogens [28] have shown to affect human milk immune factor variation. [2]

Geographic location

Geographic location is known to play a role in human milk variation, with country of residence specifically linked with immune factor variation. [29] A study found a variation in levels of growth factor in both mature milk and colostrum to be correlated with geographic location. [16] However, a larger study found support for consistency in the presence of a small group of immunological factors in mature milk independent of geographic location. [26]

Impact on health

Health outcomes for Breastfed versus formula-fed infants

Formula Nutramigen Baby Formula.JPG
Formula

Over the last century, breastfeeding has been consistently shown to reduce infant mortality and morbidity, particularly of infectious disease. [8] Comparative research between human milk and formula has pointed towards the bio-active components in human milk as potential proponents of its immunological protection. [9] Studies have shown that breastfed infants respond better to vaccines, [30] and are better protected against diarrhea, otitis media, sepsis, and necrotizing enterocolitis, [7] celiac disease, obesity, and inflammatory bowel disease than formula-fed infants. [1] Human breast milk is seen as particularly beneficial to infants born before full term and those that are underweight at birth who are at a higher risk of infectious diseases, such as sepsis and meningitis. [7] [30] Also, there is a lower chance of contamination acquired through direct breastfeeding than with mixing formula with water or other animal milks which may also help explain why human milk is more protective for the infant. [31]

Long term protection

Because various components present in human breast milk stimulate the growth of the immune system, there is a growing interest in whether breastfeeding provides a long term protective effect against auto-immune and inflammatory diseases. [7]

Milk sharing and donor milk

The WHO infant feeding guidelines advise the use of donor milk when the mother's milk is not available. [32] With the understanding that breast milk provides immune protection that is absent in formula, mothers have turned to milk sharing options to in order to give formula alternatives to their infants. [33] A donation of milk without monetary benefit defines milk sharing. [32]  In addition, milk banks have emerged to regulate and pasteurize donated milk to be sold in the legal market. [33] The main concern with bank milk is that it has lost many immune cells, commensal microbiota and bio-active proteins during the pasteurization process. [34] Donor milk is in high demand for infants in the Neonatal Intensive Care Unit (NICU). [33] who have been shown to benefit most from access to human milk [35]

Immunological consequences or benefits of milk sharing are not well documented, but it has been speculated that allo-nursing, or nursing from multiple females, may provide infants with an immune boost. [33] The reported risk associated with unregulated sharing milk includes the possibility of the transmission of drugs, toxins, pathogenic bacteria, HIV and other viruses. [33] However, some researchers believe that allo-nursing and milk sharing may have been part of our evolutionary past. Evidence of milk sharing history include the wet nursing practices of the 20th century, [33] milk kinship among Islamic tradition, [36] and documentation of allo-nursing in primates species. [33] [37]

Evolutionary implications

There is evidence of a relationship between the microbes that have co-evolved with humans as their host and the human immune system. [38] The transfer of microorganisms from mother to offspring is universal in animals. In humans, microbial exchange occurs primarily through placental transfer and breast milk. [39] The presence of these complex microbial communities in the human body suggests that the immune system has been selected to remember and mediate the colonization of these microorganisms within the human host. [40] Further, microbial dysbiosis in infants is strongly associated with immune-mediated diseases such as allergies and necrotizing enterocolitis. [17]

In early life, an infant's immune system is considered immature due to its lack of resources necessary for defense against infection. [7] An infant is not able to produce specific cytokines, [30] IgA, [7] and is limited to producing mostly IgM antibodies. [30] The human infant is unable to adequately protect itself without the immune-stimulating and immune-modulating components present in human milk. This dynamic affirms the consensus among researchers that human milk evolved to provide not only nutritional but immunological benefits to the infant. [23] Some researches have proposed that the mammary gland and milk production evolved as a part of the human innate immune system, [41] with its immunological protective role predating its nutritional role. [42]

See also

Related Research Articles

<span class="mw-page-title-main">Infant formula</span> Manufactured food designed for feeding infants

Infant formula, also called baby formula, simply formula, baby milk or infant milk, is an ultra-processed food designed and marketed for feeding to babies and infants under 12 months of age, usually prepared for bottle-feeding or cup-feeding from powder or liquid. The U.S. Federal Food, Drug, and Cosmetic Act (FFDCA) defines infant formula as "a food which purports to be or is represented for special dietary use solely as a food for infants by reason of its simulation of human milk or its suitability as a complete or partial substitute for human milk".

<span class="mw-page-title-main">Colostrum</span> Form of milk produced immediately following the delivery of newborn

Colostrum, or first milk, is the first form of milk produced by the mammary glands of humans and other mammals immediately following delivery of the newborn. It may be called beestings when referring to the first milk of a cow or similar animal. Most species will begin to generate colostrum just prior to giving birth. Colostrum has an especially high amount of bioactive compounds compared to mature milk to give the newborn the best possible start to life. Specifically, colostrum contains antibodies to protect the newborn against disease and infection, and immune and growth factors and other bioactives that help to activate a newborn's immune system, jumpstart gut function, and seed a healthy gut microbiome in the first few days of life. The bioactives found in colostrum are essential for a newborn's health, growth and vitality. Colostrum strengthens a baby's immune system and is filled with white blood cells to protect it from infection.

<span class="mw-page-title-main">Breast milk</span> Milk produced by the mammary glands in the breast of a human female

Breast milk or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates and variable minerals and vitamins. Breast milk also contains substances that help protect an infant against infection and inflammation, whilst also contributing to healthy development of the immune system and gut microbiome.

<span class="mw-page-title-main">Gut microbiota</span> Community of microorganisms in the gut

Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.

A bifidus factor is a compound that specifically enhances the growth of bifidobacteria in either a product or in the intestines of humans and/or animals. Several products have been marketed as bifidogenic factors, such as several prebiotics and methyl-N-acetyl D-glucosamine in human milk.

<span class="mw-page-title-main">Breastfeeding</span> Feeding of babies or young children with milk from a womans breast

Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be pumped and fed to the infant. The World Health Organization (WHO) recommends that breastfeeding begin within the first hour of a baby's life and continue as often and as much as the baby wants. Health organizations, including the WHO, recommend breastfeeding exclusively for six months. This means that no other foods or drinks, other than vitamin D, are typically given. The WHO recommends exclusive breastfeeding for the first 6 months of life, followed by continued breastfeeding with appropriate complementary foods for up to 2 years and beyond. Of the 135 million babies born every year, only 42% are breastfed within the first hour of life, only 38% of mothers practice exclusive breastfeeding during the first six months, and 58% of mothers continue breastfeeding up to the age of two years and beyond.

<span class="mw-page-title-main">Lactation</span> Release of milk from the mammary glands

Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process of feeding milk in all female creatures is called nursing, and in humans it is also called breastfeeding. Newborn infants often produce some milk from their own breast tissue, known colloquially as witch's milk.

<span class="mw-page-title-main">Galactooligosaccharide</span> Class of prebiotics

Galactooligosaccharides (GOS), also known as oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides (TOS), belong to the group of prebiotics. Prebiotics are defined as non-digestible food ingredients that beneficially affect the host by stimulating the growth and/or activity of beneficial bacteria in the colon. GOS occurs in commercially available products such as food for both infants and adults.

<span class="mw-page-title-main">Extended breastfeeding</span> Defined as after age 12–24 months

In Western countries extended breastfeeding usually means breastfeeding after the age of 12 to 24 months, depending on the culture.

Infant feeding is the practice of feeding infants. Breast milk provides the best nutrition when compared to infant formula. Infants are usually introduced to solid foods at around four to six months of age.

Late preterm infants are infants born at a gestational age between 34+0⁄7 weeks and 36+6⁄7 weeks. They have higher morbidity and mortality rates than term infants due to their relative physiologic and metabolic immaturity, even though they are often the size and weight of some term infants. "Late preterm" has replaced "near term" to describe this group of infants, since near term incorrectly implies that these infants are "almost term" and only require routine neonatal care.

Human milk oligosaccharides (HMOs), also known as human milk glycans, are short polymers of simple sugars that can be found in high concentrations in human breast milk. Human milk oligosaccharides promote the development of the immune system, can reduce the risk of pathogen infections and improve brain development and cognition. The HMO profile of human breast milk shapes the gut microbiota of the infant by selectively stimulating bifidobacteria and other bacteria.

<span class="mw-page-title-main">Milk fat globule membrane</span>

Milk fat globule membrane (MFGM) is a complex and unique structure composed primarily of lipids and proteins that surrounds milk fat globule secreted from the milk producing cells of humans and other mammals. It is a source of multiple bioactive compounds, including phospholipids, glycolipids, glycoproteins, and carbohydrates that have important functional roles within the brain and gut.

<span class="mw-page-title-main">Human milk microbiome</span> Community of microorganisms in human milk

The human milk microbiota, also known as human milk probiotics (HMP), refers to the microbiota (community of microorganisms) residing in the human mammary glands and breast milk. Human breast milk has been traditionally assumed to be sterile, but more recently both microbial culture and culture-independent techniques have confirmed that human milk contains diverse communities of bacteria which are distinct from other microbial communities inhabiting the human body.

The first 1000 days describes the period from conception to 24 months of age in child development. This is considered a "critical period" in which sufficient nutrition and environmental factors have life-long effects on a child's overall health. While adequate nutrition can be exceptionally beneficial during this critical period, inadequate nutrition may also be detrimental to the child. This is because children establish many of their lifetime epigenetic characteristics in their first 1000 days. Medical and public health interventions early on in child development during the first 1000 days may have higher rates of success compared to those achieved outside of this period.

<span class="mw-page-title-main">Delayed onset of lactation</span>

Delayed onset of lactation (DOL) describes the absence of copious milk secretion (onset of lactation) within the first 72 hours following childbirth. It affects around 20–40% of lactating women, the prevalence differs among distinct populations.

<span class="mw-page-title-main">Establishment of breastfeeding</span>

Establishment of breastfeeding refers to the initiation of providing breast milk of mother to baby. According to the World Health Organisation(WHO), breastfeeding is the best way to provide nourishment, including essential nutrients, energy and antibodies, to infants and toddlers. The start of breastfeeding is supported by the milk production which depends on the development of internal and external breast structure and hormonal control on milk secretion. Besides milk supply, adopting the correct approach of breastfeeding helps build up the maternal bond, which in turn promotes breastfeeding. Not only does nursing strengthen the mother-child relationship, but it also improves the intelligence and immunity of breastfed children and diminishes breastfeeding mothers' risks to have ovarian and breast cancer.

Milk immunity is the protection provided to immune system of an infant via the biologically active components in milk, typically provided by the infant's mother.

Breastmilk medicine refers to the non-nutritional usage of human breast milk (HBM) as a medicine or therapy to cure diseases. Breastmilk is perceived as an important food that provides essential nutrition to infants. It also provides protection in terms of immunity by direct transfer of antibodies from mothers to infants. The immunity developed via this mean protects infants from diseases such as respiratory diseases, middle ear infections, and gastrointestinal diseases. HBM can also produce lifelong positive therapeutic effects on a number of chronic diseases, including diabetes mellitus, obesity, hyperlipidemia, hypertension, cardiovascular diseases, autoimmunity, and asthma.

Breast milk-mediated drug delivery refers to the use of breast milk to transport a pharmaceutical compound, protein, or other treatment to achieve a desired effect. Delivery of these substances via milk provides an oral alternative for transport of a compound to the gut, specifically in infants. Breast milk-mediated drug delivery provides a way for pharmaceuticals and proteins to travel through the gastrointestinal system of an infant while minimizing the potential for irritation within gastrointestinal tissue.

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