Bioactive Factors in Human Milk

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Human milk is considered the ideal food for newborns during the first 4 to 6 months of life.21 Nutritionally, human milk is specifically adapted to the needs of newborn infants.47 Also unique to milk, and so far not duplicated by infant formula, is the great array of “bioactive factors,” which provide infants with protection from infection by various microorganisms,17 hormones and growth factors that affect development,28 agents that modulate immune function,12 and anti-inflammatory components.13 Some components have several functions (i.e., some cytokines or vitamins modulate specific aspects of functional organ maturation).39, 59 Even the major nutrients in milk have specific bioactive functions before being digested to provide energy and precursors for growth25 (Table 1).

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PROTECTION AGAINST MICROORGANISMS

Although protection against acute infections of the digestive and respiratory tracts of breastfed infants was reported 2 decades ago,58 most of these studies, carried out mainly in developing countries, were methodologically flawed.2, 20 In the 1990s, carefully designed studies confirmed that breastfeeding protects newborns from diarrhea, respiratory infections, and otitis media in developing countries (where inocula might be higher)48 and industrialized countries,7, 33 where sanitary standards

IMMUNOGLOBULINS

The topic of immunoglobulins has been reviewed elsewhere.60, 61 Briefly, although immunoglobulin G, M, D, and E are present in human milk and might protect the lactating mammary gland and newborns from infection, polymeric IgA is the main component of human milk (consumption by the infant is 4 g on day 1 post partum and about 1 g/d after day 4 post partum). The plasma cells that produce IgA home to the interstitium underlying the mammary secretory cells after migrating from lymphoid tissue in

NONIMMUNE PROTECTION

Nonimmune protection is provided by many components in human milk that, contrary to immune protection against specific antigens provided by milk immunoglobulins, protect in a nonspecific way and, thus, provide a broad spectrum of anti-infective activity (Tables 1 and 2). These components are reviewed only briefly here because many excellent reviews are available.**

PROTEINS

Lactoferrin, a 79-kD, 692-amino-acid, single-chain glycosylated protein, consists of two globular lobes, each containing one iron binding site (Table 3).29 Although the anti-infective function of this protein was ascribed to its high affinity for iron that may deprive microorganisms of needed iron, studies show that lactoferrin-associated protection is provided by several other mechanisms. Although iron-unsaturated lactoferrin contributes to bacteriostasis in milk and other mucosal secretions,50

LYSOZYME

Lysozyme, a 14.4-kD, 130-amino-acid-containing glycoprotein, hydrolyzes the 1–4 linkage between N-acetyl glucosamine and N-acetylmuramic acid in bacterial walls. Lysozyme, like lactoferrin, is present in other exocrine secretions and lyses mostly gram-positive and few gram-negative bacteria. Contrary to the other protective proteins in human milk (i.e., IgA and lactoferrin), the concentration of which decreases during lactation, those of lysozyme increase with prolonged lactation.

CASEIN

κ-Casein, a 30- to 40-kD, 162-amino-acid, highly glycosylated human milk protein has been shown to inhibit adherence of H. pylori to human gastric mucosa and of Streptococcus pneumoniae and Haemophilus influenzae to human respiratory-tract epithelial cells. The C-terminus proteolysis product of k-casein is a strong growth-promoting factor for Bifidobacterium bifidium, an acid-producing anaerobe that reduces the growth of intestinal pathogenic microorganisms in breastfed infants.29 The genes for

GLYCOCONJUGATES AND OLIGOSACCHARIDES

The milk components glycoconjugates and oligosaccharides act as ligands for microorganisms and viruses and their toxins, thereby inhibiting binding of pathogens to epithelial surfaces (Table 4).44, 46 These components present in the milk-fat globule membrane and in skim milk, amount to 1.5 g/dL, and thus are the third most abundant components in human milk. Among the best known components in this group are mucin-1 (400 kD) and lactadherin (46 kD) in the milk-fat globule membrane,46 which

LIPIDS

Milk-fat globules, the second most abundant component of human milk, protect infants from infection by two mechanisms: the membrane glycoconjugates act as specific bacterial and viral ligands, whereas the digestive product of the core triglycerides, free fatty acids (FAs), and monoglycerides, have a detergentlike lytic action on enveloped viruses, bacteria, and protozoa23 (Table 5). Although products of lipolysis are qualitatively similar among formula-fed and breastfed infants, quantitatively,

IMMUNOMODULATING AGENTS

Immunomodulating agents can affect the development of newborns' immune systems. Among these components are the cytokines defined as “pluripotent polypeptides that act in autocrine/paracrine fashion by binding to specific cellular receptors.”12 Production of these cytokines is less in newborns than in adults, with the extent of immaturity varying with the specific cytokine (Table 6). Many of these components are contained in human milk,3, 12, 13 and new agents continue to be found (e.g., IL-123

ANTI-INFLAMAMTORY COMPONENTS

Anti-inflammatory components in human milk are reviewed in detail elsewhere13 (see Table 7 for details). In general, these milk components consist of antioxidants (e.g., vitamins A, C, and E and enzymes such as catalase and glutathione peroxidase); E prostaglandins; enzyme inhibitors (e.g., platelet activating factor [PAF] acetylhydrolase, a 40-kD hydrolase that degrades PAF, a potent ulcerogen that is associated with development of necrotizing enterocolitis in newborns); protease inhibitors,

CELLS

The subject of cells in human milk, first mentioned in 1844, has been studied extensively and reviewed elsewhere.60, 61 Studies show that enterally administered human-milk leukocytes adhere to baboon intestinal epithelium for 60 hours and were able to cross into the circulation and migrate to spleen and liver.61 Also, milk cells were able to traverse intact human fetal intestinal transplants in mice and migrate into mice tissues.54, 61 Therefore, human milk cells may remain active in the

NUCLEOTIDES

Nucleotides in human milk differ qualitatively and quantitatively from those in bovine milk, enhance intestinal repair after injury, and potentiate the immune response to some vaccines. Some nucleotides also may promote the growth of Lactobacillus bifidus, which suppresses the growth of enteropathogens in newborns' intestine.

ENZYMES

Human milk, like the milk of other species, contains many enzymes27; however, the specific enzymes present and their activity levels vary among species. Enzymes in human milk can be characterized as functioning in the mammary gland in the process of milk production and secretion, enzymes that have putative or demonstrated activity in newborns, and enzymes with unknown function in mothers and infants.27 The reader is referred to reference 27 and additional references cited therein for more

HORMONES AND GROWTH FACTORS

Many hormones and growth factors are present in human milk. In general, their concentration is higher in early mammary secretion (i.e., prepartum and colostrum) than during later lactation. The structure of hormones in milk may differ from that in plasma because of glycosylation or phosphorylation in the mammary gland before secretion into milk. These structural differences may result in specific effects of milk-borne hormones that are not elicited by the serum hormone, as reported for

PROLACTIN

The role of prolactin in mammary-gland development and milk secretion has been investigated for several decades (see reviews in references 11,19, and 28). Its presence in the milk of many species, including humans, has been studied extensively, with the following finding19:

  • Multiple isoforms (8>66 kD) of glycolysated and phosphorylated prolactin

  • Bioactivity (Nb2 lymphoma test) higher than immunoactivity; bioactivity to immunoactivity ratio 1.2 to 3.5 and 1.2 to 2.1 in humans and rats

ERYTHROPOIETIN, MELATONIN, AND LEPTIN

Erythropoietin,38 melatonin,36 and leptin55 are present in human milk (Table 11). In newborns,11, 35, 40 the latter two hormones decrease rapidly after birth. Data for these three hormones are reviewed in reference 28.

CASOMORPHINS

Casomorphins are produced during the digestion of casein. These short peptides are opioid agonists with behavioral25 and immunomodulating16 effects.

General characteristics of milk bioactive components, common to most milk peptides and proteins, are a high degree of glycosylation that prevents their digestion by newborns, a prerequisite for function within the GI tract and systemically. The protective factors in milk often act synergistically, which may improve their efficiency in newborns.

SUMMARY

This article reviews the bioactive components of human milk. Special emphasis is given to immune and nonimmune protective function of major and minor nutrients in human milk. Immune modulating components, such as cytokines, nucleotides, hormones, and growth factors, are discussed. Milk enzymes with digestive function in the newborn are reviewed.

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    Address reprint requests to Margit Hamosh, PhD Department of Pediatrics Georgetown University Medical Center 3800 Reservoir Road NW Washington, DC 20007–2197 e-mail: [email protected]

    *

    Department of Pediatrics, Georgetown University Medical Center, Washington, District of Columbia

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