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Lactation Biology


The Neonate and Colostrum


W L Hurley
Department of Animal Sciences
University of Illinois
Urbana-Champaign


This lesson includes discussions on:

The Neonate
Intestinal Absorption of Immunoglobulins
Colostrum Formation
Immunoglobulin Transport in the Mammary Gland
Intestinal Protective Factors in Colostum and Milk
Bioactive Factors in Colostrum and Milk
Return to Lactation Biology Topic Areas


The Neonate
In nature, the mother's colostrum and milk is the only external source of everything required by the neonate, except for air it breaths. The neonate is constantly and rapidly changing, both structurally and physiologically. In the uterus, the fetus is living in a warm, moist, protected environment, and receiving all its needs from the mother. Major metabolic and physiological changes occur in the transition from a fetus to the newborn.

At birth, most mammalian neonates -

have limited fat stores
the fat stores which are present are not readily available for metabolism
use up their limited glycogen stores rapidly after birth
have poor gluconeogenic capacity (synthesis of glucose by the liver)
are agammaglobulinemic (they have very low concentrations of immunoglobulin in their blood)
neonate of many species have low iron stores
have stucturally immature intestines
have immature digestive capabilities, including:
low activities of all pancreatic enzymes
low activities of stomach pepsin
low activities of many intestinal enzymes
immature stomach acid generating mechanism (stomach pH is ~3.5)


Many mammalian neonates do have -

high rennin activity - for precipitation of casein, curd formation in the stomach
increasing lactase activity - forbreakdown of lactose in the intestine
high salivary lipase activity - for breakdown of milk triglycerides
In addition, the composition of mammary gland secretions is constantly changing, particularly over the initial 3 to 5 days postpartum (see below on Colostrum Formation and Immunoglobulin Transport in the Mammary Gland; also see the Milk Composition Lesson). There is considerable inter- and intra-species variation in how the colostrum changes during the initial days after parturition.

What controls the yield and composition of mammary secretions or the transition of colostrum to "mature" milk ?

- The physiological state or state of differentiation of mammary epithelial tissue.
- Repeated removal of milk from the gland.

So, there is an effect of mammary function on neonate survival and vitality, and an effect of the neonate on mammary function.


Intestinal Absorption of Immunoglobulins
See Staley and Bush, 1985, J. Dairy Sci. 68:184; Bush and Staley, 1980, J. Dairy Sci. 63:672; Larson et al., 1980 J. Dairy Sci. 63:665.

Normally we think of ingested food as being degraded in the digestive tract and digestion products being absorbed into the animal. For example, proteins would be degraded to amino acids or small peptides and those are absorbed. However, for a short time after birth most mammals will absorb macromolecules intact. This is particularly important for absorption of colostral immunoglobulins which would be rendered inactive if digested. In most species this absorption occurs by a nonspecific pathway (not receptor mediated) where macromolecules are taken into the intestinal absorptive cells (enterocytes) by formation of tubules at the base of the apical microvilli.

These tubules pinch off in the cell to form small vesicles that can transport the contents to the basolateral membrane and release their contents into the extracellular space. From there the macromolecules can be absorbed into the blood. This process of macromolecule absorption only occurs in the jejunum, not in the ileum.

Macromolecules are taken up into ileal enterocytes, but are degraded in lysosomes within the cell. In those cases where intestinal absorption is not selective, most anything will be absorbed including carbon aggregates and plastic. Therefore, there is little discrimination in absorption of the different immunoglobulins.

Intestinal transport of macromolecules is extensive but not selective in some species (such as the bovine, porcine and canine neonate), while in others (human infants, guinea pigs, rabbits) there is little intestinal absorption of macromolecules at all. In the latter cases, maternal immunoglobulins are transported to the fetus before birth and the neonate is born with high concentrations of immunoglobulins inthe blood.

Rats, and mice are an intermediate group because, in addition to the limited intestinal nonselective uptake after birth, there is a highly specific receptor-mediated intestinal absorption of IgG that continues for about the first 20 days of life.

The process of macromolecular absorption is initially high at the first suckling, then declines gradually. Intestinal closure to uptake of macromolecules has occurred when no more intact macromolecules can be absorbed.

Intestinal closure is a continual, gradual process that starts immediately after birth and proceeds until there is no longer transport of macromolecules. Time of closure is the time after birth when macromolecules (including immunoglobulins) can no longer pass from the intestinal lumen, through the intestinal cell and into the neonate's vascular system.

Closure is complete in the calf by about 24 hr after birth, in the piglet at about 36 to 48 hr, in the foal at about 24 to 48 hr, in cats and dogs at about 24 to 48 h.

 

Colostrum Formation

Composition of the mammary secretion at the first milking or the first suckling reflects the functional changes that have occurred in the gland up to that time.

These functional changes include the secretions resulting from the two stages of lactogenesis (see the Lactogenesis Lesson), as well as other functional changes in the epithelial cells occurring in concert with lactogenesis, such as selective transport of immunoglobulins. After repeated milk removal, the composition of the mammary secretions changes rapidly over the initial 2 to 3 days after parturition, so that there is a continuous transition of composition from colostrum to mature milk.

All components of the mammary secretion are changing during this transition period.

Study of the hormonal control of mammary differentiation around the time of parturition mostly has focused on lactogenesis, and specifically on the synthesis of lactose and/or the expression of casein and a-lactalbumin genes and secretion of those proteins. However, a great deal is occurring in the mammary gland that ultimately results in the formation of colostrum.

Compositional Changes - Colostrum to Milk


The major compositional changes in cow milk during the first 7 days of lactation have been discussed previously (see Milk Composition Lesson).

In sow milk, milk fat percentage generally increases from colostrum to milk, but declines in cow milk after parturition. Milk fat percentage is the most variable component of milk. Lactose concentration generally is lower in colostrum of both species, then increases over the next few hours and days.

Protein concentration is highest in colostrum (first milking or first suckling), then declines rapidly over the next day or two. The major proportion of this change in protein concentration is accounted for by the immunoglobulins.

A closer look at the changes in sow colostrum composition (in the Figure below) shows that there is little change during the initial 4 to 6 hr after birth of the first piglet (total length of parturition for the sow can be 2 hr), then the composition begins to change.

This probably is similar in the cow where the calf suckles every few hours as opposed to the typical 12 hr interval when the cow is milked.

Other compositional differences between colostrum and milk - (Note that these are for the cow, other species may be different)

Colostrum has 10 fold more vitamin A than milk.
Colostrum has 3 fold more vitamin D than milk.
Colostrum has 10 to 17 fold more iron than milk.
Colostrum has higher Ca, P, Mg, Cl, and lower K than milk.
Colostrum has higher levels of oligosaccharides than milk.
Colostrum has a higher proportion of glycosylated k-casein than milk.

 


Immunoglobulin Transport in the Mammary Gland


The young of most and perhaps all mammalian species do not develop an effective immune system until after birth. Humeral immune protection (immunoglobulins) is supplied to the neonate by a process of transfer of passive immunity from the mother to the neonate. This generally occurs by transfer of maternal serum IgG from the mother to the offspring either in utero or, after birth, by ingestion of immunoglobulin-rich colostrum by the neonate.

These maternal immunoglobulins offer immune protection until development of a competent immune system in the neonate and even may be involved in modulating the neonate's developing immune system.

In species where transfer of immunity occurs via colostrum, the lack of colostrum intake shortly after birth can lead to neonate mortality rates approaching 100%. This process of transfer of immunoglobulins from mother to the young is of paramount importance to neonate survival.

IgG1 is the major immunoglobulin transported by the cow mammary gland during colostrum formation. Specific transport of IgG2 also may be increased some.

The IgG1 and IgG2 make up the majority of immunoglobulin in cow colostrum and primarily come from the blood (that is they are pre-formed). Most of the IgA and IgM that are transported into colostrum are synthesized by the plasma cells (B lymphocytes) that reside in the mammary tissue.

Transport of the IgGs and the IgA/IgM occurs through the epithelial cells by a process involving small transport vesicles. However, the receptors for the IgGs and the IgA/IgM are different receptors.

The receptor for IgA/IgM is called secretory component (SC) and is proteolytically cleaved off the membrane during transport of the IgA. The SC remains bound to the IgA and the SC-IgA complex is called secretory IgA.

There is also a lot of non-bound SC in milk and colostrum, suggesting that the proteolytic cleavage of SC does not require that it be bound to IgA. The receptor(s) for IgG transport in the mammary gland has not been completely identified at this time.

Transport of maternal immunoglobulins into colostrum probably occurs in all mammals to varying extents, but the significance of the immunoglobulins in colostrum depends on the species. Humans and other primates transport immunoglobulins to the fetus through the placenta via a receptor-mediated, intra-epithelial mechanism similar to that in the mammary gland. Therefore, when the infant is born it already has a full complement of immunoglobulins in its blood to protect it for disease until its own immune system is fully functional. Transport of immunoglobulins into colostrum in primates does occur (primarily IgA/IgM) but to a more limited extent.

However, in most species immunoglobulins are not transported across the plactenta, therefore the colostral immunoglobulins are critically important to neonate survival.

This is the case in the domestic farm species. In the dairy cow, as much as 2 kilograms of IgG can be secreted into the colostrum during the first five milkings. Another exception is the rat which transports some immunoglobulin across the placental yolk sac and some via the colostrum.

After ingestion of colostrum by the neonate, the immunoglobulins are absorbed intact into the neonate's blood stream. This process of immunoglobulin absorption in the intestine stops after a time postpartum depending on the species. This halt in intestinal absorption of immunoglobulins and other macromolecules is called closure.

Immunoglobulin concentrations decline rapidly over the first 24 hr after parturition (see handouts). The total amount of immunoglobulins secreted in the colostrum increases with parity of the mother. For example, the first lactation cows will have about one half the IgG1 concentration that third and fourth lactation cows will have (see handouts). Concentrations of colostral IgG2 and IgM also are lower in first lactation cows, while the concentration of IgA is only slightly lower.

Some references on immunglobulin transport in the mammary gland:
Larson et al., 1980, J. Dairy Sci. 63:665
Guidry et al., 1980, Vet. Immunol. Immunopathol. 1:329
Stott et al., 1981, J. Dairy Sci. 64:6459
Devery-Pocius and Larson, 1983, J. Dairy Sci. 66:221
Staley, TE, Bush, LJ 1985 Receptor mechanisms of the neonatal intestine and their relationship to immunoglobulin absorption and disease. J. Dairy Sci. 68:184-205.

 


Intestinal Protective Factors in Colostrum and Milk


Several factors found in milk may function in the neonate's digestive tract to minimize the potential for enteric disease. These include:

Immunoglobulins - Even after closure the immunoglobulins in milk may protect the intestinal lumen. Immunoglobulins are relatively resistant to digestion. IgA is of particular interest in the human infant because it is the major immunoglobulin in human milk.

Lactoferrin - The iron-binding capacity of lactoferrin gives it bacteriostatic and bactericidal properties. Lactoferrin is high in human milk, low in cow milk.

Lysozyme - May degrade the cell wall of some bacteria and allow them to be lysed. Lysozyme is high in human milk, but there is essentially none in cow milk. Lysozyme can act in concert with IgA, lactoperoxidase and ascorbate to lyse bacteria.

Lactoperoxidase - Uses hydrogen peroxide and halogens (I, Cl) to halogenate proteins and make them inactive. Also causes peroxidation of substances. The lactoperoxidase system also includes an interaction of the enzyme with thiocyanate. Lactoperoxidase activity is ~20 fold lower in human milk than cow milk, but the human infant also secretes considerable lactoperoxidase in the saliva.

Milk cells - Generally the leukocytes in normal milk (in the absence of mastitis) are macrophages. These cells probably retain some of their phagocytic abilities when ingested into the neonate. However, a role for these cells in the neonate has not been completely described.

Gut Flora - One of the best mechanisms for protecting against digestive tract infections is the establishment of the proper intestinal flora. In human milk there is a carbohydrate growth factor (called the Bifidus Factor, probably an oligosaccharide) which stimulates the growth of Lactobacillus bifidus. The high lactose concentration, low protein content, low bulk and low buffering capacity of human milk also encourages L. bifidus growth. The high lactose content means that lactose is still available for bacterial fermentation in the intestine, resulting in an acidic environment which reduces viability of many potentially pathogenic bacteria.

Although similar factors to the Bifidus factor have not been identified in milk of other species, there may be other milk factors that contribute specifically to the establishment of the optimal microbial flora in the digestive tract. See the Human Lactation Lesson.

Some references related to intestinal protective factors:


Welsh, JK, May, JT 1979 Anti-infective properties of breast milk. J. Pediatr. 94:1-9.
Hanson, LA, Carlsson, B, Jalil, F, Hahn-Zoric, M, Hermodson, S, Karlberg, J, Thiringer, K, Zaman, S 1988 Antiviral and antibacterial factors in human milk. In Biology of Human Milk, Ed. LA Hanson, Nestle Nutrition Workshop Series, Vol. 15, Nestle Ltd, Vevey/Raven Press, NY.

For further information on antimicrobial proteins in milk, see Antimicrobial Proteins in Milk from the Illinois Dairy Report 1996.


Bioactive Factors in Colostrum and Milk


What is there in colostrum and milk that may have non-nutritional effects on the neonate ?

Nutrient sources:

Milk Fat Globule -
Fat Soluble Vitamins
Steroid Hormones
Progesterone less than 1 to more than 30 ng/ml whole milk
Estrogens Estradiol-17ß - peaks in colostrum is ~.6 ng/ml, then declines
Estrone -peaks in colostrum is 2 ng/ml, then declines
Corticosteroids ~3 ng/ml at parturition, .2 - .5 ng/ml in milk
Androgen Low concentrations
Casein - Provides a balanced source of amino acids.
In addition to a nutritional source of amino acids, partial digestion of ß-casein;yields casomorphins - Tyr-Pro-Phe-Pro-Gly-Pro-Ile
These pepides have opioid activity in several assays
Generally are protease resistant
Have been identified in calf blood after milk ingestion
May regulate development of the intestinal mucosal immune system in the neonate
Other immunomodulatory activities have been identified in peptides generated by proteolytic hydrolysis of ß-lactoglobulin and a-lactalbumin.

Enzymes
Milk and colostrum contain many enzymes. There is considerable species variation. Some have fairly high activities in some species.
High in cow milk, low in human milk :
Lactoperoxidase
Xanthine oxidase
Ribonuclease
Alkaline Phosphatase
High in human milk, low in cow milk :
Lipase activity (bile salt activated)
Lysozyme
Protease activity
Milk and colostrum also contain plasmin and plasminogen, and plasminogen activator activity, as well as trypsin inhibitor activity (Cow has high TIA in colostrum and during mastitis, low in milk; Human milk has ~.7 mg/ml in colostrum, ~.05 mg/ml in mature milk)
Carrier Proteins in Colostrum and Milk
Vitamin-binding proteins for Folate and B12
Mineral-binding proteins Fe - lactoferrin, transferrin; Ca - casein and a- lactalbumin; Cu - lactoferrin
Lipid-binding proteins
ß-lactoglobulin; binds fatty acids, retinol (?)
serum albumin binds fatty acids
Hormone-binding proteins
Corticosteroid-binding globulin
IGF-binding proteins
Growth Factors
A range of growth factor activities have been identified in milk, including:

IGF-I is in milk at about 25 - 50 ng/ml.
IGF-II is in milk at about 80 - 120 ng/ml.
EGF is in HUMAN milk at about 50 ng/ml (it is the major growth factor activity in human milk); in mouse milk, EGF is at about 150 - 400 ng/ml milk. EGF stimulates enterocyte (crypt cell) proliferation. It is effective when administered orally. Effects are probably indirect, because it is ineffective in vitro.
TGF-a is in milk. It is similar in activity to EGF
NGF (nerve growth factor) has been identified at least in mouse milk.
Hormones in Milk
A wide range of hormones have been identified in milk, including:

Prolactin is in cow milk at about 50 - 200 ng/ml; in mouse milk at about 100 - 250 ng/ml; in rat milk at about 200 - 400 ng/ml. 16% of milk PRL passes into the blood of the neonate. It has in vivo effects on rat pup PRL regulation later in life.
Growth hormone is in milk.
GHRH is in human milk at about 25 - 40 pg/ml
Somatostatin is in milk at about 90 pg/ml
LH is in milk at about 1ng/ml milk, but an LHRH-induced LH surge is not detectable.
LHRH
ACTH
TSH
TRH
Thyroid hormones
Insulin is in milk at about 5 -50 ng/ml
Melatonin
Relaxin
Other Factors
Numerous other bioactive factors have been identified in milk, including:

Erythropoietin
MDGF1 (mammary derived growth factor 1) Isolated from human milk, mammary tumors Stimulates growth of mammary cells and production of collagen mRNA. Receptors on mammary and kidney cells.
HMGF I and HMGF II (Human milk growth factors)
CBGF (Colostric basic growth factor), similar to PDGF
Calcitonin-like peptide is in milk at about 600 pg/ml. It is an inhibitor of PRL release. Passive immunization of rat pups with anti-CT increases serum PRL. No CT-like RNA in the rat mammary gland.
Parathyroid hormone-like peptide mRNA is expressed in the rat mammary gland only during lactation It is only expressed for about 2 - 4 hr after suckling.
CAMP
CGMP
Prostaglandins
Neurotensin
Bombesin (Gastrin-releasing peptides). Bombesin stimulates proliferation of fibroblasts and bronchial epithelial cells, in vitro. In vivo, induces gastric cell hyperplasia and increased pancreatic DNA content Other effects - Hypertension, satiety, change in sugar metabolism, hypothermia, modulation of levels of gastrointestinal-associated peptide hormones, increased gastric acid secretion


Conclusion


In addition to supplying nutrients and factors directly involved in protection against pathogens, colostrum and milk contain a many components that may affect the growth and development of the neonate. These include:

Enzymes Growth factors
Carrier proteins
Immunoglobulins
Hormones
Immunomodulators
Steroid
Leukocytes
Protein
Intestinal protective factors
Peptide

 

References
Some references related to the presence and action of bioactive factors in milk:


Koldovsky, O 1989 Search for role of milk-borne biologically active peptides for the suckling. J. Nutr. 119:1543-1551.
Koldovsky, O 1995 Do hormones in milk affect the function of the neonate intestine? Amer. Zool. 35;446-454.
Lo, CW, Kleinman 1996 Infant formula, past and future: opportunities for improvement. Am. J. Clin. Nutr. 63:646S-650S.
Lonnerdal, B 1985 Biochemistry and physiological function of human milk proteins. Am. J. Clin. Nutr. 42:1299-1317.
Odle, J, Zijlstra, RT, Donovan, SM 1996 Intestinal effects of milkborne growth factors in neonates of agricultural importance. J. Anim. Sci. 74:2509-2522.