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-17? - 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 ?-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 ?-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
?-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.
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