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Colostrum and milk-derived peptide
growth factors for the treatment of gastrointestinal disorders1,2,3,4
Raymond J Playford, Christopher E Macdonald and Wendy S Johnson
1 From the Department of Gastroenterology, Imperial College School of
Medicine, Hammersmith Hospital, London; Leicester General Hospital,
Leicester, United Kingdom; and SHS International Ltd, Liverpool, United
Kingdom.
2 The use of transforming growth factor ß or bovine
colostrum for the prevention of nonsteroidal antiinflammatory drug–induced
gut injury was patented by SHS International Ltd (no. 9619634.0); RJ
Playford is the named inventor on the patent.
3 Supported by the Medical Research Council, the Wellcome
Trust, and SHS International Ltd, formerly known as Scientific Hospital
Supplies Ltd.
4 Address reprint requests to RJ Playford, Department
of Gastroenterology, Hammersmith Hospital, Du Cane Road, London W12
0NN, United Kingdom. E-mail: r.playford@ic.ac.uk.
Colostrum is the specific first diet of mammalian neonates and is rich
in immunoglobulins, antimicrobial peptides, and growth factors. In this
article we review some of these constituents of human and bovine colostrum
in comparison with those of mature milk. Recent studies suggest that
colostral fractions, or individual peptides present in colostrum, might
be useful for the treatment of a wide variety of gastrointestinal conditions,
including inflammatory bowel disease, nonsteroidal antiinflammatory
drug–induced gut injury, and chemotherapy-induced mucositis. We
therefore discuss the therapeutic possibilities of using whole colostrum,
or individual peptides present in colostrum, for the treatment of various
gastrointestinal diseases and the relative merits of the 2 approaches.
Key Words: Gastrointestinal tract • gastrointestinal disease •
intestinal injury • repair • colostrum • milk •
peptide growth factor • nutrition • nonsteroidal antiinflammatory
drugs • review
INTRODUCTION
Colostrum is the first milk produced after birth and is particularly
rich in immunoglobulins, antimicrobial peptides (eg, lactoferrin and
lactoperoxidase), and other bioactive molecules, including growth factors.
As is the milk that is subsequently produced, colostrum is important
for the nutrition, growth, and development of newborn infants and contributes
to the immunologic defense of neonates. The composition of mammary secretions
changes continuously throughout the suckling period; however, for the
purposes of this review we define colostrum as the milk produced in
the first 48 h after birth.
Recent studies suggest that the peptide growth factors in colostrum
might provide novel treatment options for a variety of gastrointestinal
conditions. We initially provide a brief overview of the control of
gut growth and the constituents of human and bovine colostrum. Next,
we focus on the peptide growth factor constituents of colostrum and
how their concentrations vary from those of the later occurring, mature
milk. In the final section, we discuss the possibilities of using whole
colostrum or individual peptides in the colostrum for the treatment
of various gastrointestinal diseases and the relative merits of the
2 approaches. Because of the broad nature of these topics, the reader
is referred to appropriate reviews of specified topics throughout the
text.
OVERVIEW OF THE CONTROL OF GUT GROWTH AND REPAIR
The bowel shows a remarkable ability to respond to changes in dietary
intake. Fasting results in marked atrophy of the intestine and this
process can be rapidly reversed by refeeding. The molecular processes
underlying these changes are poorly understood, although it has been
proposed that humoral factors, local nutrition, and luminal growth factors
are involved.
Hormonal factors
Cross-circulation experiments support the concept of circulating trophic
factors influencing gut growth, although the identity of such factors
remains unclear. Gastrin probably plays a role as a trophic factor for
mucosal growth within the stomach and there is currently much interest
in the role of glucagon-like peptide 2 (GLP-2) because systemic infusion
of GLP-2 was shown to result in a general trophic response within the
gut (1). In contrast, early enthusiasm for a major trophic role for
the gut hormones peptide YY and cholecystokinin within the gastrointestinal
tract has diminished because of the absent or weak response in gut growth
when recombinant forms of the hormones are infused. A general review
of the actions of gastrointestinal hormones and their actions is provided
by Walsh (2).
Local nutrition
Circulating trophic factors are unlikely to explain regional variations
in growth, as shown by studies using isolated loops of bowel or experiments
involving ileojejunal transposition. Studies that showed direct effects
on growth when nutrients are administered intraluminally to isolated
loops (eg, 3) support the concept of the "luminal workload hypothesis."
It is important to note, however, that not all studies showed a positive
result, ie, hyperplasia of the loop (4).
Luminal growth factors
Peptide growth factors are constantly present in the gastrointestinal
lumen, being secreted by glands, eg, epidermal growth factor (EGF) from
the salivary glands, or ingested in foodstuffs such as milk and colostrum.
The role of luminal growth factors in modulating intestinal growth in
the normal adult gastrointestinal tract is, however, unclear because
there is increasing evidence that the receptors for many of these peptides
are restricted to the basolateral membranes of the mucosal cells, ie,
are not present on the apical (luminal) membranes. The luminal ligands
may therefore not be able to reach their receptor under normal circumstances
in the adult nondamaged gut.
This may not be the case, however, in the normal neonatal bowel or
in the adult damaged gut because, in these conditions, the permeability
of the bowel is increased. Furthermore, some studies have suggested
that inflammation of the gastrointestinal tract, in conditions such
as inflammatory bowel disease, might result in a shift in receptor distribution
to include apical membranes (5). Some of these aspects are discussed
in further detail later.
Role of peptides in the maintenance of mucosal mass and integrity
Tissue mass is dependent on the equilibrium established between cell
production, migration, and loss (including apoptosis). Peptide growth
factors in milk and colostrum can influence all of these aspects.
For example, EGF stimulates cell proliferation and migration and also
influences crypt fission, an identified mechanism by which new crypts
are produced (6). Recent reports also suggested that peptides in colostrum
and milk might influence the rate of programmed cell death (apoptosis)
within the gut, acting via the Fas/Fas ligand (FasL) signaling system.
Fas is a member of the tumor necrosis factor –nerve growth factor
receptor family and is expressed in various cells, including the gastrointestinal
mucosa. Binding of FasL triggers apoptosis. The presence of soluble
Fas in milk might therefore function as an alternative receptor site
for any FasL produced within the mucosa by activated immune cells, thereby
reducing the rate of mucosal apoptosis (7).
The gastrointestinal tract is constantly under attack from acid, proteolytic
enzymes, and ingested noxious agents, such as aspirin or alcohol. The
presence of multiple defense mechanisms—including the mucus-bicarbonate
layer in the stomach, a rapid mucosal turnover, and a good blood supply—ensure
that the mucosa remains intact most of the time. If a small area of
injury is sustained, the healing process usually proceeds successfully
via standard mechanisms. Surviving cells from the edge of the wound
migrate over the denuded area to re-establish epithelial continuity.
This process begins within a few minutes after injury and is termed
restitution. This is followed by increased proliferation and remodeling,
which begins 24–48 h after the injury. Many factors, including
peptide growth factors, stimulate these various processes and some of
these are discussed below. Interested readers are referred to studies
by Playford (8) and Murphy (9).
OVERVIEW OF TROPHIC FACTORS IN COLOSTRUM AND MILK
Colostrum and milk contain many factors that can influence cell growth,
differentiation, and function. A full review of the influence of nutrients
on gut growth and development is beyond the scope of this article but
can be found in the review by Koletzo et al (10). Some of the major
constituents of colostrum and milk that can interact with peptide growth
factors are discussed briefly below.
Nonpeptide trophic factors
Several nonpeptide constituents of colostrum, when added to cells in
vitro or when infused into animal models, have resulted in increased
proliferation. These factors include glutamine, polyamines, and nucleotides.
It is debatable whether these factors should be considered growth factors
per se because the increased proliferation is not mediated by the classic
receptor-ligand, secondary messenger system. Factors such as glutamine
are therefore often referred to as preferred substrates. Nevertheless,
these factors play an important role in maintaining gastrointestinal
mucosal mass and modulating the immune system via multiple mechanisms,
eg, altering intestinal flora and influencing the actions of growth
factors. For example, the trophic response of EGF on the rat small intestinal
cell line IE6 requires the presence of glutamine within the medium (11).
These subject areas are reviewed further by Levy (12) and Carver and
Barness (13).
Hormones
It is well established that milk and colostrum contain many hormones,
which, when infused systemically, influence a wide variety of end-organ
systems. These systems include the hypothalamic-hypophyseal system (because
milk contains prolactin, somatostatin, oxytocin, and luteinizing hormone-releasing
hormone), thyroid gland (because milk contains thyroid-stimulating hormone,
thyroxine, and calcitonin), sexual glands (because milk contains estrogen
and progesterone), and adrenal and pancreatic glands. It is probable
that at least some of these hormones (eg, luteinizing hormone-releasing
hormone) influence plasma concentrations and the development of various
end organs of suckling neonates (14) because of the passage of the hormones
through the bowel wall into the systemic circulation.
These hormones are likely to be less influential in adults because
the lower permeability of the adult bowel is likely to restrict passage
of most of these factors. However, it is important to appreciate that
when these factors are administered to adult patients with a damaged
bowel, eg, those with celiac or Crohn disease, the increased bowel permeability
associated with these conditions might allow these hormones to reach
their receptors and mediate pathophysiologic effects. Readers interested
in the physiologic significance of hormones in milk in relation to neonatal
development and the effect of hormones on milk production are referred
to the work of Koldovsky (15, 16).
Cytokines
The protein molecules known as cytokines have a broad range of cellular
function and are active in picomolar to nanomolar concentrations. In
general, cytokines do not regulate normal cellular homeostasis but alter
cellular metabolism during times of perturbation, eg, in response to
inflammation (17).
Cytokines trigger acute cellular responses, such as chemotaxis, protein
synthesis, and cellular differentiation. Colostrum and milk contain
many cytokines, including interleukin (IL) 1ß, IL-6, IL-10, tumor
necrosis factor , and granulocyte, macrophage, and granulocyte-macrophage
colony-stimulating factors. It is likely that in newborn animals and
infants, these factors play an important role in modulating immunologic
development, working in combination with the ingested maternal immunoglobulins
and the nonspecific antibacterial components, such as lactoperoxidase,
in colostrum.
Although cytokines and growth factors are often considered to be separate
entities, it is important to appreciate that the distinction between
them is sometimes blurred. For example, IL-8 has been shown to stimulate
migration of the human colonic epithelial cell line LIM 1215 (18), an
effect that is usually attributed to growth factors such as EGF and
transforming growth factor (TGF) ß.
In addition, some studies have shown "cross-talk" between
cytokines and growth factors. For example, Yasunaga et al (19) examined
the molecular mechanisms underlying Helicobacter pylori (H pylori)–induced
gastric hyperproliferation in patients with large-fold gastritis. The
presence of H pylori caused the gastric mucosa to release the cytokine
IL-1ß, which in turn resulted in the local production of hepatocyte
growth factor.
Further information regarding the functions of cytokines within the
gastrointestinal tract can be found in a review by Przemioslo and Ciclitira
(20), and a useful review of the cytokine constituents of human milk
and their importance in the development of the neonatal immune system
was published by Garofalo and Goldman (21).
Growth factors
Growth factors are so called because historically they have been identified
by their ability to stimulate the growth of various cell lines in vitro
but, in reality, the functions of these peptide-based molecules are
considerably more diverse. Different names have been ascribed to molecular
species as they have been identified.
As characterization has become more sophisticated, however, it is apparent
that some of these differently named species are structurally and functionally
similar and may, in fact, be identical. Although there are many similarities
among species, there are also marked species differences in the nature
and concentration of growth factor constituents, eg, human colostrum
has much higher concentrations of EGF than does the bovine equivalent,
whereas the reverse is true for insulin-like growth factor (IGF) I and
II. Further details of individual peptides that form the major peptide
growth factor constituents of colostrum and milk are given in the next
section.
MAJOR PEPTIDE GROWTH FACTOR CONSTITUENTS OF COLOSTRUM AND MILK
Epidermal growth factor receptor ligand family
This group of polypeptides, with the common property of binding to the
EGF receptor (also known as the c-erb1 receptor), includes EGF itself,
TGF-, mammary-derived growth factor II (MDGF-II), and human milk growth
factor III (HMGF-III), which might be the same molecule as EGF (see
below). Other related polypeptides with these binding characteristics,
but that are not present in significant concentrations in colostrum,
are amphiregulin, betacellulin, and heparin-binding EGF (for a more
comprehensive review of these peptides see reference 22).
Epidermal growth factor
EGF is a 53–amino acid peptide produced by the salivary glands
and the Brunners glands of the duodenum in adults. EGF is present in
human colostrum (200 µg/L) and milk (30–50 µg/L) and
in many other species but is not found in significant amounts in bovine
secretions (23), although related molecules have been identified and
characterized. In vitro experiments using gastric juice from preterm
infants indicate that milk-borne EGF is not deactivated under typical
gastric proteolytic conditions (24). In contrast, we showed that adult
gastric juice digests EGF1–53 to an EGF1–49 form that has
only 25% of the biological activity of the intact EGF molecule (25).
Once EGF enters the small intestine, it is susceptible to proteolytic
digestion under fasting conditions but is preserved in the presence
of ingested food proteins (26).
There is controversy over the physiologic function of EGF in the gastrointestinal
lumen under normal (nondamaged) conditions. Most studies examining the
distribution of EGF receptor in the normal adult human gastrointestinal
tract showed it to be present only on basolateral membranes and not
on the apical (luminal) surfaces (27).
The distribution of the EGF receptors might, however, vary between
species, eg, autoradiographic studies identified apical receptors in
the pig intestine (28). If EGF receptors are distributed only on the
basolateral membranes of the normal adult human gut, then EGF in the
intestinal lumen is unlikely to exert any biological activity, except
at sites of injury. Evidence in favor of this role for EGF include the
finding that rats that have had their salivary glands removed do not
develop spontaneous ulcers or atrophy of the gut. However, compared
with control animals, they do develop more extensive ulceration with
diminished repair if artificial ulcers are induced (29). This has led
to the suggestion that EGF acts as a "luminal surveillance peptide"
in the adult gut, readily available to stimulate the repair process
at sites of injury (8). It is important to note, however, that luminal
EGF might gain access to basolateral receptors in the immature neonatal
gut (30) because of its increased permeability. The EGF in colostrum
and milk may therefore play a role in preventing bacterial translocation
(31) and stimulating gut growth in suckling neonates.
Transforming growth factor
TGF- is a 50–amino acid molecule that is present in human colostrum
and milk at much lower concentrations [2.2–7.2 µg/L (32)]
than is EGF. In contrast with EGF, TGF- is produced within the mucosa
throughout the gastrointestinal tract (33). Systemic administration
of TGF- stimulates gastrointestinal growth and repair, inhibits acid
secretion, stimulates mucosal restitution after injury, and increases
gastric mucin concentrations (22).
Within the small intestine and colon, TGF- expression occurs mainly
in the upper (nonproliferative) zones, which suggests that its physiologic
role may be to influence differentiation and cell migration rather than
cell proliferation. TGF- may therefore play a complementary role to
that of TGF-ß (see below) in controlling the balance between proliferation
and differentiation in the intestinal epithelium (34). Up-regulation
of TGF- expression has been shown to occur in the gastrointestinal mucosa
at sites of injury as well as in the liver after partial hepatectomy,
supporting a role for TGF- in mucosal growth and repair (35).
Further evidence for this role comes from research in mice that have
had the TGF- gene "knocked out" by homologous recombination.
These rats have a relatively normal phenotype under control conditions
but an increased sensitivity to colonic (36), although not small intestinal
(37), injury. These findings support the role of TGF- in maintaining
epithelial continuity but suggest that the relative importance of peptides
such as this might vary from one region of the gut to another. Taken
together, most studies suggest that the major physiologic role of TGF-
is to act as a mucosal-integrity peptide, maintaining normal epithelial
function in the nondamaged mucosa (8).
Other peptides within this family are MDGF-II (38) and HMGF-III. HMGF-III
has a molecular mass of 6 kDa and is the predominant growth factor in
human milk, accounting for 75% of total mitotic activity (39). There
is uncertainty as to whether HMGF-III is a distinct molecule or is,
in fact, the same as EGF.
Transforming growth factor ß family
This family of molecules is structurally distinct from TGF- and, in
most systems, actually inhibits proliferation. There are 5 different
isoforms of TGF-ß and their major site of expression in the normal
gastrointestinal tract is in the superficial zones, where they may inhibit
proliferation once the cells have left the crypt region (34). TGF-ß
has many diverse functions; it is a potent chemoattractant for neutrophils
and stimulates epithelial cell migration at wound sites (40). It is
therefore likely to be a key player in stimulating restitution, the
early phase of the repair process during which surviving cells from
the edge of a wound migrate over the denuded area to reestablish epithelial
continuity. TGF-ß and TGF-ß-like molecules are present in
high concentrations in both bovine milk (1–2 mg/L) and colostrum
(20–40 mg/L).
These concentrations are sufficient to prevent indomethacin-induced
gastric injury in rats (41), suggesting that the TGF-ß in colostrum
may be a key component in mediating its ability to maintain gastrointestinal
integrity in suckling neonates. A TGF-ß-like milk growth factor
has been described as being associated with the casein fraction of cow
milk; this has since been shown to be a mixture of TGF-ß1 and
TGF-ß2, predominantly the ß2 form (85%) (42).
Insulin-like growth factors (somatomedins) and their binding proteins
IGF-I and IGF-II promote cell proliferation and differentiation (43).
They are similar in structure to proinsulin and it is possible that
they also exert insulin-like effects at high concentrations. The liver
is a major site of IGF synthesis (44); IGF-I and IGF-II are both also
expressed in particularly high amounts in the developing human fetal
stomach and small intestine, with expression reaching a maximum soon
after birth (45).
Bovine colostrum contains much higher concentrations of IGF-I than
does human colostrum (500 compared with 18 µg/L) (46, 47), with
lower concentrations in mature bovine milk (10 µg/L) (48). These
growth factors are relatively stable to both heat and acidic conditions.
They therefore survive the harsh conditions of both commercial milk
processing and gastric acid to maintain their biological activity (49).
IGF-I is known to promote protein accretion, ie, it is an anabolic agent
(50) and is at least partly responsible for mediating the growth-promoting
activity of growth hormone (GH). IGF-II is present in bovine milk and
colostrum at much lower concentrations than is IGF-I, but like IGF-I,
it has anabolic activity and has been shown to reduce the catabolic
state in starved animals (51).
IGFs in bovine and human colostrum and milk are present in both free
and bound forms. The amount of free IGF varies during the perinatal
period, with most of the IGF-I in bovine colostrum being present in
the free form (ie, not associated with its binding protein), whereas
the reverse is true in the antepartum period and in mature milk (52).
Six IGF binding proteins (IGFBPs) have been identified and cloned. It
was initially thought that the main function of IGFBPs was to act as
carrier proteins, reducing the proteolytic digestion of IGF and limiting
its biological activity because only the free forms of IGF are thought
to have any major proliferative activity. Additional roles for IGFBPs
have been suggested because it has been shown that different IGFBPs
have distinct patterns of distribution in different tissues and their
concentrations are altered in response to hormonal or nutrient status.
Examples include the findings that administration of dexamethasone to
rats increases hepatic production of IGFBP-1 (53) and that malnutrition
of neonatal rats decreases serum IGF-I and IGF-II but increases serum
IGFBP-2 (54). The detailed functions of IGFBPs are unclear, although
it is probable that one of the roles of secreted or soluble IGFBP is
to inhibit IGF-mediated proliferation or amino acid uptake by limiting
the availability of free IGF to bind to its receptors.
Conversely, cell surface– and cell matrix–associated IGFBPs
may potentiate the actions of IGF by increasing local concentrations
of IGF-I and IGF-II next to their receptors. A detailed review of IGFBPs
was published by Rechler (55) and a general review of the role of IGFs
and IGFBPs was published by Lund and Zimmermann (44). Changes in the
secretion and mammary uptake of IGF-related peptides in the peripartum
period of dairy cows have also been described (56).
Platelet-derived growth factor
Platelet-derived growth factor (PDGF) is an acid-stable molecule that
was originally identified from platelets but is also synthesized and
secreted by macrophages. It consists of 2 disulfide-linked polypeptides:
chain A (14 kDa) and chain B (17 kDa). The dimer, therefore, exists
in 3 isoforms (AA, AB, and BB) that bind to tyrosine kinase–type
receptors. PDGF is a potent mitogen for fibroblasts and arterial smooth
muscle cells and administration of exogenous PDGF has been shown to
facilitate ulcer healing when administered orally to animals.
Although PDGF is present in human and bovine milk and colostrum, most
of the PDGF-like mitogenic activity in bovine milk is actually derived
from bovine colostral growth factor, which shares sequence homology
with PDGF (57, 58). A general review of the effects of PDGF were published
by Szabo and Sandor (59).
Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF) is a homodimeric 34–42-kD
heparin-binding glycoprotein with potent angiogenic, mitogenic, and
vascular permeability–enhancing factors that is related to PDGF
(60). VEGF is present in human breast milk at a concentration of 75
µg/L during the first week of lactation, and concentrations fall
to 25 µg/L during the second postnatal week (61). Specific receptors
for VEGF have been identified on the apical membranes of the human colonic
cell line Caco-2 (61) and also on the human cell line H-4. Although
VEGF bound to these cell lines, it did not induce a proliferative response
(61). The pathophysiologic role of VEGF is therefore unclear, although
its angiogenic activity may play an important role in the healing of
conditions such as peptic ulceration.
Lactoferrin
Lactoferrin is an iron binding glycoprotein (80 kDa) that is present
in human colostrum at a concentration of 7 g/L, with mature milk having
a lower concentration (1 g/L). Bovine milk also contains lactoferrin,
but the concentration is only 10% of that of human milk (0.1 g/L) (62,
63). Lactoferrin exerts multiple effects, including facilitating iron
absorption and acting as an antimicrobial agent (64, 65). In addition,
lactoferrin has been shown to stimulate the growth of various cell lines
in vitro, including fibroblasts and intestinal epithelial cells (66),
suggesting that its presence in milk may be important in regulating
gut growth in developing neonates.
Growth horm
Growth hormone (GH), along one and its releasing factorwith its releasing
factor (GHRF) and binding protein (67), is present in human and bovine
colostrum and milk. Human GHRF concentrations have been reported to
be 41 ng/L in colostrum, falling to 23 µg/L in mature milk (68).
Suckling neonates have high circulating concentrations of GH, probably
because of a combination of GH and GHRF ingestion, which stimulates
the neonate to release GH from the pituitary gland (69). Many of the
growth-promoting effects of GH are mediated by release of IGF-I (70),
although GH may also have direct mitogenic effects (71). There is increasing
evidence that systemic GH plays important modulatory roles in gut growth
and function. GH receptors have been reported to be present throughout
the human gastrointestinal tract (72) and transgenic mice that overexpressed
GH had higher total body weights and heavier small intestines than did
control (nontransgenic) mice (71). The importance of GH in the lumen,
however, is unclear. It is not known whether GH receptors are present
on the apical membranes of enterocytes. Further studies examining the
effect of GH in adults and neonates, when given via the lumen, are required
to determine the pathophysiologic significance of GH in milk and colostrum.
Other less-well-defined peptides
Bovine and human milk contain several other peptides whose structure
and function are less clearly defined, including
MDGF-I, a 62-kDa peptide that has been shown to stimulate the growth
of mammary cells and enhance collagen production (73);
HMGF-I and -II, acidic polypeptides that are poorly characterized (74);
bovine colostral growth factor, a 35-kDa molecule responsible for most
of the mitogenic activity of bovine colostrum that appears to be biochemically
similar to HMGF-II and possibly to PDGF (57, 58); and
other bovine MDGFs, such as b-MDGF-I, which has a molecular mass of
30kDa and exhibits EGF-like activity, and b-MDGF-II, which is larger
(50–150 kDa) (75).
Several other peptides reportedly exist; however, some of these were
shown subsequently to be highly homologous with known existing molecules,
whereas for others, the details of structure and function have not been
elucidated. It is likely, however, that over the next few years, additional
novel potent growth factors with clinical potential will be identified
within colostrum and milk (76).
CLINICAL APPLICATIONS FOR THE GASTROENTEROLOGIST
Esophagitis and H pylori–related disease
Colostrum, milk, and recombinant peptides are unlikely to be of major
clinical value for the treatment of reflux esophagitis or H pylori–induced
peptic ulceration. This is because acid-suppressant therapies, particularly
proton-pump inhibitors, are highly efficacious and cheap (compared with
recombinant peptides). Furthermore, standard H pylori–eradication
regimens, usually consisting of a proton-pump inhibitor and 2 antibiotics
for 7 d, have an eradication success rate of >90% and effectively
provide a life-long cure for H pylori–induced peptic ulceration.
There are, however, many serious gastrointestinal pathologies for which
novel therapies might prove useful; these pathologies are discussed
below.
Short-bowel syndrome
Some patients have an insufficient length of bowel to digest and absorb
food adequately, usually as a result of massive intestinal resection
for vascular insufficiency or after repeated operations for inflammatory
bowel disease. Current therapeutic options are unpleasant and associated
with a high risk of morbidity or mortality, eg, long-term parenteral
(intravenous) feeding and small-bowel transplantation. Strategies to
optimize the function of residual bowel and ultimately wean patients
off total parenteral nutrition would therefore be of great benefit.
There is evidence that growth factors could be instrumental in achieving
this goal; eg, systemic administration of individual growth factors
such as EGF have been shown to stimulate bowel growth in rats receiving
total parenteral nutrition (77). In addition, oral administration of
EGF helped restore glucose transport and phlorizin binding in rabbit
intestines after jejunal resection (78), and colostrum supplementation
of piglet feeding regimens resulted in a significant increase in intestinal
proliferation (79). Colostrum supplementation may be of particular value
in young children who have undergone intestinal resection because gut
adaptation is more likely during early childhood than it is in adulthood.
Nonsteroidal antiinflammatory drug–induced gut injury
Nonsteroidal antiinflammatory drugs (NSAIDs) are widely prescribed and
are effective in the treatment of musculoskeletal injury and chronic
arthritic conditions. Nevertheless, 2% of subjects taking NSAIDs for
1 y suffer from gastrointestinal adverse effects, including bleeding,
perforation, and stricture formation of the stomach and intestine (80).
Acid suppressants and prostaglandin analogues have been shown to be
effective in reducing gastric injury induced by NSAIDs but are less
effective in preventing small intestinal injury. Novel therapeutic approaches
to deal with these problems, such as the use of recombinant peptides,
are therefore still required. A recent series of in vivo and in vitro
studies support this idea; EGF (25) and TGF- and TGF-ß (81) have
all been shown to reduce NSAID-induced gastric injury.
The beneficial effects of recombinant growth factors on NSAID-induced
small and large intestinal injury is, however, less well documented.
It was shown recently that a defatted colostrum preparation, which is
rich in the growth factors discussed earlier, reduced NSAID-induced
gastric and intestinal injury in rats and mice (Figure 1) (81). This
material was also shown to effectively reduce gastric erosions in human
volunteers taking NSAIDs (J Hunter, personal communication, 1998). Further
support for this approach comes from our recent finding that this defatted
colostrum preparation reduced small intestinal permeability, which was
used as a marker of intestinal damage in human volunteers taking clinically
relevant doses of the drug indomethacin (82). Clinical trials involving
patients taking NSAIDs long term are under way.
FIGURE 1. Effect of the administration of bovine
colostrum, indomethacin, or both on nonsteroidal antiinflammatory drug–induced
small intestinal injury in mice. Mice received placebo or colostrum
supplementation in their drinking water for 14 d. Twenty-four hours
before being killed, some animals also received 85 mg indomethacin/kg
subcutaneously. The morphology of microdissected villi was determined
throughout the small intestine (200x magnification). Top: Control mice
did not receive indomethacin or colostrum and had long, slightly tapering,
villi. Middle: Mice that received indomethacin alone had markedly shortened
villi with bulbous expansion of the tips. Bottom: Mice that received
indomethacin and colostrum showed much less marked changes to the villi.
These results were published previously (81); however, the figure was
not.
Chemotherapy-induced mucositis
Current regimens for the treatment of cancers require patients to take
much higher doses of chemotherapeutic agents than were used previously.
As a result of these higher doses, toxic adverse effects on the bone
marrow and gastrointestinal tract can be the factor limiting the dose
or duration of treatment. Strategies to protect these tissues and encourage
their recovery may facilitate the use of higher doses of chemotherapy,
with greater potential for cure.
For example, EGF enhances the repair of rat intestinal mucosa damaged
by methotrexate (83), TGF-ß ameliorates chemotherapy-induced mucositis
(84), and administration of a cheese whey–derived preparation reduces
methotrexate-induced gut injury in mice (85). Not all studies have shown
favorable results, however, because EGF had only a minor beneficial
effect in reducing mouth ulceration in a phase I clinical study of patients
undergoing chemotherapy (86).
If peptides with growth stimulatory or inhibitory effects are to be
used, the timing of administration is likely to be critical; growth-arresting
factors might protect bone marrow or gut from the damaging effects of
chemotherapy, which tend to affect areas with the highest cell turnover,
if given before chemotherapy. In contrast, growth-stimulating factors
might "rescue" recovery of injured areas if administered after
chemotherapy.
This latter approach is already being used clinically, eg, colony-stimulating
growth factor is being used to stimulate bone marrow recovery after
chemotherapy.
Inflammatory bowel disease
The etiology of ulcerative colitis and Crohn disease is unknown and,
therefore, current treatment of these severe, incapacitating conditions
has to be on an empiric basis. Studies examining the effect of administration
of EGF, PDGF, TGF-ß or IGF-I in animal models of colitis have
had encouraging results (87), and a cheese whey growth factor extract
containing several of these growth factors had positive results in a
similar model (88). Other peptides, not present in milk or colostrum
in significant concentrations, under study as potential therapeutic
agents for these conditions include keratinocyte growth factor (89)
and trefoil peptides (90). These studies are in the very early (animal
model) stages and the agents are unlikely to be in standard clinical
use for many years.
Milk-derived products are already in clinical use for the treatment
of inflammatory bowel disease; casein-based enteral feeds are used for
the treatment of Crohn disease and their efficacy might be due, in part,
to the presence of MDGFs in the preparation, which are preserved during
the processing of the milk protein (see above). In addition, clinical
trials of the use of colostrum enemas for the treatment of ulcerative
colitis and resistant proctitis are under way and the results are awaited
with interest.
Necrotizing enterocolitis
Necrotizing enterocolitis (NEC) is a severe life-threatening illness
of young children that causes severe ulceration of the small and large
bowel. Its etiology is unclear, although there are many possible risk
factors, including prematurity, enteric infections, intestinal ischemia,
and abnormal immune responses. Although many proinflammatory molecules
are likely to be involved in the etiology of NEC, there is currently
interest in the role of the phospholipid-mediator platelet activating
factor (PAF), which is produced by intestinal flora and inflammatory
cells during the development of NEC. The finding that human colostrum
contains the enzyme PAF acetylhydrolase (91), which degrades PAF, might
therefore be relevant in explaining why human milk feeds protect against
the development of NEC.
These areas are discussed further by others (91–93). Although
the molecular mechanisms underlying the development of NEC are unclear,
there is no doubt that once it is established, it is associated with
a very high mortality rate. Current treatment consists of general supportive
measures consisting of fluid-replacement and antibiotic therapy, although
intestinal resection is often required. There is therefore a need for
novel therapeutic approaches, eg, the use of peptides to stimulate the
repair process. Support for this idea comes from a recent case study
in which a continuous infusion of EGF resulted in a remarkable restorative
effect on gut histology in a child with NEC (Figure 2) (94). Larger
clinical trials are ongoing.
FIGURE 2. Hematoxylin and eosin stain of small
intestinal biopsies of a child with necrotizing enterocolitis (200x
magnification) before (top) and 7 d after (bottom) infusion of epidermal
growth factor. Before therapy the mucosa is virtually completely ulcerated
and after therapy the mucosa is almost completely regenerated. Details
of this case report were published previously (94); however, the figure
was not.
Infective diarrhea
Most cases of infective diarrhea resolve spontaneously and only occasionally
require a short course of antibiotics. For immunocompromised subjects,
such as those with HIV infection, prophylaxis against the unusual organisms
that they are susceptible to, eg, Cryptosporidium, may be beneficial.
Hyperimmune milk or colostrum preparations have been shown to be of
benefit in the prevention and treatment of infection and to increase
weight gain in both clinical and veterinary practice, eg, vaccination
of cows with specific viruses or bacteria to produce hyperimmune milk
has been shown to be beneficial in the prevention and treatment of enteropathic
infections due to Escherichia coli (95) and rotavirus (96). The use
of whole hyperimmune colostrum rather than specific antibodies purified
from milk (97) or other sources has the added value of potentially stimulating
the repair process (due to the presence of growth factors) as well as
facilitating the eradication of the infection by mechanisms involving
nonspecific antibacterial factors in colostrum and milk.
SHOULD WE USE SINGLE OR MULTIPLE PEPTIDES AND HOW SHOULD THEY BE ADMINISTERED?
Advances in molecular biology techniques now allow the large-scale production
of individual recombinant peptides. Some of these have already found
a place in clinical practice, eg, erythropoietin for the treatment of
renal failure–induced anemia and interferon for the treatment of
viral hepatitis. The use of growth factors for the prevention and treatment
of gastrointestinal disease is, however, at a much earlier stage of
development (98).
Although the potent growth factor activity of many of these peptides
appears advantageous for stimulating the repair process, there is concern
over their potential risks. Systemically administered growth factors
could induce proliferation in other regions of the body that harbor
premalignant cells. In contrast, luminally administered growth factors,
given orally or via enema, could be delivered at much higher local concentrations.
A further advantage of luminal administration is that a proliferative
response could be specifically targeted to affect only injured areas.
This could be achieved by administering a growth factor, such as EGF,
whose receptors are normally restricted to basolateral membranes because
it is only at sites of injury that these receptors would be exposed.
If the luminal administration of growth factors is to be effective,
they must be protected from proteolytic digestion in the stomach and
intestine (26).
Possible strategies would be to deliver the growth factors in site-specific
delivery formulations, to coadminister acid suppressants to reduce proteolytic
digestion within the stomach (25), or to coadminister proteins that
would act as competitive substrates for the proteolytic enzymes—milk
proteins such as casein are particularly beneficial in this regard (26).
Until recently, most research has focused on the use of a single peptide
for the treatment of a particular condition. There is now increasing
evidence, however, that administration of a combination of many peptides,
whether purified or recombinantly produced, can result in additive or
synergistic activity.
For example, the coadministration of GH and IGF-I stimulate anabolism
(99) and the coadministration of bovine lactoferrin and EGF stimulate
the growth of the rat intestinal epithelial cell line IEC-18 (66). Orally
administered colostrum-derived preparations therefore appear to be an
attractive therapeutic option because they contain many different growth
factors in a formulation that provides inherent protection against proteolytic
digestion.
Other approaches currently under scrutiny include 1) altering the volume
and nature of the components of mature milk [eg, GH (100), prolactin,
and colony-stimulating factor 1 (101)] before administering the milk
to animals and 2) using genetic modification technology to improve milk's
healing and protective properties. With the use of recombinant technology,
the production of the required peptides, including human homologues,
can be specifically targeted to the breast tissue of the animal by using
specific promoters such as the ß-lactoglobulin gene (102). This
approach, therefore, provides the potential to specifically modify bovine
or ovine milk to increase its content of beneficial peptides, including
human homologues. These products could then be used in a way similar
to that of colostrum for the prevention and treatment of gut injury.
Interested readers are referred to the excellent review by Dalrymple
and Garner (103).
Several bovine colostral preparations are already available in health-food
shops and, as for any other milk product for human consumption, their
manufacture is regulated by food hygiene standards. All of these colostral
preparations are pasteurized, microfiltered, or otherwise treated to
prevent the risk of contamination with enteropathogens and the concentration
of endotoxins in these preparations is similar to that of standard commercial
milk.
If colostrum or modified milk products are to be used in clinical practice,
several issues regarding their safety will, however, need to be addressed.
It is unlikely that human colostrum or milk will find a major role in
clinical practice because of its limited supply and because of concerns
regarding the transmission of infectious agents such as HIV or cytomegalovirus.
It is therefore likely that further research into the commercial aspects
of using purified peptides to treat gastrointestinal diseases will focus
on milk and colostrum derived from ruminants. Regulatory authorities
require bovine herds to be certified free from bovine spongiform encephalopathy
and require sheep, which are being used in several studies to produce
recombinant peptides in milk (102, 103), to be free from the ovine equivalent
of bovine spongiform encephalopathy, scrapie.
An additional area of research concerns the use of recombinant hormones,
such as bovine somatotropin, to increase milk yields. Although approval
for the use of bovine somatotropin was granted by the US Food and Drug
Administration in 1993, the European Union banned its use until at least
the end of 1999 and there is continuing controversy regarding the safety
of its use. For further discussion of the use of bovine somatotropin,
readers are referred to the article by Morris (104). Commercially available
bovine colostral preparations are essentially cell free because they
are microfiltered during the production process; therefore, theoretic
concerns about graft versus host disease are probably unwarranted. However,
graft versus host disease is a concern if fresh, nonfiltered products
are used. Our own (unpublished) studies of several of the commercially
available colostral products showed that their bioactivity, determined
by cell proliferation assays, is maintained for many months when the
products are frozen or stored at 4°C. In addition, we found that
dried formulations have biological activity similar to that of liquid
forms when prepared in equivalent concentrations of protein.
Current farming methods allow the production of large amounts of bovine
colostrum for clinical use. It is important that batch variations during
production be kept to a minimum to ensure consistency of the product
produced and that processing methods be developed to prevent deactivation.
Such preparations have the advantage of being perceived as "natural"
products, which might result in greater patient acceptance and compliance.
Further therapeutic advantages might also be gained by developing formulations
specifically tailored for individual conditions, eg, the use of a hyperimmune
milk or colostrum formulation for the treatment of immunocompromised
patients who have gut disease, thereby reducing the incidence of gut
infection while stimulating gut repair.
In summary, research examining the potential benefits of using recombinant
peptides or colostral-derived preparations for a wide range of gastroenterologic
conditions is underway. Early results are encouraging and we envisage
the standard use of these products in the clinical management of gastrointestinal
diseases within the next decade.
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Received for publication April 30, 1999. Accepted for publication January
14, 2000.
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