COLOSTRUM BIOLOGICAL ACTIVITIES: A REVIEW
Abstract
Colostrum, and, particularly, two of its main components, lactoferrin (Lf) and proline-rich peptide (PRP), act to regulate and balance the immune system. This biological activity is not only important in newborns just beginning to live in a hostile environment, but also in adults with over- or under-active immune systems, perhaps resulting from various types of stress. Colostrum and its components also have potent anti-bacterial, anti-viral, and anti-fungal activities to help protect the body from invading pathogens. Colostrum and its growth factors enhance wound healing, cartilage formation, and bone repair, stimulate muscle protein synthesis/inhibit protein breakdown, benefit GI tract structure and function, and act on the immune system to inhibit tissue inflammation and allergic response. The Lf component of colostrum also acts to regulate iron absorption and availability, and has been shown to significantly inhibit tumor development, growth, and metastasis. Colostrum and its components exert their biological activities when given orally, in some cases as a dietary supplement; communication with the immune system via the oral mucosa is believed to be important in initiating many of colostrum's immunomodulatory activities. Moreover, the composition of bovine (cow) and human colostrum is similar, and colostrum from both sources is biologically active in its own as well as other mammalian species when given orally or injected.
Introduction
Colostrum is the first complete food available to newborn mammals and is even essential for life in some mammalian species.1 It is also the first mammary secretion obtained within the first few hours after birth, and provides many important biological elements and nutrients present in the mother's blood. This pre-milk substance is nature's way of providing protection for the newborn against viruses, bacteria, allergens, and toxins. While the health benefits of colostrum consumption for newborns have been intuitively understood by human cultures throughout time, some cultures have also recognized it as an important food for adults. For example, the Amish once prepared a pudding made from the colostrum produced by the mother of a newborn calf. To this day in India, colostrum is consumed by adults.2
Colostrum contains various immune factors, such as lactoferrin (Lf), immunoglobulins (Ig), and proline-rich peptides (PRP), as well as important growth factors for developing healthy muscles and bones.3 , 4 Colostrum also activates and regulates numerous immune, growth, and repair processes.5 , 6 , 7 , 8 , 9 , 10 Additionally, numerous studies cited in this review show that colostrum and its components continue to exert important biological activities when given to adults, so that its beneficial effects extend well beyond the neonatal period of development.
Many examples cited in this review also attest to the biological effectiveness of orally administered colostrum and its components. In fact, much of the communication of immunologically active substances with the immune system appears to occur via the membranes that line the oral cavity. Signals in the form of food, germs, and poisonous substances are initially recognized in the oral cavity, and messages are distributed by a variety of communication pathways to pertinent parts of the body. There are also protective substances that prevent digestion of the active components of orally administered colostrum before they can exert their biological effect(s).11
The biological activities of colostrum, as well as its major components, have been studied in model animal test systems both in vitro (cultured cells) and in vivo (live animals) in both newborns and adults. Some controlled clinical studies have also been conducted in humans of various ages. This review will attempt to summarize the most recent scientific literature describing the results of these studies (further summarized in Tables 1 and 2). Earlier reviews of the biological activities of colostrum are also available for those desiring additional information.9 , 12
COMPONENT SOURCE ACTIVITY TYPE OF STUDY
WHOLE COLOSTRUM bovine improved functioning of GI tract in vivo newborn calves
bovine enhanced efficiency of gamma-globulin absorption in vivo newborn calves
bovine increased small intestine villus size in vivo newborn calves
human stimulated B cell proliferation and antibody secretion in vitro mouse
human inhibited proliferation of activated T cells in vitro human
human inhibited production of IL-2 in vitro human
human anti-inflammatory in vitro human
human anti-inflammatory in vivo rats
ovine increased serum IGF levels in vivo neonatal pigs
bovine inhibited muscle protein degradation in vitro rat and human cells
human antioxidant in vitro human
human anti-amoebic in vitro human
CELLULAR FRACTION human bactericidal and fungicidal in vitro against E. coli and C. albicans
IMMUNOGLOBULINS
IgA bovine antibacterial in vitro against E. coli and Shigella
human antibacterial in vitro against Vibrio cholerae in rats
human inhibited cytokine release in vitro human
GROWTH FACTORS bovine salivary gland and kidney accelerated wound healing in vivo rats
bovine bone induced cartilage formation and bone repair in vitro rat
bovine inhibited growth of cancer cells in vitro human
bovine inhibited muscle protein breakdown in vitro rat
protected body protein reserves during dietary nitrogen restriction In vivo rats
Promoted GI tract cell proliferation in vivo newborn pigs
reduced insulin requirements in diabetics in vivo human
stimulated would healing in vivo rats
stimulated glucose transport in skeletal muscle in vitro human
*The activities of lactoferrin are discussed in a separate review.
COLOSTRUM SOURCE MODE OF DELIVERY SUBJECT EFFECT
bovine oral children with GI tract infection ameliorated diarrhea
bovine oral adults with AIDS with GI tract infection ameliorated diarrhea
bovine oral adult athletes increased serum IGF levels
sheep (PRP complex) oral patients with Alzheimers disease improved dementia symptoms
bovine (Lactoferrin) rats and mice with tumors anti-tumor
Biological Activity of Whole Colostrum
Several studies with fresh, whole colostrum have examined its biological activities in newborn animals. Perhaps its most apparent effects are illustrated in calves. For example, calves fed colostrum within 1-3 days after birth show increased energy, improved functioning of the gastrointestinal (GI) tract, enhanced efficiency of gamma-globulin absorption, and higher serum levels of insulin-like growth factor-1 (IGF-1), insulin, glucose and albumin compared to calves deprived of colostrum.13 Prolonged feeding of colostrum to calves stimulates postnatal development of the GI tract by enhancing small intestine villus size.10 Beneficial effects in the GI tract of humans given colostrum have also been observed. For example, both bovine and human colostrum, given orally, ameliorate diarrhea from GI tract infections in children.14 , 15 In a pilot study, bovine colostrum was also effective in treating diarrhea resulting from Cryptosporidium parvum infection in adult AIDS patients.16
Colostrum has been shown to have significant antibacterial activity in vitro. For example, bovine colostrum is bactericidal to Helicobacter pylori.17 This bacterium is a frequent cause of gastric inflammation in humans.18 Bovine and human colostrum also inhibit binding of H. pylori to target tissue lipids in vitro.19 In addition, the cellular component of human colostrum has been shown to phagocytize and kill Escherichia coli and Candida albicans in vitro.20 Bovine colostrum is also bactericidal to E. coli in vitro.21 Human colostrum also stimulates B-cell proliferation and antibody secretion in mouse spleen cells, which is also an anti-infection activity.22
Of course, the most important biological activities of colostrum and its major components are those related to activation and regulation of the immune system. These activities will be discussed for each component, but let us first consider colostrum itself. For example, in cell culture, human colostrum has been shown to inhibit the proliferation of immune system T cells that have been previously activated, as well as inhibit production of a key immune system cytokine, interleukin-2 (IL-2).5 , 23 , 24 Human colostrum has also shown anti-inflammatory activity (such as inhibition of pro-inflammatory enzymes and antioxidant properties) in neutrophil cell cultures8 , 25 and in adult rats injected with human colostrum.6 These immunosuppressive qualities can help overcome a hyperactive immune system, which can mediate certain autoimmune disorders. Conversely, human colostrum has been shown to activate the immune system by stimulating secretion of cytokines (IL-1, IL-3, and IL-6) by peripheral blood mononuclear cells in vitro.26 This activation is important when the immune system is needed, for example, to fight infection or cancer.
Various other biological activities for colostrum have been observed in in vitro and in vivo studies, such as its important role in skeletal muscle development. For example, in colostrum-fed neonatal pigs, there is an increase in IGF-1,27 which markedly increases muscle protein synthesis7 (see also Biological Activities of Colostrum Growth Factors section). Bovine colostrum has also been shown to inhibit protein breakdown in cultured myoblasts,28 hepatoma cells, and fibroblasts.29 Other miscellaneous biological activities of whole human colostrum include an antioxidant property,25 apparently due to a component which is similar to ascorbate30 and an anti-amoebic property.31 Bovine colostrum, given orally as a dietary supplement, enhances resistance to intestinal colonization by C. parvum in mice32 and protects piglets from the clinical effects of pig rotavirus.33
Biological Activities Of Colostrum Immunoglobulins
The major components of colostrum are probably responsible for most of its biological activity. One of the most important immune components of colostrum, secretory IgA (S-IgA), plays an important role in protecting against infection.3 For example, an immunoglobulin preparation from bovine colostrum that contains IgA reacts against toxins associated with E. coli and Shigella infections in cell cultures in vitro.34 S-IgA from human colostrum also inhibits adherence of Vibrio cholera to intestinal tissue in vitro, an activity that is consistent with the ability of IgA to prevent bacterial colonization.35 S-IgA and IgM autoantibodies from human colostrum also protect in vitro against GI autoantigens that can cause autoimmune disease, and thus act to maintain immune homeostasis.36 , 37 Results from three separate clinical studies also show that oral immunoglobulins from bovine colostrum are anti-diarrheal in adult AIDS/HIV patients suffering from infection by C. parvum,38 , 39 , 40 and probably account for this same effect reported for whole colostrum.16 In other biological activities, orally administered S-IgA-enriched anti-measles bovine colostrum has shown a weak effect in multiple sclerosis patients.41 A follow-up double-blind study, however, found that hyperimmune bovine colostrum provided no symptomatic relief to such patients.42 S-IgA also inhibits cytokine release in vitro, indicating that it may play an anti-inflammatory role in colostrum.43 Finally, orally administered immunoglobulins from bovine colostrum are biologically active in other species, such as horses, sheep, deer, and humans.1 , 44 , 45 , 46 , 47
Biological Activities Of Colostrum Growth Factors
Growth factors, also present in colostrum, activate various growth and repair processes in the body that are important for proper development, maintenance and healing of GI tract, skeletal muscle and bone structure.48 For example, transforming growth factor TGF-B from bovine salivary gland and kidney (which is also present in human colostrum)49 accelerates wound healing in rats when injected daily into wounds in nanogram amounts.50 TGF-B from bovine bone, which is identical to cartilage inducing factor, induces cartilage formation and bone repair in tissue cultures.51 TGF-B has also been found to suppress growth of cancer cells (osteogenic sarcoma cells) in vitro,52 although the mechanism(s) for this effect is unknown. Epidermal growth factor, also found in colostrum, inhibits muscle protein breakdown in cultured myoblasts in vitro.28
Another growth factor, insulin-like growth factor (IGF), has been well studied with respect to its biological activities.53 It is found in abundance in bovine colostrum54 and is structurally similar to IGF in human colostrum.55 , 56 It is most abundant immediately after parturition in human and pig colostrum.57 , 58 It has cytokine-like activities on lymphoid cells of the immune system, and thus may be a natural component of B and T cell lymphopoiesis.59
The most important biological activities of IGF are related to muscle protein metabolism, repair and glucose utilization. For example, IGF stimulates protein synthesis and inhibits muscle protein breakdown in cultured skeletal muscle cells (myoblasts)60 , 61 , 62 and hepatoma cells,63 and in diabetic rats.64 Injected IGF also appears to partly protect body protein reserves during nitrogen restriction in rats.65 Fasting or restriction of dietary protein reduces serum IGF in rats in vivo.66 Increased body weight has also been seen in aged rats when a serum IGF increase was stimulated by growth hormone in vivo.67 Oral IGF stimulates cell proliferation in the GI tract of newborn pigs.68 Injected IGF also stimulates wound healing in vivo in rats,69 and is increased naturally in the healing wound of mice; its increase is delayed in diabetic mice, consistent with the delayed wound healing experienced by diabetics.70 All of these findings underscore the apparent importance of IGF in the healing process.
In a randomized, placebo-controlled clinical study of insulin-dependent diabetics, subcutaneously injected IGF reduced both the HbA1c levels (a measure of average blood glucose levels over time) and insulin requirements, apparently by suppressing growth hormone activity.71 This activity may be due also to an IGF-induced increase in glucose utilization, since IGF stimulates glucose transport in human skeletal muscle in vitro.72
It is also of significance that serum IGF increases slightly in athletes given oral bovine colostrum supplementation to their diet during training.73 In this regard, since an adult human produces about 10,000 micrograms ((g)/day of IGF-1,74 and the range of adult human blood plasma IGF-1 levels is 42-308 (g/liter (L), 75 the low IGF-1 levels present in bovine colostrum dietary supplements would not be expected to significantly increase the normal background concentrations of IGF-1 in blood plasma. For example, it can be calculated from the study cited that athletes who consumed 125 milliliters (ml)/day of bovine colostrum containing approximately 68 (g/L of IGF-1, received approximately 8.5 (g/day of IGF-1 (assuming complete absorption from the GI tract). This compares to normal IGF-1 production of 10,000 (g/day. However, since a slight, but statistically significant, increase in IGF-1 plasma level was noted in the study, the increase may have been due to stimulation of endogenous IGF-1 production by the liver rather than absorption of dietary IGF-1 from the GI tract.
With regard to any possible adverse effects of IGF, it has been observed that levels of renal IGF-1 and IGF binding proteins rise prior to an increase in kidney size in rats with experimentally-induced diabetes; however, the authors did find any resultant kidney damage.76 Another author suggested that IGF might contribute to diabetic nephropathy (i.e., kidney disease) by decreasing collagen degradation as seen in diabetic mesangial cells in vitro.77 However, while this speculation based on in vitro data is theoretically possible, there was no evidence for nephropathy in either of the cited studies of diabetics 71 or athletes73 in which IGF was either injected or given orally.
It is also worth mentioning that IGF-1 has been suggested as a possible indicator (i.e., biomarker) for certain types of cancer, since its level sometimes increases when certain types of cancer are present.78 However, using elevated serum levels of IGF-1 as a biomarker for cancer has not been established, since a consistent association with cancer has yet to be discovered.79 , 80 Since there is no evidence that IGF-1 causes cancer or adversely alters cellular DNA, it appears that increased plasma IGF-1 is simply a characteristic of the cancer process, but is not a cause. This interpretation is consistent with the finding that IGF and IGF receptor binding proteins are increased in tumor cells.81 , 82 , 83 Moreover, since IGFs are "growth factors" produced by the liver to provide endocrine support for cell growth and development, it is not surprising that IGF-1, like many other growth-promoting substances produced by the body, is important for tumor cell, as well as normal cell, growth in vitro. 84 , 85 , 86 , 87 , 88 Finally, it should be noted that a scientific review by the U.S. Food and Drug Administration (FDA) does not support a causal relationship between IGF-1 and the appearance of tumors.89
Biological Activities Of Other Immunomodulatory Components Of Colostrum
Proline-rich peptide (PRP) is another very important immunomodulatory component of colostrum. PRP regulates the thymus gland, which produces T-cells that fight viruses and antigens, and plays a key role in balancing an overactive immune system (such as is found in individuals with autoimmune diseases) or an underactive immune system (seen in immuno-compromised individuals); PRP acts both in vitro and in vivo, and is not species specific.4 , 90 PRP has been tested clinically in the treatment of Alzheimer's disease (AD). Orally administered PRP complex from sheep colostrum (100 (g every other day) was found to significantly improve Alzheimer's dementia in a double blind, placebo-controlled study. Psychiatrists blinded to the treatment assignment assessed outcomes. All 15 AD patients stabilized or improved; none of the 31 selenium-treated or placebo control patients improved.91
Lactoferrin (Lf) is another key component of colostrum. It is also secreted in milk, tears, mucus, and saliva, particularly in response to a pathogen attack.92 , 93 Since it is the subject of a separate scientific review by this author and has been reviewed extensively in the published literature,3 , 94 , 95 , 96 , 97 its biological activities will only be summarized here. Many of the biological activities of Lf relate to its ability to regulate either the immune system98 , 99 or the availability of iron.94 Based on studies with bovine and human colostrum evaluated in vitro and/or orally or by injection in test animals or humans, its biological activities include anti-inflammatory,95 , 100 anti-allergenic,101 anti-cancer,102 , 103 ,104 , 105 , 106 , 107 , 108 , 109 , 110 anti-bacterial,3 , 111 , 112 , 113 , 114 , 115 , 116 , 117 anti-viral, 118 , 119 , 120 , 121 ; 122 , 123 , 124 , 125 , 126 , 127 and anti-fungal128 , 129 functions. Its anti-inflammatory activity relates to its ability to inhibit pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a) and IL-6.43 , 95 , 99 , 130 , 131 , 132 However, Lf also regulates the immune system by stimulating cytokine release when an activated immune system is needed to, for example, fight infection or cancer. 103 , 133 , 134 , 135 Its anti-allergenic activity may relate to its ability to inhibit mast cell tryptase, which is involved in bronchoconstriction and airway hyperreactivity.101 Bovine Lf inhibits the development,102 , 103 , 106 , 107 , 109 , 110 , 117 growth, and metastasis104 , 108 of tumors in rats and mice when injected or given orally as 0.2% of the diet, perhaps in part by its ability to stimulate natural killer cell release103 and bind to various glycosaminoglycans.135 Its anti-pathogenic activities relate primarily to its ability to bind iron and thus starve pathogens, which require iron as a nutrient.3 , 112 , 116 Bovine and human Lf also act to prevent colonization by pathogens in vivo by binding to them and preventing their adhesion to host cells.117 , 136 , 137 They are particularly effective against H. pylori, which is a common cause of gastric inflammation in humans.18 Of additional benefit is the fact that human and bovine Lf have been shown in vitro to actually promote the growth of beneficial bifidobacteria.138
Conclusions
In conclusion, colostrum, and, in particular, two of its components, Lf and PRP, act to regulate and balance the immune system. Studies suggest that this biological activity is important for adults with over- or under-active immune systems as well as for newborns. Colostrum and its components also have potent anti-bacterial, anti-viral, and anti-fungal activities. Colostrum and its growth factors enhance muscle protein synthesis, wound healing, cartilage formation, and bone repair, benefit GI tract structure and function, and are anti-inflammatory and anti-allergenic. The Lf component of colostrum regulates iron availability and has demonstrated anti-cancer activities. Colostrum and its components exert their biological activities when given orally, in many cases as a dietary supplement. Moreover, bovine and human colostrum are similar enough that they exert similar biological activities in various species.
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