Bovine colostrum contains very high amounts of more than one hundred bioactive factors, including immunoglobulins, anti-inflammatory factors, anti-microbial factors, and growth factors. The bioactive factors are contained in a complex, but important matrix together with high levels of other nutrients, minerals, vitamins, lipids, carbohydrates and proteins. Due to the complex content, bovine colostrum could be regarded as some kind of "super nutrient".

The colostrum milk matrix

Bovine colostrum contains more than one hundred known bioactive factors, and new ones are identified each year. The growing list of factors increases the colostrum milk matrix of bioactive factors and nutrients in colostrum, and makes it difficult to determine and understand the roles and mechanisms of each single component. Furthermore, it is most likely that some factors are still not identified or fully understood.

Many of the bioactive factors may interact with each other and exert accumulative effects. The benefits from colostrum are likely not caused by one or a few isolated factors, but by the sum of large groups or by them all; a concept known as food synergy (Jacobs & Tapsell, 2013). Some of these interactions are known, while others are yet to be discovered. The full bioactive potential of these factors is difficult to study when removed from the contextual composition in the colostrum milk matrix (Yan & Hancock, 2001; Chatterton et al., 2013). The milk matrix in colostrum likely influences the release, transformation and bioactivity of certain nutrients and bioactive factors in the gut, and some effects are likely caused by the interactions between several bioactive factors. Furthermore, many proteins and compounds found in colostrum survive digestion better when ingested incorporated in the milk matrix. In summon, the complex structure of whole colostrum is believed to important (Kehoe et al., 2013; Rathe et al., 2014; Pontoppidan et al., 2015).

Modifications of the colostrum milk matrix also affects its bioactivity. Excessive processing (e.g., heating, filtering, and spray drying) and drying or mixing modifies bioactive properties of colostrum components and reduces the antimicrobial properties and beneficial effects on the gastrointestinal tract (Foley & Otterby, 1978; Li et al., 2013).

Significant components in colostrum

The most important and significant attribute about bovine colostrum is the remarkably high levels of several biologically active molecules in the colostrum which are essential for specific functions. Some of the most important of these bioactive factors are the immunoglobulins, growth factors, antimicrobial factors, and anti-inflammatory factors. In addition, colostrum also contains the same vitamins, minerals, carbohydrates and proteins as mature milk, just in higher concentrations. All these compounds are important for the maturation of the gastrointestinal tract and the immune system of the newborn calf in order to face the challenges of the life outside the uterus (Pakkanen & Aalto, 1997; Kelly, 2003).

Bioactive factors

The bioactive factors found in bovine colostrum include constituents with biological effects of nutrients beyond simple macronutrient and micronutrient supply, e.g. enhancement of nutrient absorption, growth stimulation, defense against enteric pathogens, and modulation of the immune system. This group includes immunoglobulins, growth factors, anti-inflammatory factors, and anti-microbial factors.

Immunoglobulins

Colostrum is the sole natural source of immunoglobulins for the calf. These immune components are crucial in the survival of the calf as they are essential in the maturation of the immune system (Pakkanen & Aalto, 1997). Immunoglobulins are well-known parts of the immune system, and they constitute an important part of the adaptive immune system as they neutralize enteric pathogens, such as bacteria, microbes and viruses (Janeway, 2001). The immunoglobulins in bovine colostrum come in five different varieties called isotypes:

• IgA protects the intestinal epithelium from enteric pathogens and toxins, and is found in the mucosa in the gastrointestinal, respiratory and urogenital tracts, as well as in saliva and breast milk (Underdown & Schiff, 1986; Mantis et al., 2011).
• IgD can activate specific types of white blood cells to produce antimicrobial factors and is found in the blood serum (Chen et al., 2009).
• IgE is involved in allergies, as it binds to allergens and triggers release of histamine from specific white blood cells, but can also protect against enteric pathogens, such as parasitic worms. It is found in the blood serum (Pier et al., 2005).
• IgG comes in four forms, and is the most common immunoglobulin found in the circulation. It is the main component is the immunity against invading enteric pathogens (Pier et al., 2005).
• IgM is involved in eliminating enteric pathogens until sufficient amounts of IgG is present (Pier et al., 2005).

The immunoglobulins constitute the largest group of immune components in colostrum (Kehoe et al., 2007), and the levels are about 100-times higher in bovine colostrum than mature bovine milk (Pakkanen & Aalto, 1997). The dominant immunoglobulin in bovine colostrum is IgG, which makes up 85-90% of the total immunoglobulin content, with IgG1 constitutes up to 80-90% of the total IgG content (Larson et al., 1980; Barrington et al., 1997). The immunoglobulins IgG2, IgM and IgA are present at lower concentrations, but still in much higher concentrations than in mature milk, see Table 1 (Weaver et al., 2000; McGuirk & Collins, 2004).

Table 1. Concentrations of the immunoglobulins IgG1, IgG2, IgA, and IgM in bovine colostrum and mature milk (Pakkanen & Aalto, 1997; Kelly, 2003; Kehoe et al., 2007; Stelwagen et al., 2009).

The concentration and class of immunoglobulins in the colostrum and milk reflect the route and origin of the immunoglobulins. The very high levels of IgG1 is because this immunoglobulin is being selectively transported into the milk fluid in the cow, while the presence of the immunoglobulins IgA and IgM is due to active transport from local synthesis in the udder (Larson et al., 1980). High quality colostrum is defined by having an IgG concentration higher than 50 g/L (McGuirk & Collins, 2004).

The immunoglobulin content and composition in colostrum is influenced by a number of factors, such as breed, herd, age of dam, season of calving, nutrition in the parturition period, volume of colostrum produced, time of collection, vaccination of the dam, feed, number calf and number of lactation (Weaver et al., 2000; Kelly, 2003; Godden, 2008).

Immune-regulating and anti-inflammatory factors

The contents in bovine colostrum belong to both the innate and the adaptive immune system. The innate immune system is the first line of defense and protects against enteric infectious pathogens by detecting and eliminating them through a complex interaction between cellular and molecular processes. Later, the adaptive immune system takes over by a response mediated through T and B cells relying on memory to quickly respond to threats to which it has previously been disposed (Stelwagen et al., 2009).

Immunoglobulins are the main component in the adaptive immune system, but bovine colostrum contains a wide range of other immune-regulating factors that are important for the maturation of the immune system in the calf (Kehoe et al., 2007; Rathe et al., 2014). Trypsin inhibitor is a protease that protects IgGs and other bioactive proteins against degradation in the intestine. It is present in bovine colostrum in concentrations nearly 100 times higher than in mature milk (Godden, 2008). A wide variety of components linked to the innate immune system have been identified in bovine colostrum, such as cytokines, maternal leukocytes, oligosaccharides, gangliosides, proteins and peptides and many more (Stelwagen et al., 2009).

Cytokines are small hormone-like proteins that are involved in cell signaling, pathogen recognition and immune cell recruitment in the immune system. They regulate the development and expression of a broad array of immune responses against a variety of enteric pathogens, as they are the critical determinants of which types of immune cells that are needed to regulate and participate in both innate and adaptive immune responses. As such, they act both in local environments, but also in a systemic manner. Cytokines are also themselves directly antimicrobial (Banyer et al., 2000; Mookherjee and Hancock, 2007). Cytokines include interleukins (e.g., IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-17), tumor necrosis factor (TNF-α), interferon (INF-γ) and other compounds that contribute to control of infections and inflammations (Wheeler et al., 2007; Rathe et al., 2014).

Bovine colostrum also contains maternal leukocytes. The concentration is normally more than 1.000.000 cells/mL of immunological active white blood cells, including macrophages, T and B lymphocytes, neutrophils and epithelial cells (Barrington et al., 1997). These cells are involved in protecting the body against enteric pathogens and infectious diseases, both by direct killing and by stimulating a local immune response, including formation of IgG, cytokines and antimicrobial peptides (Godden, 2008; Stelwagen et al., 2009).

Bioactive oligosaccharides are also found in bovine colostrum, and they may also help protect against pathogens and promote growth of beneficial bacteria flora in the gut lumen, as they act as competitive inhibitors for the binding sites on the epithelial surfaces of the gut (Gopal & Gill, 2000; Godden, 2008; Rathe et al., 2014).

Gangliosides are polar lipids found in the milk fat globule membrane and are involved in several functions. They are also involved in several biological procedures such as neural development, pathogen binding and activation of the immune system (Lee et al., 2013).

Certain microRNA with immune-regulating potential are also present in bovine colostrum. These compounds are present in micro vesicles that are stable under the conditions in the gastrointestinal tract, and may therefore be able to reach the immune cells of the lymphoid tissues in the gut (Pakkanen & Aalto, 1997).

Growth factors

Bovine colostrum contains several different growth factors that especially stimulate the growth and development of the gut, such as insulin-like growth factors, epidermal growth factors, transforming growth factors, and platelet-derived growth factors (Thapa, 2005). They control cell division and cell differentiation and thus promote growth and development of all sorts of tissues in calf (Rathe et al., 2014). Some growth factors are especially important for the maturation of the gastrointestinal tract, as they are involved in both tissue growth and epithelial cell modifications, which ultimately closes the intestine and makes it a formidable barrier for alien bacteria, microbes and pathogens (Xu, 1996; Elfstrand et al., 2002).

The most abundant and best describes growth factors are the insulin growth factors (IGF-I and IGF-II). These proteins promote cellular growth, differentiation and development of tissues in newborn calves and are important for the maturation and maintaining of the integrity of the gut. They are heat and acid stable and can withstand the degradative conditions of the gastrointestinal tract, and their effect may thus both be local or mediating systemic effects (Pakkanen & Aalto, 1997; Rathe et al., 2014). The homology between human and bovine insulin growth factors is 100%, indicating similar physiological effects and pointing to bovine colostrum as efficient human diet supplementation (Chatterton et al., 2013). Reported concentrations are listed in Table 3.

Table 2. Concentrations of growth factors found in bovine colostrum and mature bovine milk (Pakkanen & Aalto, 1997; Chatterton et al., 2013).

Transforming growth factors (TGF-α and TGF-βs) are also present in bovine colostrum. They are included in maintaining epithelial functional and integrity, and in the regulation of the immune system by induction of regulatory T cells, and are also anti-inflammatory. TGF-βs are important for the tissue repair and stimulation of restitution, formation of bone and cartilage, and control of the immune system. (Pakkanen & Aalto, 1997; Playford et al., 2000). TGF-βs in bovine and human colostrum are 100% structurally similar (Chatterton et al., 2013). Transforming growth factor-α is a peptide involved in maintaining epithelial function and integrity in the gut (Playford et al., 2000; Rathe et al., 2014).

Epidermal growth factors (EGFs) are present in far smaller amounts than insulin-like growth factors. They stimulate production of epithelial cells and promote wound healing, especially in the gut (Dvorak et al., 2003). They are only minimally degraded by heat and gastric acid and can thus maintain their biological activity until they reach the gut (Britton et al., 1989). TGF-α could actually be included in this groups also as it is involved in maintaining and developing epithelial function and integrity (Pakkanen & Aalto, 1997). The milk fat globule epidermal factors-8 (MFG-E8) have recently been reported to be significantly anti-inflammatory, and is present in bovine colostrum in high concentrations, ensuring adequate levels in the intestine (Chatterton et al., 2013).

Platelet-derived growth factors (PGFs) in a bioactive factor that triggers cell division in fibroblasts, the cells responsible for synthesizing the structural framework for animal tissue, and are thus important for wound healing (Pakkanen & Aalto, 1997; Playford et al., 2000).

Other growth factors found in bovine colostrum are betacellulin, which is important in neonatal organ development, and vascular endothelial growth factors that promote formation of new blood vessels and cell division and thus participate in wound healing (Playford et al., 2000).

Antimicrobial factors

Bovine colostrum contains several bioactive factors with antimicrobial activity that helps protect against enteric pathogens. They provide passive immunity for the calf and protect against infections (Pakkanen & Aalto, 1997). Specific peptides and proteins belonging to the innate immune system has also been reported to likely be antibacterial, antifungal, or antiviral products, or their combination (Christoffersen, 2006; Fernandes, 2006).

Much of the antimicrobial activity of colostrum is due to the immunoglobulins, although colostrum also contains other antimicrobial factors. Lactoferrin and lactoperoxidase are two antibacterial immune factors belonging to the innate immune system (Pakkanen & Aalto, 1997). Lactoferrin is a glycoprotein with iron-binding, lipopolysaccharide-binding, immune-modulating, antibacterial and growth-regulating effects, and it has been reported to reduce mortality and improve growth in newborn calves (Robblee et al., 2003; Wheeler et al., 2007). Lactoperoxidase is an enzyme that inhibits bacterial metabolism and it is toxic to a range of Gram-positive and Gram-negative bacteria (Seifu et al., 2005). Lysozyme is an antibacterial enzyme also found in the innate immune system that is also toxic to Gram-negative bacteria causing cell death by lysis and to Gram-positive bacteria by inhibiting growth (Clare et al., 2003; Wheeler et al., 2007). The presence of lactoferrin enhances the antibacterial activity of lysozyme against the bacteria Escherichia coli (Pakkanen & Aalto, 1997). The concentrations of the three bioactive factors are shown in Table 2 below.

Table 3. Concentrations of lactoferrin, lactoperoxidase and lysozyme, three antimicrobial factors in bovine colostrum and mature bovine milk (Pakkanen & Aalto, 1997; Kehoe et al., 2007).

Nutrients

Bovine colostrum contains the same basic nutrients as mature milk, but in significantly higher concentrations. The nutrients constitute the basic components needed to survive and grow, and provide the energy needed for the metabolic system to function and the necessary compounds needed for metabolism to work. This group include proteins and peptides, carbohydrates, lipids, vitamins, and minerals and ash.

Proteins and peptides

Colostrum contains markedly more protein than mature milk, which is mostly due to the increased levels of immunoglobulins and casein. Milk proteins can be divided into two groups: soluble proteins, called whey proteins, and insoluble proteins, named caseins. In bovine colostrum the total concentration of protein in bovine colostrum is 150 g/L, with concentrations of 124 g/L whey protein and 26 g/L casein. This equals a protein amount in the first milking on about 15%, but the amounts decreases to 3% in mature milk (Godden, 2008). This decrease includes a change in the ratio between whey protein and casein from 70:30 in colostrum to 20:80 in mature milk. The change in ratio is important for the digestion and the motility in the gastrointestinal tract, and is optimized accordingly to the infant diet. Degradation of casein forms peptides that regulate intestinal motility and enhance absorption of calcium (Zanker et al., 2001; McGuirk & Collins, 2004; Kehoe et al., 2007; Chatterton et al., 2013). An overview of the physical, chemical and structural aspects of milk proteins can be found in Table 1 in Chatterton et al., 2013.

Caseins are immune-regulating, antibacterial and anti-inflammatory proteins. They are also important mineral binders, especially for calcium and phosphorus, and improve digestion by forming a clot in the gut thereby decreasing gut transition time and increasing the time for nutrient uptake (Pereira, 2014). They are poorly soluble and are found as small micelles in milk, bound together by hydrophobic interactions. Caseins form a clot in the stomach which provide a slow stable release of nutrients, thus making caseins very efficient in nutrient supply (Chatterton et al., 2013). Casein has a high proportion of the amino acids histidine, methionine, phenylalanine (Pereira, 2014).

Whey protein describes the collection of soluble globular proteins in whey, and is typically a mixture of α-lactalbumin, β-lactalbimun, serum albumins, immunoglobulins, Lactoferrin, lactoperoxidase and lysozyme (Pereira, 2014). The whey protein α-lactalbumin is present in bovine colostrum in large amounts and constitute 28 % of the total protein amount and 40% of the whey protein amount, while β-lactalbumin is present in lower concentrations. Both have very high nutritional value due to high levels of essential amino acids (Kelleher et al., 2003), while α-lactalbumin also possess antimicrobial properties, and is important in the absorption of calcium and other minerals (Håkansson et al., 2000; Chatterton et al., 2006). Whey is especially rich in the branched amino acids, such as leucine, isoleucine, valine and lysine (Pereira, 2014).

Carbohydrates

Carbohydrates in bovine milk include lactose, glycolipids, glycoproteins, nucleotide sugars and oligosaccharides. The dominant saccharide in bovine milk products is lactose, and mean percentages of lactose in colostrum have been reported to be 2.5 % (Kehoe et al., 2007), corresponding to a concentration of 1 g/L (Saito, 2004), which is lower than in bovine mature milk and human milk (Urashima et al., 2001).

Dietary oligosaccharides have shown to have bioactive properties. They are not digested in the upper intestine and arrive intact in the colon, where they are important for the gut health; they function as prebiotics and act as substrates for beneficial gut microflora while also protecting against infectious pathogens that causes diarrhea (Koletzko et al., 1998; Zivkovic & Barile, 2011). Bovine milk contains several oligosaccharides that are analogous and structurally similar to oligosaccharides found in human milk (Gopal & Gill, 2000).

Fat and lipids

Mean percentages of fat in bovine colostrum have been reported to be 6.7 % (Kehoe et al., 2007). The lipid fraction in milk is found as dispersed droplets called milk fat globules. These droplets are surrounded by a tri-layered membrane called the milk fat globule membrane, which is mainly build by polar lipids, more than a hundred proteins, neutral lipids and some other minor components. The size of the fat globules is much higher in colostrum than in mature milk (Spitsberg, 2005).

Colostrum contains both saturated and unsaturated fatty acids, and some these lipid fractions are themselves bioactive. Some of the potentially bioactive saturated fatty acid are butyric acid, which is a modulator of gene function, caprylic acid that are potential anti-viral, and lauric acid may be both anti-viral and antibacterial and is known to kill the bacteria Heliobactor pylori (Haug et al., 2007). Unsaturated fatty acids that are potentially bioactive include oleic acid is produced during intestinal digestion of colostrum fatty acids, and is reported to prevent cryptosporidium parasites to stick to the gut wall (Schmidt & Kuhlenschmidt, 2008).

Gangliosides are polar lipids found in the milk fat globule membrane and are involved in several functions (Lee et al., 2013). Fat-soluble betacarotene and other carotenoids antioxidants and are also fund in the milk fat globule membrane, and the high concentration of these lipids is the reason for the yellow color of colostrum (Patton et al., 1990).

Vitamins

Vitamins are antioxidants and help improving the immunity of different cell types. Colostrum contains both fat-soluble (A, D, and E) and water-soluble (B, and C) vitamins. The vitamins in the complex of vitamin B are important in several metabolic pathways, such as energy production from nutrients and hormone synthesis (Pereira, 2014), while vitamin C is essential for the production of collagen in the connective tissue. Mean concentrations of some of the water-soluble vitamins found in bovine colostrum are 0.34 g/mL niacin, 0.90 g/mL thiamine, 4.55 g/mL riboflavin, 0.60 g/mL vitamin B12, 0.15 g/mL pyridoxal, 0.21 g/mL pyridoxamine, and 0.04 g/mL pyridoxine (Kehoe et al., 2007).

The amount of fat-soluble vitamins depend on the milk fat content. Vitamin A is especially important for growth, development, and immunity; vitamin D promote uptake of calcium and phosphorus in the gut and have immune-regulating activities; vitamin E is a group of compounds protecting the body cells from degradation by (Pereira, 2014). The tocopherols belong to the vitamin E-group and are thus antioxidant. Unlike immunoglobulins, tocopherols pass through the placental membranes to the fetus, neonates are still born with very low levels and rely on colostrum for full supply of this vitamin (Zanker et al., 2000). Mean concentrations of some fat-soluble vitamins are reported to 4.9 g/g retinol, 2.9 g/g tocopherol, and 0.7 g/g β-carotene (Kehoe et al., 2007).

Minerals and ash

Resent findings reveal that the mean concentrations of several essential minerals are markedly higher in colostrum than in mature bovine milk. Colostrum and milk in general are considered very good natural sources of calcium and phosphorus (Pereira, 2014). Calcium is important for maintaining healthy bones and teeth, and is thus critically for the growth of the calf, while phosphorus is vital for the metabolic rate (Haug et al., 2007). Magnesium is also found in relatively large quantities in bovine colostrum, together with zinc and selenium (Pereira, 2014).
Mean concentrations of selected minerals in bovine colostrum have been determined to be (Kehoe et al., 2007):

• Calcium 4716 mg/kg
• Phosphor 4452 mg/kg
• Magnesium 733 mg/kg
• Sodium 1058 mg/kg
• Potassium 2845 mg/kg
• Zink 38 mg/kg
• Iron 5.3 mg/kg
• Copper 0.3 mg/kg
• Sulphur 2595 mg/kg
• Manganese 0.1 mg/kg

Factors that influence colostrum contents

The concentrations of bioactive factors in bovine colostrum are affected by a number of factors, such as breed, herd, age of dam, season of calving, nutrition in the parturition period, volume of colostrum produced, time of collection, vaccination of the dam, feed, number calf and number of lactation (Weaver et al., 2000; Elfstrand et al., 2002; Kelly, 2003; Kehoe et al., 2007; Godden, 2008).

Colostrum management

Keeping bovine colostrum intact instead of purifying each bioactive component is important to maximize the beneficial effects as modifications of the colostrum milk matrix affects its bioactivity.(Kehoe et al., 2013; Rathe et al., 2014; Pontoppidan et al., 2015). Excessive processing modifies bioactive properties of milk and reduces the antimicrobial properties and beneficial effects on the gastrointestinal tract (Li et al., 2013). Such diary processes include heat treatment, ultrafiltration, freeze-drying, spray-drying, and removal of lipids, carbohydrates, casein or salts (Elfstrand et al., 2002). Dilution and mixing of bovine colostrum has also been shown to reduce the quality of bovine colostrum, probably caused by insufficient provision of certain bioactive factors and nutrients (Foley & Otterby, 1978). Freezing results in virtually no loss of nutrients from the colostrum during storage, while fermentation or chemical treatment change the physical characteristics and unavoidable results in loss of nutrients (Foley & Otterby, 1978). Regarding the importance of the milk matrix these results highlight the importance of using whole colostrum as diet supplements for calves and humans.

Additional processing of bovine colostrum in order to generate a product with an extra high levels of immunoglobulins includes pasteurization, powdering, and removal of most of the milk fat, includes casein, lactalbumin, and lactose. However, removal of the fat phase of colostrum often includes removal of several fat-soluble vitamins and bioactive factors. This might influence on the nutritional value of the product as several important vitamins are fat-soluble and are found in the micelles, specialized fat globules which are located all around the milk or colostrum. There is a significant correlation between fat in colostrum and fat-soluble vitamin concentrations (Weiss et al., 1990; Kelly, 2003).

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