The Eye on Fire
Modulating The Morbidity of InflammationWritten by Larry J Alexander OD FAAO Tuesday, 29 October 2013
Inflammation is a necessary and critical component of the healing system and the overall actions of the immune system. The immune system is an integrated network of organs and cells that protect the host from invasion and modulate reaction once invasion has occurred. The immune system depends on self-regulation to dampen the potential for unrelenting self -destruction of autoimmune reactions. The balance in the system (immunomodulation ) is critical to the overall health of the immune system and thus the human system. Acute inflammation is modulated by the immune system to take care of an immediate problem…then it is supposed to shut itself off. Chronic inflammation is an issue that is a representation of the immune system out of control…an immune system that does not shut itself off. The immune (inflammatory) system then becomes a smoldering fire that creates significant issues throughout the bodily systems including the eye. Chronic inflammation is responsible for destabilizing cholesterol deposits (heart attack and stroke), destroying nerve cells (dementias), proliferating abnormal cells and potentially transforming them to cancer, and impacting on devastating disorders of the eye such as macular degeneration, uveitis and glaucoma.
The body needs the characteristic of acute inflammation, which is an integral part of the immune system, to fight-off disease. Fever is an example of the immune system at work to shut down viral and bacterial invasion. However, at the same time the system must be modulated to minimize the onset of chronic inflammation….a fever out of control becomes devastating to the health of tissue. Diet, exercise, environment and proper nutrition are critical to this modulation or maintenance of balance. Many pharmaceutical agents suppress inflammation but result in suppression of the good with the bad. Side effects of very effective anti-inflammatories such as COX 2 inhibitors are legend. COX 1 controls vascoconstriction and thrombotic activity. If you suppress COX 2 rather than modulate COX 2, COX 1 dominates allowing for vasoconstriction and thrombotic activity which precipitates cardiac complications. COX 2 inhibitors created morbidity on the pathway to suppressing inflammation. Other methods of suppressing inflammation include aspirin and steroids that likewise have untoward side effects.
The ideal anti-inflammatory agent would modulate or balance the system without creating a significant negative effect. This discussion will describe a possible agent to be used in immune system disorders…Colostrum. The article is solely for informational purposes at this point to precipitate interest in activities and research that might contribute to the use of Colostrum in the co-management of some ocular disorders.
THE IMMUNE SYSTEM AND THE EYE
There are numerous ocular issues associated with the immune system from the tear layer through the eye to the sclera. The ocular adnexa and its impact on the proper functioning of the eye is also maintained in a healthy state by the immune system. The presence of IgA in mucous secretions is an excellent example of the one of the components of the immune system that is the first line of defense for potential invasion. Other anti-inflammatory markers that present in the tears include lactoferrin and lysozyme among others. Any breakdown in the immune system allows a window of opportunity for invasion, and the immune system out-of-control creates an inflammatory opportunity that leads to further tissue destruction. The immune system out-of-modulation is involved in all of the following major ocular disorders, but is not limited to just these disorders:
- Herpes simplex
- Herpes zoster
- Infestation e.g. Demodex
- Related to Inflammatory Systemic Disease
- Ocular Surface Disease
- Related to Inflammatory Systemic Disease
- Sjogren’s Syndrome
- Related to Local Irritants Like Contact Lenses
- Corneal Ulcers
- Anterior Uveitis Granulomatous and Non-Granulomatous
- Related to Inflammatory Systemic Disease
- Traumatic Anterior Uveitis
- Vitritis Associated with Uveitis
- Demyelinizing Optic Neuropathy
- Ischemic Optic Neuropathy
- Arteritic Optic Neuropathy
- Open angle
- Normal tension
- C-Reactive Protein and NTG
- Infectious NeuroRetinitis…Cat Scratch Fever
- Age Related Macular Degeneration
- C-Reactive Protein and ARM
- Ocular Histoplasmosis
- Posterior Uveitis/Scleritis
- Various Forms of Retinitis
- Including HIV
- Infectious NeuroRetinitis…Cat Scratch Fever
- Auto-Immune Retinitis
- RetinoChoroiditis (e.g. Toxoplasmosis)
MODIFIABLE RISK FACTORS FOR SYSTEMIC INFLAMMATION
Topics identified below are scientifically proven to be related to the inflammatory response. Modulation to near normalcy for each of these topics would facilitate the management of all associated inflammatory disorders.
- Glycemic Index Control with Careful Diet
- Hyperhomocysteinemia Control with Folic Acid, B6 and B12
- Obesity…Maintain the Best Possible BMI…Obesity precipitates inflammation. Fat begets inflammation and inflammation begets further adiposity.
- Exercise…The Immune System Does Not Have Pump System Like the Vascular System. It Moves the Components of Health Maintenance by Muscular Contraction
- Diet…Utilize an Anti-inflammatory Diet (J Am Coll Cardiol. 2008;51:249)
- Choose low glycemic index high fiber carbs
- Avoid processed foods
- Choose berries, dark chocolate, red wine, some teas that improve vaso-relaxation (J Nutr 2000;130:2105s)
- Tree nuts reduce risks coronary artery disease and diabetes mellitus by 20% and 50%-1 handful/day
- Vinegar and cinnamon reduces post-prandial glycemia
- Lean protein reduces post-prandial glycemia
- Alcohol in moderation reduces post-prandial glucose and insulin
- Exercise 30 min day reduces post-prandial glucose and triglycerides
- Stop smoking
- Improve sleep habits…remember no computer 2 hours before bed
- Reduce stress
- Utilization of Nutritional Supplements Known to Have a Positive Impact on the Immune System When Diet is not Optimal
The Recipe For The Successful Anti-Inflammatory Agent For Prolonged Usage:
- First must have a relatively healthy Gastrointestinal system
- Humans live in symbiosis with 1014 commensal bacteria among which >99% resides in their gastrointestinal tract.
THIS HAS TO WORK PROPERLY
- Must be well-tolerated… Gastrointestinal-friendly
- Must not have significant side effects
- Must not create potential choking issues by capsules that are too big or hard to swallow
- Must be as natural as possible as this is best assimilated by the body
- Must be relatively inexpensive…to treat as many persons as possible for a minimal expenditure
- Must be immune-modulatory in nature…which means it must create a good response without also creating a bad response.
- Humans live in symbiosis with 1014 commensal bacteria among which >99% resides in their gastrointestinal tract.
NATURAL COLOSTRUM IN HUMANS
Colostrum is the fluid that is produced by the breasts of humans, cows and other mammals in the period after birthing prior to the production of true milk. The change to transitional milk occurs quickly. Colostrum is produced to give the newborn an infusion of disease-fighting and immune-modulating agents. While there are a number of agents that facilitate metabolism, the antibody levels are extremely high in colostrum. In the literature one can find reference to hyper-immune bovine colostrum that is produced by mammals given a vaccination against a specific disease. Reportedly this vaccination hyper-activates the production of specific antibodies.
Colostrum is the consummate natural immune-modulator especially when coupled with behavior modification. Prior to the discovery of antibiotics colostrum was the main source of immunoglobulins used to control infection. It is the “mother’s milk” that is intended to protect the newborn in their radical new environment. Bovine colostrum is the first milk secreted by cows after parturition and is a rich source of immunoglobulins (Igs) and other antimicrobial factors, including lactoferrin, lysozyme and lactoperoxidase [Eur J Nutr 42 : 228–232 (2003)
THE ROLE OF BOVINE COLOSTRUM AND LYSOZYME IN IMMUNOMODULATION
Caution: Must not be used by persons with milk allergies but otherwise is extremely well tolerated with no reported significant adverse reactions.
Bovine Colostrum is known to have an antibacterial effect and functions in the modulation of immune responses. Bovine colostrum contains powerful, neutralizing agents called immunoglobulins for protection against a host of pathogens. Colostrum is also a source of other immune and growth factor components including antibodies, specific growth factors, proline-rich polypeptides, lactoferrin, leukocytes, and lactoperoxidases. It has been proposed that colostrum can have therapeutic effects against a variety of infections of bacterial, viral, and parasitic origin, may stimulate the immune system, may build lean muscle and burn fat, may increase stamina, and may create a sense of well-being. The human research is, however, limited. Research related to the eye is basically non-existent. Many claims have been made without total clinical proof of efficacy.
One other issue with bovine colostrum is that the components are very dependent on the number of milkings and the time frame of the milkings for collection of basic product. http://www.colostrum.com/colostrum-components/
It is important to know that:
- In the first milking collected within six hours, over 80% of the albumin fraction is bioactive components produced in the bone marrow and circulatory system.
- At the second milking collected between 12 and 24 hours, only 50% is considered bioactive.
- Production of the whey proteins beta-lactoglobulin and alpha lactalbumin produced from amino acids in the alveoli of the mammary gland now account for the majority of the protein. While they have biological function in addition to their primarily nutritional role, these proteins are available in many consumer foods, whey protein concentrates and isolates.
- When the transition to milk has been completed, the bio-actives are less than 1% of that contained in colostrum.
- Because the transfer of all factors is not diminished at the same rate during the period after birth, 1st milking bovine colostrum has a different balance (ratio) of factors compared to the subsequent transitional period milkings as well.
The consumable supplement of Colostrum is formulated by a number of manufacturers. One question to the manufacturers would relate to the 1st versus subsequent milkings to assure maximal composition. Colostrum has the following characteristics and components:
The Major Components (Over 90 Have Been Described) of Colostrum Include:
Immunoglobulins (Ig): Complex proteins also known as antibodies, which are used by the immune system to identify, attack and neutralize foreign objects such as bacteria and viruses. Absorption of immunoglobulins is essential for the passive immunity of neonatal mammals after birth.
IgG: bovine colostrum has more IgG than all the other immunoglobulins found in colostrum. It provides a large portion of immunity against invading pathogens in spite of the delay after insult. IgG helps to initiate the cascade of other immune functions including complement.
IgA: strategically resides in areas like the gastrointestinal, respiratory and urogenital tracts to play a critical role in mucosal immunity by preventing specific pathogens from colonizing. This is the first line of human defense of invasion as it protects the mucosal surfaces. IgA also is involved in a complement cascade.
IgM: the first responder to pathogens entering the body. IgM attacks bacteria, rendering them inactive. IgM is very efficient at triggering the complement cascade.
IgE: plays an important role in allergenic reactions and aids in the response to parasites in the digestive system. Minimal in Colostrum.
IgD: functions closely with IgM to send a signal to B cells to activate them. Once activated, the B cells begin to participate with other immunoglobulins to bolster the body’s immune system. B cells also help in creating specificity to antigens. Minimal in Colostrum.
Cytokines are the immune system communicators. Colostrum contains many of these biological response modifiers (messengers). These can be protein, peptide or glycoprotein that signal molecules that are used in cellular communications. Cytokines have a specific role as regulators of epithelial cell growth and development, including intestinal inflammation and epithelial restoration following mucosal damage. They are also important mediators in the regulation of immune and inflammatory responses.
Lactoferrin is an iron-binding glycoprotein that is one of the antimicrobial components of the immune system that fights bacteria and fungi in the body. It binds metal ions which are necessary bacterial metabolites, making them unavailable for bacterial development. This anti-inflammatory glycoprotein binds free iron ions in biological fluids, transporting the iron to blood cells. Lactoferrin has been shown to inhibit the growth of specific microbes, like E. coli and Salmonella. Lactoferrin has additionally demonstrated antiviral effects. In addition to its antimicrobial activity, lactoferrin plays an important role in immune responses and is present in the tears. Transferrin is another mineral-binding protein that attaches to iron.
Lysozyme is an antibacterial enzyme that helps to support the immune system by disrupting the cell walls of harmful bacteria. A special attribute of lysozyme is its interaction with other colostrum components. It has been shown to work in a synergistic effect with lactoperoxidase, IgA and lactoferrin. With lactoperoxidase, lysozyme partly activates it by forming a complex. With IgA, it works in synergy to combat E. coli. And in the presence of lactoferrin, the antimicrobial effects of lysozyme are also enhanced. A combination of Colostrum with additional Lysozyme would, theoretically, create a super weapon.
Lactalbumin is another important nutrient and water-soluble protein found in milk which contains essential amino acids necessary for body growth and development.
Lactoperoxidase is a major antibacterial enzyme found in colostrum. Lactoperoxidase protects the lactating mammary gland from infections. As previously stated, it is activated by forming a complex with lysozyme. It is also shown to work with lactoferrin for some antibacterial effects. Some viruses, like polioviruses, are sensitive to lactoperoxidase’s toxic effects.
Proline Rich Polypeptides (PRPs) are hormone-like proteins composed of small chains of amino acids that have a powerful effect in initiating and balancing immune responses. Functions of PRPs include modulating the immune system, acting as molecular signaling devices, promoting growth and the differentiation of B-cells, stimulating Natural Kill cell (NK cell) activity and promoting the proliferation of leukocytes (white blood cells).
Growth Factors found in Colostrum help stimulate cell growth, cell differentiation and cell maturation. Growth factors act as signaling molecules from one cell to another as well as regulating a variety of cellular processes. Growth Factors included in Colostrum are:
Epidermal Growth Factors (EGF play an important role in the regulation of cell growth, proliferation and differentiation. The EGF family of growth factors can help modulate development of the epidermis, mammary gland, and gut.
Fibroblast Growth Factors (FGFs) are involved in the growth of new blood vessels and facilitate wound healing.
Insulin-like Growth Factor (IGF-1) is the most abundant growth factor in bovine colostrum. These proteins are single chain polypeptides with amino acids and are in the family of the IGF Binding Proteins (IGFBP) which are responsible for cell growth and reproduction. They play an important role in childhood growth and have a major role in the maintenance of the metabolic pathway in adults.
Platelet-derived Growth Factor (PDGF) is one of numerous proteins that regulate cell growth and division, playing a significant role in blood vessel formation and clotting.
Transforming Growth Factors (TGF-alpha & TGF-beta). TGF-alpha induces epithelial tissue development. TGF-beta plays a crucial role in tissue regeneration, cell differentiation, formation of bone cartilage, and regulation of the immune system.
Colostrum also provides energy and nutrients. It is rich in energy-creating ingredients like carbohydrates, lipids, and proteins. Carbohydrates are naturally available in colostrum, along with vitamins and minerals like calcium, sodium, magnesium, potassium and zinc.
Vitamins included in Colostrum are A, B2, B9, B12, E and D. Vitamins are essential organic nutrients that, like minerals, work as catalysts or co-factors in biological functions. They are important for such processes as retinol development, transportation of important matter across cellular walls, and processing other nutrients.
Minerals include calcium, chloride, iron, magnesium, phosphorus, potassium, sodium and zinc. Minerals act as catalysts in body functions such as metabolism and ATP formation. Minerals are also important building blocks of bone and teeth.
Carbohydrates are included in Colostrum and range from simple sugars to complex oligosaccharides, carbohydrates are an important energy source and used in cellular recognition.
Amino Acids consist of a large number of compounds that are the building blocks of proteins through the linking of peptide bonds and function as cellular messengers. Amino acids are important for nutrition and muscle development.
Protein from Colostrum provides essential nutritional components for muscle and tissue development.
THE SCIENCE OF COLOSTRUM AS RELATED TO HUMANS
A recent bibliography of related-animal and human clinical research includes:
T Adar, A Ben Ya'acov, G Lalazar, Y Lichtenstein, D Nahman, M Mizrahi, V Wong, B Muller, G Rawlin, Y Ilan
Clin Exp Immunol. 2012 February; 167(2): 252–260.
Insulin resistance and metabolic syndrome are chronic inflammatory conditions that lead to hepatic injury and non-alcoholic steatohepatitis (NASH). Bovine colostrum has therapeutic effects in a variety of chronic infections. However its effectiveness in NASH was never studied. Natural killer T (NKT) cells have been shown to be associated with some of the pathological and metabolic abnormalities accompanying NASH in leptin-deficient (ob/ob) mice. In the present study, we used hyperimmune bovine colostrum to treat hepatic injury and insulin resistance and we also assessed the effects on NKT cells. We used ob/ob mice that were fed for 6 weeks with either 0·1 mg bovine colostrum prepared from non-immunized cows, 0·1 mg hyperimmune colostrum raised against a bacterial lipopolysaccharide (LPS) extract or 0·001, 0·1 or 1 mg of immunoglobulin (Ig)G purified from hyperimmune colostrum (IgG–LPS). NKT cells were phenotyped by flow cytometry, and hepatic injury and insulin resistance were assessed by measuring fasting glucose levels, glucose tolerance tests and liver enzymes. Fat accumulation was measured in the liver and plasma. Oral administration of hyperimmune colostrums decreased alanine aminotransferase (ALT) serum levels and serum triglycerides compared to controls. Glucose intolerance was also improved by the hyperimmune colostrum preparations. These results were accompanied by a decrease in serum tumour necrosis factor (TNF)-α levels following oral treatment with 0·1 or 1 mg of IgG–LPS. The beneficial effects of hyperimmune colostrums were associated with an increase in the number of splenic NKT cells. These data suggest that oral administration of hyperimmune colostrum preparations can alleviate chronic inflammation, liver injury and insulin resistance associated with NASH.
Alleviation of insulin resistance and liver damage by oral administration of Imm124-E is mediated by increased Tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH
Meir Mizrahi, Yehudit Shabat, Ami Ben Ya’acov, Gadi Lalazar, Tomer Adar, Victor Wong, Brian Muller, Grant Rawlin, Yaron Ilan
J Inflamm Res. 2012; 5: 141–150.
Nonalcoholic steatohepatitis (NASH) is considered to be part of the nonalcoholic fatty liver disorders and its incidence is increasing. Imm124-E (Immuron Ltd, Melbourne, Australia), containing hyperimmune bovine colostrum, has been shown to exert an immunomodulatory effect and to alleviate target organ damage in animal models of NASH. The aim of our study was to determine the safety and efficacy of oral administration of Imm124-E to patients with insulin resistance and NASH. Methods In an open-label trial, ten patients with biopsy-proven NASH and insulin resistance were orally treated with Imm124-E for 30 days. Results Oral administration of Imm124-E was safe, and no side effects were noted. Alleviation of insulin resistance was reflected by significantly improved hemoglobin A1c (HbA1c) values in all ten treated patients. For between five and eight responders, the following effects were noted: a decrease in fasting glucose levels; improved oral glucose tolerance test (OGGT) and homeostatic model assessment insulin resistance (HOMA) scores; and alleviation in lipid profile. These effects were accompanied by increased serum levels of glucagon-like peptide 1 (GLP-1), adiponectin and T regulatory cells. Conclusion Hyperimmune colostrum alleviates NASH.
Marit Kramski, Rob J. Center, Adam K. Wheatley, Jonathan C. Jacobson, Marina R. Alexander, Grant Rawlin, Damian F. J. Purcell
Antimicrob Agents Chemother. 2012 August; 56(8): 4310–4319.
Bovine colostrum (first milk) contains very high concentrations of IgG, and on average 1 kg (500 g/liter) of IgG can be harvested from each immunized cow immediately after calving. We used a modified vaccination strategy together with established production systems from the dairy food industry for the large-scale manufacture of broadly neutralizing HIV-1 IgG. This approach provides a low-cost mucosal HIV preventive agent potentially suitable for a topical microbicide. Four cows were vaccinated pre- and/or postconception with recombinant HIV-1 gp140 envelope (Env) oligomers of clade B or A, B, and C. Colostrum and purified colostrum IgG were assessed for cross-clade binding and neutralization against a panel of 27 Env-pseudotyped reporter viruses. Vaccination elicited high anti-gp140 IgG titers in serum and colostrum with reciprocal endpoint titers of up to 1 × 105. While nonimmune colostrum showed some intrinsic neutralizing activity, colostrum from 2 cows receiving a longer-duration vaccination regimen demonstrated broad HIV-1-neutralizing activity. Colostrum-purified polyclonal IgG retained gp140 reactivity and neutralization activity and blocked the binding of the b12 monoclonal antibody to gp140, showing specificity for the CD4 binding site. Colostrum-derived anti-HIV antibodies offer a cost-effective option for preparing the substantial quantities of broadly neutralizing antibodies that would be needed in a low-cost topical combination HIV-1 microbicide.
James Friedman, S. Munir Alam, Xiaoying Shen, Shi-Mao Xia, Shelley Stewart, Kara Anasti, Justin Pollara, Genevieve G. Fouda, Guang Yang, Garnett Kelsoe, Guido Ferrari, Georgia D. Tomaras, Barton F. Haynes, Hua-Xin Liao, M. Anthony Moody, Sallie R. Permar
PLoS One. 2012; 7(5): e37648.
Generation of potent anti-HIV antibody responses in mucosal compartments is a potential requirement of a transmission-blocking HIV vaccine. HIV-specific, functional antibody responses are present in breast milk, and these mucosal antibody responses may play a role in protection of the majority of HIV-exposed, breastfeeding infants. Therefore, characterization of HIV-specific antibodies produced by B cells in milk could guide the development of vaccines that elicit protective mucosal antibody responses. We isolated B cells from colostrum of an HIV-infected lactating woman with a detectable neutralization response in milk and recombinantly produced and characterized the resulting HIV-1 Envelope (Env)-specific monoclonal antibodies (mAbs). Results The identified HIV-1 Env-specific colostrum mAbs, CH07 and CH08, represent two of the first mucosally-derived anti-HIV antibodies yet to be reported. Colostrum mAb CH07 is a highly-autoreactive, weakly-neutralizing gp140-specific mAb that binds to linear epitopes in the gp120 C5 region and gp41 fusion domain. In contrast, colostrum mAb CH08 is a nonpolyreactive CD4-inducible (CD4i) gp120-specific mAb with moderate breadth of neutralization. These novel HIV-neutralizing mAbs isolated from a mucosal compartment provide insight into the ability of mucosal B cell populations to produce functional anti-HIV antibodies that may contribute to protection against virus acquisition at mucosal surfaces.
Mahenderan Appukutty, Ammu Kutty Radhakrishnan, Kalavathy Ramasamy, Rajesh Ramasamy, Abu Bakar Abdul Majeed, Mohd Ismail Noor, Nik Shanita Safii, Poh Bee Koon, Karuthan Chinna, Nagaraja Haleagrahara
BMC Res Notes. 2012; 5: 649.
This study examined the effects of bovine colostrum on exercise –induced modulation of antioxidant parameters in skeletal muscle in mice. Adult male BALB/c mice were randomly divided into four groups (control, colostrum alone, exercise and exercise with colostrum) and each group had three subgroups (day 0, 21 and 42). Colostrum groups of mice were given a daily oral supplement of 50 mg/kg body weight of bovine colostrum and the exercise group of mice were made to exercise on the treadmill for 30 minutes per day. Total antioxidants, lipid hydroperoxides, xanthine oxidase and super oxide dismutase level was assayed from the homogenate of hind limb skeletal muscle. Exercise—induced a significant oxidative stress in skeletal muscles as evidenced by the elevated lipid hydroperoxides and xanthine oxidase levels. There was a significant decrease in skeletal muscle total antioxidants and superoxide dismutase levels. Daily colostrum supplement significantly reduced the lipid hydroperoxides and xanthine oxidase enzyme level and increased the total antioxidant levels in the leg muscle. Thus, the findings of this study showed that daily bovine colostrum supplementation was beneficial to skeletal muscle to reduce the oxidant-induced damage during muscular exercise.
HUMAN STUDY REVIEW
Walter L. Hurley, Peter K. Theil. Nutrients. 2011 April; 3(4): 442–474.
Immunoglobulins form an important component of the immunological activity found in milk and colostrum. They are central to the immunological link that occurs when the mother transfers passive immunity to the offspring. The mechanism of transfer varies among mammalian species. Cattle provide a readily available immune rich colostrum and milk in large quantities, making those secretions important potential sources of immune products that may benefit humans. Immune milk is a term used to describe a range of products of the bovine mammary gland that have been tested against several human diseases. The use of colostrum or milk as a source of immunoglobulins, whether intended for the neonate of the species producing the secretion or for a different species, can be viewed in the context of the types of immunoglobulins in the secretion, the mechanisms by which the immunoglobulins are secreted, and the mechanisms by which the neonate or adult consuming the milk then gains immunological benefit. The stability of immunoglobulins as they undergo processing in the milk, or undergo digestion in the intestine, is an additional consideration for evaluating the value of milk immunoglobulins. This review summarizes the fundamental knowledge of immunoglobulins found in colostrum, milk, and immune milk.
Wlodzimierz Otto, Boguslaw Najnigier, Teodor Stelmasiak, Roy M Robins-Browne
Scand J Gastroenterol. 2011 July; 46(7-8): 862–868.
Enterotoxigenic Escherichia coli (ETEC) is the leading cause of travelers' diarrhea. The aim of this study was to investigate the ability of a powdered extract of hyperimmune bovine colostrum to protect against diarrhea in volunteers challenged with ETEC. Tablets were manufactured from a colostrum extract from cattle immunized with 14 ETEC strains, including serogroup O78. Two separate randomized, double-blind, placebo-controlled trials involving 90 healthy adult volunteers were performed to investigate the ability of different tablet formulations to protect against diarrhea following an oral challenge with an O78 ETEC strain. Results. The first study with 30 participants evaluated the efficacy of tablets, containing 400 mg of colostrum protein, taken thrice daily with bicarbonate buffer. This regimen conferred 90.9% protection against diarrhea in the group receiving the active preparation compared with the placebo group (p = 0.0005). The second study examined the efficacy of tablets containing 400 mg colostrum protein given with buffer (83.3% protection;p = 0.0004) or without buffer (76.7% protection;p =0.007), and tablets containing 200 mg colostrum protein given without buffer (58.3% protection; p = 0.02), compared with placebo. The difference between buffered and unbuffered treatments was not significant (p > 0.1). Active tablet formulations were significantly more effective than placebo in protecting volunteers against the development of diarrhea caused by ETEC. These results suggest that administration of a tablet formulation of hyperimmune bovine colostrum containing antibodies against ETEC strains may reduce the risk of travelers' diarrhea.
Amandine Mathias, Blaise Corthésy. J Biol Chem. 2011 May 13; 286(19): 17239–17247.
Humans live in symbiosis with 1014 commensal bacteria among which >99% resides in their gastrointestinal tract. The molecular bases pertaining to the interaction between mucosal secretory IgA (SIgA) and bacteria residing in the intestine are not known. Previous studies have demonstrated that commensals are naturally coated by SIgA in the gut lumen. Thus, understanding how natural SIgA interacts with commensal bacteria can provide new clues on its multiple functions at mucosal surfaces. Using fluorescently labeled, nonspecific SIgA or secretory component (SC), we visualized by confocal microscopy the interaction with various commensal bacteria, including Lactobacillus, Bifidobacteria, Escherichia coli, and Bacteroides strains. These experiments revealed that the interaction between SIgA and commensal bacteria involves Fab- and Fc-independent structural motifs, featuring SC as a crucial partner. Removal of glycans present on free SC or bound in SIgA resulted in a drastic drop in the interaction with Gram-positive bacteria, indicating the essential role of carbohydrates in the process. In contrast, poor binding of Gram-positive bacteria by control IgG was observed. The interaction with Gram-negative bacteria was preserved whatever the molecular form of protein partner used, suggesting the involvement of different binding motifs. Purified SIgA and SC from either mouse hybridoma cells or human colostrum exhibited identical patterns of recognition for Gram-positive bacteria, emphasizing conserved plasticity between species. Thus, sugar-mediated binding of commensals by SIgA highlights the currently underappreciated role of glycans in mediating the interaction between a highly diverse microbiota and the mucosal immune system.
Wy Ching Ng, Victor Wong, Brian Muller, Grant Rawlin, Lorena E. Brown
PLoS One. 2010; 5(10): e13622. Published online 2010 October 26.
Despite the availability of specific vaccines and antiviral drugs, influenza continues to impose a heavy toll on human health worldwide. Passive transfer of specific antibody (Ab) may provide a useful means of preventing or treating disease in unvaccinated individuals or those failing to adequately seroconvert, especially now that resistance to antiviral drugs is on the rise. However, preparation of appropriate Ab in large scale, quickly and on a yearly basis is viewed as a significant logistical hurdle for this approach to control seasonal influenza. In this study, bovine colostrum, which contains approximately 500 g of IgG per milking per animal, has been investigated as a source of polyclonal antibody for delivery to the respiratory tract. IgG and F(ab')2 were purified from the hyperimmune colostrum of cows vaccinated with influenza A/Puerto Rico/8/34 (PR8) vaccine and were shown to have high hemagglutination-inhibitory and virus-neutralizing titers. In BALB/c mice, a single administration of either IgG or F(ab')2 could prevent the establishment of infection with a sublethal dose of PR8 virus when given as early as 7 days prior to exposure to virus. Pre-treated mice also survived an otherwise lethal dose of virus, the IgG- but not the F(ab')2-treated mice showing no weight loss. Successful reduction of established infection with this highly virulent virus was also observed with a single treatment 24 hr after virus exposure. These data suggest that a novel and commercially-scalable technique for preparing Ab from hyperimmune bovine colostrum could allow production of a valuable substitute for antiviral drugs to control influenza with the advantage of eliminating the need for daily administration.
Rafia Mir, Nagendra Singh, Gopalakrishnapillai Vikram, Ramasamy Prem Kumar, Mau Sinha, Asha Bhushan, Punit Kaur, Alagiri Srinivasan, Sujata Sharma, Tej P. Singh
Biophys J. 2009 December 16; 97(12): 3178–3186.
Nonsteroidal antiinflammatory drugs (NSAIDs), due to their good efficacy in the treatment of pain, inflammation, and fever, are among the most prescribed class of medicines in the world. The main drawback of NSAIDs is that they induce gastric complications such as peptic ulceration and injury to the intestine. Four NSAIDs, indomethacin, diclofenac, aspirin, and ibuprofen were selected to induce gastropathy in mouse models. It was found that the addition of C-terminal half of bovine lactoferrin (C-lobe) reversed the NSAID-induced injuries to the extent of 47–70% whereas the coadministration of C-lobe prevented it significantly. The C-lobe was prepared proteolytically using serine proteases. The binding studies of C-lobe with NSAIDs showed that these compounds bind to C-lobe with affinities ranging from 2.6 to 4.8 × 10−4 M. The complexes of C-lobe were prepared with the above four NSAIDs. All four complexes were crystallized and their detailed three-dimensional structures were determined using x-ray crystallographic method. The structures showed that all the four NSAID molecules bound to C-lobe at the newly identified ligand binding site in C-lobe that is formed involving two α-helices, α10 and α11. The ligand binding site is separated from the well known iron binding site by the longest and the most stable β-strand, βj, in the structure. Similar results were also obtained with the full length lactoferrin molecule. This novel, to our knowledge, binding site in C-lobe of lactoferrin shows a good complementarity for the acidic and lipophilic compounds such as NSAIDs. We believe this indicates that C-lobe of lactoferrin can be exploited for the prevention of NSAID-induced gastropathy.
Prevention of Influenza Episodes With Colostrum Compared With Vaccination in Healthy and High-Risk Cardiovascular Subjects: The Epidemiologic Study in San Valentino.
M R Cesarone, i Belcaro, A Di Renzo, et al. Clinical and Applied Thrombosis/Hemostasis13. 2OO7 130-136
The efficacy of a 2-month treatrnent with oral colostrum in the prevention of flu episodes compared with antiinfluenza vaccination was evaluated. Groups induded healthy subjects without prophylaxis and those receiving both vaccination and colostrum. After 3 months of followup, the number of days with flu was 3 tirnes higher in the non-colostrum subjects. The colostrum group had 13
episodes versus 14 in the colostrum + vaccination group, 41 in the group without prophylaxis, and 57 in non-treated subjects. Part 2 of the study had a similar protocol with 65 very high-risk cardiovascular subjects, all of whom had
prophylaxis. The incidence of complications and hospital admission was higher in the group that received only a vaccination compared with the colostrum groups. Colostrum, both in healthy subjects and high-risk cardiovascular patients, is at least 3 times more effective than vaccination alone to prevent flu and is very cost-efifective.
Concentrated bovine colostrum protein supplementation reduces the incidence of self-reported symptoms of upper respiratory tract infection in adult males.
GD Brinkworth, JD Buckley. Eur J Nutr 2003. 42;228-232
Anecdotal reports suggest that bovine colostrum may prevent upper respiratory tract infection (URTI). There is scant evidence to support such claims, although salivary IgA protects against URTI, and it was recently shown that bovine colostrum increases salivary IgA. The present investigation examined whether concentrated bovine colostrum protein (CBC) affected the incidence or duration of self-reported symptoms of URTI in adult males. We examined logbooks containing self-reported symptoms of illness from previous studies which examined physiological effects of CBC. In these double-blind, placebo controlled studies, subjects had been randomly allocated to consume 60 g · day–1 of CBC (n=93) or whey protein (WP) (n =81) for eight weeks. Symptoms were coded using established criteria to identify those related to URTI. Since the incubation period for an URTI is up to five days, symptoms reported during the first week of supplementation (PRE-EXP) were analyzed separately to preclude those arising from infection prior to study commencement. During PRE-EXP, there was no difference in the proportion of subjects taking the different supplements who reported symptoms of URTI (CBC, 11%,WP, 5%; 95% Confidence Interval (95% CI) –14% to 2%; P=0.16). During the subsequent seven weeks (i. e. the experimental period), a significantly lesser proportion of subjects taking CBC reported symptoms of URTI compared with those taking WP (CBC, 32%,WP, 48%, P=0.03; 95 % CI –30 % to –2 %), but symptom duration did not differ (CBC, 6.8±4.2 days,WP, 6.0±4.4 days; P=0.27). This study provides preliminary evidence that CBC may enhance resistance to the development of symptoms of URTI.
Oral findings in patients with primary Sjögren’s syndrome and oral lichen planus – a preliminary study on the effects of bovine colostrum-containing oral hygiene products.
A.M. Pedersen · L. Andersen Torpet · J. Reibel P. Holmstrup · B. Nauntofte.
Clin Oral Invest (2002) 6:11–20
Bovine colostrum is rich in antimicrobial substances and growth factors. The purpose of this open study was to examine and compare the interventory
effects of daily use of bovine colostrum-containing oral hygiene products (CHP) on oral symptoms and findings in 20 patients with primary Sjögren’s syndrome (pSS) and 20 age-matched patients with oral lichen planus (OLP). Objective oral measures and self-assessment of oral symptoms and general health were conducted before and after 90 days’ use of CHP. The pSS patients had more systemic diseases, medication intake, oral dryness, poorer general health and lower salivary secretion than the OLP patients, who had the highest plaque index (PI) and the most mucosal soreness. Oral dryness and soreness were correlated to general health. In both patient groups, unstimulated whole saliva flow rate (UWS) had increased, PI and periodontal pocket depth (PPD) were reduced, and general health and oral dryness and soreness had improved after using CHP. A decrease in hyphae was found in candida smears from both groups and
in blastospores in OLP smears. A reduction in the extension of the mucosal lesions was observed in 15 OLP patients. Results suggested beneficial effects of intervention with CHP on oral symptoms, general health, UWS, PI, PPD and candidal load in two patient groups – pSS and OLP – representing different oral symptomatology.
Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability
R J PLAYFORD, CE MACDONALDP, D P CALNAN., D N FLOYD., T PODAS., W JOHNSON, A C WICKS., 0 BASHIR, T MARCHBANK
CLIN SCI 2001;100:627-633
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics but cause gastrointestinal injury. Present prophylactic measures are suboptimal and novel therapies are required. Bovine colostrum is a cheap, readily available source of growth factors, which reduces gastrointestinal injury in rats and mice. We therefore examined whether spray-dried, defatted colostrum could reduce the rise in gut permeability (a non-invasive marker of intestinal injury) caused by NSAIDs in volunteers and patients taking NSAlDs for clinical reasons. Healthy male
volunteers (n = 7) participated in a randomized crossover trial comparing changes in gut permeability (lactulose/rhamnose ratios) before and after 5 days of 50 mg of indomethacin three times daily (tds) per oral with colostrum (125 ml, tds) or whey protein (control) coadministration. A second study examined the effect of colostral and control solutions (1 25 ml, tds for 7 days) on gut permeability in patients (n = 15) taking a substantial, regular dose of an NSAID
for clinical reasons. For both studies, there was a 2 week washout period between treatment arms. In volunteers, indomethacin caused a 3-fold increase in gut permeability in the control arm (lactulose/rhamnose ratio 0.36k0.07 prior to indomethacin and 1.17+0.25 on day 5, P < O.Ol), whereas no significant increase in permeability was seen when colostrum was co-administered. In patients taking long-term NSAID treatment, initial permeability ratios were low (0.13 *0.02), despite continuing on the drug, and permeability was not influenced by co-administration of test solutions. These studies provide preliminary evidence that bovine colostrum, which is already currently available as an over-the-counter preparation, may provide a novel approach to the prevention of NSAID-induced gastrointestinal damage in humans.
R Playford, D Floyd, C Macdonald, D Calnan, R Adenekan, W Johnson, R Goodlad, T Marchbank. zGut. 1999 May; 44(5): 653–658.
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective for arthritis but cause gastrointestinal injury. Bovine colostrum is a rich source of growth factors and is marketed as a health food supplement. To examine whether spray dried, defatted colostrum or milk preparations could reduce gastrointestinal injury caused by indomethacin. Effects of test solutions, administered orally, were examined using an indomethacin restraint rat model of gastric damage and an indomethacin mouse model of small intestinal injury. Effects on migration of the human colonic carcinoma cell line HT-29 and rat small intestinal cell line RIE-1 were assessed using a wounded monolayer assay system (used as an in vitro model of wound repair) and effects on proliferation determined using [3H]thymidine incorporation. Pretreatment with 0.5 or 1 ml colostral preparation reduced gastric injury by 30% and 60% respectively in rats. A milk preparation was much less efficacious. Recombinant transforming growth factor β added at a dose similar to that found in the colostrum preparation (12.5 ng/rat), reduced injury by about 60%. Addition of colostrum to drinking water (10% vol/vol) prevented villus shortening in the mouse model of small intestinal injury. Addition of milk preparation was ineffective. Colostrum increased proliferation and cell migration of RIE-1 and HT-29 cells. These effects were mainly due to constituents of the colostrum with molecular weights greater than 30kDa. Bovine colostrum could provide a novel, inexpensive approach for the prevention and treatment of the injurious effects of NSAIDs on the gut and may also be of value for the treatment of other ulcerative conditions of the bowel.
A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea.
A Plettenberg, A Stoehr, H-J Stellbrink, H Albrecht, W Meigel.
Clin Investig 1993;71:42-45.
In a prospective, open, uncontrolled study 25 patients infected with the human immunodeficiency virus with chronic refractory diarrhea and either confirmed cryptosporidiosis (n = 7) or absence of demonstrable pathogenic organisms (n = 18) were treated with a daily oral dose of 10 g of an immunoglobulin preparation from bovine colostrum over a period of 10 days. Among the 7 patients with cryptosporidiosis, this treatment led to complete remission in 3 and partial remission in 2. Among the 18 patients with diarrhea and negative stool culture, complete remission of diarrhea was obtained in 7 and partial remission in 4. In the remaining 2 patients with cryptosporidiosis and the 7 patients with diarrhea but no demonstrable pathogens treatment produced no significant improvement of the diarrhea. Subsequent doubling of the Lactobin dose (2 x 10 g daily) in 8 of the non-responders led to complete remission in one case and at least partial remission in a further 4 patients. Treatment of refractory diarrhea
with 10 g immunoglobulins from bovine colostrum per day constitutes an important therapeutic approach and led to complete (40%) or partial (24%) remission of diarrhea in 64% of the patients described here.
Inhibition of Helicobacter pylori and Helicobacter mustelae binding to lipid receptors by bovine colostrum.
Helicobacter pylori, the etiologic agent of chronic-active gastritis and duodenal ulcers in humans, and Helicobacter mustelae, a gastric pathogen in ferrets, bind to phosphatidylethanolamine (PE), a constituent of host gastric mucosal cells, and to gangliotetraosylceramide (Gg4) and gangliotriaosylceramide (Gg3). The effect of a bovine colostrum concentrate (BCC) on the interaction of H. pylori and H. mustelae to their lipid receptors was examined. BCC blocked attachment of both species to Gg4, Gg3, and PE. Partial inhibition of binding was observed with native bovine and human colostra. BCC lacked detectable antibodies (by immunoblotting) to H. pylori surface proteins (adhesins). However, colostral lipid extracts contained PE and lyso-PE that bound H. pylori in vitro. These results indicate that colostrum can block the binding of Helicobacter species to select lipids and that binding inhibition is conferred, in part, by colostral PE or PE derivatives. Colostral lipids may modulate the interaction of H. pylori and other adhesin-expressing pathogens with their target tissues.
Bovine colostrum ameliorates diarrhea in infection with diarrheagenic Escherichia coli, shiga toxin-producing E. Coli, and E. coli expressing intimin and hemolysin.
Diarrheagenic Escherichia coli may cause serious extraintestinal complications, but there is no specific treatment. Patients with diarrhea caused by diarrheagenic E. coli, specifically Shiga toxin-producing E. coli and E. coli-expressing intimin and enterohemorrhagic E. coli-hemolysin were treated by administration of pooled bovine colostrum, rich in antibodies to Shiga toxin and enterohemorrhagic E. coli-hemolysin, in a placebo-controlled, double-blind study. Symptom resolution and fecal excretion of infecting strains were assessed. No side effects were attributable to colostrum. Stool frequencies in the group treated with bovine colostrum were significantly reduced compared with those in the placebo group. No effect of therapy on the carriage of the pathogens or on complications of the infection could be demonstrated. Bovine colostrum is well tolerated and diminishes frequency of loose stools in children with E. coli-associated diarrhea. A prospective study should be conducted among a larger number of children with Shiga toxin-producing E. coli identified early in illness, to determine the effectiveness of colostrum therapy.
Use of the 'nutriceutical', bovine colostrum, for the treatment of distal colitis: results from an initial study.
Bovine colostrum is a rich source of nutrients, antibodies and growth factors. To examine the efficacy of colostrum enemas in the treatment of distal colitis using a randomized, double-blind, controlled protocol. Fourteen patients (eight female), with a mean age of 45 years (range, 16-75 years) and mild to moderately severe distal colitis (Powell-Tuck scoring system), received colostrum enema (100 mL of 10% solution) or placebo (albumin solution) b.d. for 4 weeks. Both groups also received mesalazine (1.6 g/day) or, if already taking it, had a dose increment of 1.6 g/day. Disease activity was documented at 0, 2 and 4 weeks. After 4 weeks, the colostrum group showed a mean reduction in symptom score of - 2.9 (95% confidence interval (CI), - 5.4 to - 0.3), whereas the placebo group showed a mean response of + 0.5 (95% CI, - 2.4 to +3.4). The histological score improved in five of the eight patients in the colostrum group (mean response, - 0.9; 95% CI, - 1.69 to - 0.03), whereas the histological scores only improved in two of the six patients in the placebo group (mean response, 0.2; 95% CI, - 2.4 to +2.6). Bovine colostrum enema shows potential as a novel therapy for left-sided colitis with additional benefits over using mesalazine alone. Further studies appear to be warranted.
Effects of oral bovine colostrum supplementation on serum insulin-like growth factor-I levels.
We investigated whether supplementation with 60 g/d of bovine colostrum affects blood levels of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 in relation to doping testing. Nine endurance-trained men ingested 60 g/d of bovine colostrum for 4 wk. Blood and urine were sampled before starting supplementation. After 4 wk urine and blood samples were taken after an overnight fast and 2 h after ingestion of the last portion to study possible acute effects. Blood IGF-I levels before supplementation were (mean +/- standard deviation) 31 +/- 13 nM/L, and no acute effects were observed after 4 wk of supplementation (33 +/- 9 nM/L). Levels of IGF-binding protein-3 were 136 +/- 11 nM/L before supplementation and 135 +/- 16 nM/L after 4 wk of supplementation. Two hours after ingestion of the last portion, the level of IGF binding protein-3 was 131 +/- 19 nM/L, which was not different from baseline values. Drug testing in a laboratory accredited by the International Olympic Committee did not show any forbidden substance before or after 4 wk of supplementation. Daily supplementation with 60 g of bovine colostrum for 4 wk does not change blood IGF-I or IGF binding protein-3 levels and does not elicit positive results on drug tests.
Successful treatment of rotavirus diarrhea in children with immunoglobulin from immunized bovine colostrum.
Oral ingestion of immunoglobulins in humans has been shown to be effective as prophylaxis against enteric infections. However, its therapeutic effect in children with infectious diarrhea has hitherto not been proven. We treated children with rotavirus diarrhea with immunoglobulins extracted from immunized bovine colostrum (IIBC) containing high titers of antibodies against four rotavirus serotypes. In this double blind placebo-controlled trial, 80 children with rotavirus diarrhea were randomly assigned to receive orally either 10 g of IIBC (containing 3.6 g of antirotavirus antibodies) daily for 4 days or the same amount of a placebo preparation. The daily stool output (grams/kg/day), intake of oral rehydration solution (ml/kg/day), stool frequency (number of stools/day) and presence of rotavirus in stool were monitored for the 4 days during treatment. Children who received IIBC had significantly less daily and total stool output and stool frequency and required a smaller amount of oral rehydration solution than did children who received placebo (P < 0.05). Clearance of rotavirus from the stool was also earlier in the IIBC group compared with the placebo group (mean day, 1.5 vs. 2.9, P < 0.001). No adverse reactions from the colostrum treatment were observed. Treatment with anti-rotavirus immunoglobulin of bovine colostral origin is effective in the management of children with acute rotavirus diarrhea.
The influence of bovine colostrum supplementation on exercise performance in highly trained cyclists.
The aim of this experiment was to investigate the influence of low dose bovine colostrum supplementation on exercise performance in cyclists over a 10 week period that included 5 days of high intensity training (HIT). Over 7 days of preliminary testing, 29 highly trained male road cyclists completed a VO(2max) test (in which their ventilatory threshold was estimated), a time to fatigue test at 110% of ventilatory threshold, and a 40 km time trial (TT40). Cyclists were then assigned to either a supplement (n = 14, 10 g/day bovine colostrum protein concentrate (CPC)) or a placebo group (n = 15, 10 g/day whey protein) and resumed their normal training. Following 5 weeks of supplementation, the cyclists returned to the laboratory to complete a second series of performance testing (week 7). They then underwent five consecutive days of HIT (week 8) followed by a further series of performance tests (week 9). The influence of bovine CPC on TT40 performance during normal training was unclear (week 7: 1+/-3.1%, week 9: 0.1+/-2.1%; mean+/-90% confidence limits). However, at the end of the HIT period, bovine CPC supplementation, compared to the placebo, elicited a 1.9+/-2.2% improvement from baseline in TT40 performance and a 2.3+/-6.0% increase in time trial intensity (% VO(2max)), and maintained TT40 heart rate (2.5+/-3.7%). In addition, bovine CPC supplementation prevented a decrease in ventilatory threshold following the HIT period (4.6+/-4.6%). Low dose bovine CPC supplementation elicited improvements in TT40 performance during an HIT period and maintained ventilatory threshold following five consecutive days of HIT.
SUMMARY OF THE SCIENCE OF COLOSTRUM AS RELATED TO HUMANS
In this day when we see diseases of all types on the rise, we must address the relationship of morbidity and mortality related to the spectrum of the causes. Most modern-day diseases have a strong relationship to the immune system and inflammation. The development of any way to shore-up the immune system ought to pique our interest. This discussion offers a potential for future research and management of a number of ocular as well as systemic disorders that we are facing. While limited in broad-based research, the topic of Colostrum deserves some investigation. Colostrum apparently has some strong support in modulation of inflammatory disorders of the gastrointestinal system. Likewise there are isolated reports of benefits in the management of oral disorders such as lichen planus.
Nutritional supplementation is, at best, controversial. This article is an offer for intellectual stimulation and perhaps a deeper look into the possibilities. Colostrum is not the solution to immune modulation but may offer a critical piece of the puzzle.
- Tags: Adnexa, Anterior Chamber, Anti-inflammatory, Colostrum, Conjunctiva, Cornea, Inflammation, Lids, Lysozyme, Macula, Optic Nerve, Vitreous
- Pycnogenol® For Diabetes Mellitus
- Mirtogenol™….is It The Real Deal?
- Is There a Significant Relationship of Smoking and Obesity to Glaucoma
About the Author(s)
Dr. Alexander (1948-2016) was a 1971 graduate of Indiana University School of Optometry. He served in the US Navy then served as a Professor at the University of Alabama Birmingham School of Optometry. Larry contributed to a number of chapters in textbooks and has published three editions of Primary Care of the Posterior Segment, as well as contributed to the professional literature. He also lectured extensively in the area of ocular and systemic disease. His areas of special interest included dysfunctional tear syndrome, glaucoma and macular degeneration. His lessons are the basis for this site and he will be dearly missed.