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KIB 500 - A Natural Break-through in Infection Control                                                                                                                       

Author: Paul Clayton PhD.

 

Abstract: Antibiotic resistance is substantially reducing our ability to control infection, and alternative approaches are urgently needed. The most promising at this time use natural compounds to enhance the cellular and humoral components of the innate immune system. These are an important and credible alternative to the moribund pharma model, and provide nutritional therapists with therapeutic tools they can use to prevent and cure a wide range of infections.

 

The End of the Era of Antibiotics                                                                                                                                                            

Many experts now concede that the widespread emergence of ‘superbugs’ in our hospitals and on the streets signals the imminent end of the brief era of antibiotics. In April 2005, Professor George Poste, head of the Biodesign Unit at the University of Arizona, said ‘We are facing a relentless increase in antibiotic resistance across all classes of drug. The age of infectious disease control is coming to an end, and most governments are asleep at the switch. By 2010, antibiotics will be effectively useless.’

 

Poste was not the first to sound a warning. In 1992, Mitchell Cohen of the Centres for Disease Control in Atlanta published a paper entitled ‘Epidemiology of drug resistance: implications for a post anti-microbial era’ (1). This paper, which became one of the most frequently cited scientific papers of all time, charted the relentless rise of antibiotic resistance in hospitals and in the community between 1950 and 1990. Cohen’s paper, however, although influential in academia, was not understood or acted on by governments; and the scientific illiteracy of our political classes has lead us, inevitably, to the point where pharmaceutical approaches to infection control are near the point of failing.

 

This is not a new scenario. Throughout history, the main causes of illness and death have been starvation, trauma, exposure, and above all infection. The degenerative diseases that dominate public health today were minority issues, and it was only after the infectious diseases were beaten back by improved sanitation, vaccination and latterly the antibiotics, that the degenerative diseases assumed their modern significance. Now, however, we are in imminent danger of reverting to a situation where, once more, infection will be the greatest killer. 

 

The excessive and inappropriate use of antibiotics, combined with high population densities, mass travel and mass dysnutrition, has brought the age of infection control close to its end. The situation will be considerably worsened if global warming proceeds, as a mere 3-meter rise in sea levels will destroy the bulk of our sewage processing facilities. Factor in the continuing spread of viral diseases such as HIV-1 and -2, Hepatitis-B and –C, and Coxsackievirus B which between them infect around a third of the global population (2); and the pending flu pandemic which may, in the worst eventuality, kill up to 1.5% of humanity all on its own, and the future looks rather bleak. 

 

Fortunately, there is an alternative. The growing understanding of the cellular and humoral components of the human innate immune system, and their modulation by dietary factors, opens a whole new area for nutritional and pharmaco-nutritional interventions. These look to be effective enough to largely replace antibiotics for both the prevention and treatment of infection.

 

Novel Strategies - Prevention                                                                                                                                                                 

One recently developed prophylactic strategy involves the use of yeast-derived 1-3, 1-6 beta glucans, a borderline class of phyto-nutrients derived from yeast that enhance the cellular components of the innate immune system. They act at the CR3 receptor on innate immune cells and greatly enhance their ability to kill pathogens (3–5). There is strong evidence, for example, that the 1-3, 1-6 beta glucans increase resistance to influenza. They enhance the innate immune response and reduce lung damage in swine flu in pigs (6); and will undoubtedly enhance the innate immune response to the current H1N1 virus, as this viral strain binds complement (7, 8).   

 

‘Vitamin’ D is as important as the beta glucans. Among its many actions, it enhances one of the humoral components of the innate immune system as is essential for the synthesis of antibiotic proteins called Anti-Microbial Proteins (AMP’s). These include the beta-defensins and cathelicidins (9). Hypovitaminosis D, which is very common, impairs innate immunity and reduces resistance to infection. This form of immuno-incompetence can only be remedied with vitamin D supplementation. Sunlight was long considered to be a treatment for tuberculosis, and more recently, vitamin D supplements have been shown to enhance immunity to the bacteria that cause TB (10). Returning to influenza, a recent highly regarded paper from Harvard presented findings indicating that seasonal hypovitaminosis D is the main reason why flu epidemics generally start in the winter months (11).

 

Selenium is anther key micronutrient. A number of seleno-proteins are involved in immune function (12), which is why selenium depletion – very common in the UK – reduces immune competence  (13–15). The picture, however, is a complex one and certainly does not justify selenium mono-supplementation. On the one hand, selenium depletion is linked to increased influenza viral mutation rates in animal models (16) and to increased cell damage in ‘in vitro’ models utilising human respiratory tract epithelial cells (17). On the other hand, another illuminating paper from Beck’s group at the University of North Carolina showed that the impaired immune function caused by selenium deficiency reduced mortality in their mouse model (18). This is not entirely unexpected as with the virulent strains of influenza, mortality is mediated by a cytokine storm (19). In the face of the pending H1N1 pandemic, selenium should therefore always be combined with beta glucans and vitamin D.

 

Vitamins A, E and the mineral iron are also essential for innate immune function. (20-21). As our low-energy lifestyles and consequently low food intakes have left most people depleted in these and indeed most other micro- and phyto-nutrients (22), a sustained intervention programme containing the nutrients listed above would undoubtedly increase individual and herd immunity.

 

This type of nutritional support is entirely appropriate as a prophylactic regime, but would be less useful in infection management. A new technical development, however, has brought infection control into the nutritional arena. It involves the effective amplification of the enzyme lactoperoxidase (LPO).

 

Novel Strategies - Treatment                                                                                                                                                                  

LPO is one of the most important humoral elements in the innate immune system, and is a major first-line defence against infection. Present in many secretions including tears, saliva, milk and airway and gut surface fluids (23), LPO produces a cascade of ions (such as HOSCN, below), which have an incredibly broad spectrum of activity against gram-positive and gram-negative bacteria, viruses and fungi (24-26). It is important for the control of pathogens in milk from lactating animals, and is critically involved in cell-mediated pathogen killing. 

 

LPO utilises dietary thiocyanate as one substrate, producing hypothiocyanite (HOSCN) ions. These ions are extremely toxic to most pathogenic bacteria (Table 1), via three separate mechanisms. They inhibit bacterial glycolysis; they inhibit bacterial nicotinamide adenine dinucleotide (NADH)/nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reactions (27); and they oxidise bacterial sulphydril groups (28, 29).

 

HOSCN ions also have potent anti-viral activities. Many viruses have sulfhydryl groups on their coat (ie 30); when this is oxidised the virus coat structure is damaged or destroyed (31). LPO also utilises iodine, forming hypohalide ions. These also have an additional spectrum of anti-bacterial activity.

 

These are impressive modes of action, but LPO is also important in protecting host tissues. Its other substrate is hydrogen peroxide, which is produced by a number of bacterial species and by inflammatory reactions mounted by the host. Excessive levels of hydrogen peroxide cause significant tissue damage. By preventing hydrogen peroxide build-up, LPO is a doubly important defence mechanism. 

 

Hypothiocyanite ions are not toxic to human cells at the levels produced by LPO, and have little if any effect on probiotic species, making them a near-perfect antibiotic system. Furthermore, it is very difficult indeed for micro-organisms to acquire resistance to LPO. If it was easy for pathogens to develop resistance to LPO, a key element in our immune system would have been disabled and we would not have survived as a species. 

 

Today, however, the LPO system is frequently compromised. Lactoperoxidase is a ferroprotein, and iron depletion / deficiency is one of the most common forms of dysnutrition. There are also growing problems with LPO’s twin substrates, thiocyanate and iodine. Thiocyanates are derived from dietary glucosinolates (in brassica), or from cyanogenic glycosides (in beans, sweet potato and millet). Since 1950, UK consumption of fresh vegetables has fallen by 24% (33). Iodine depletion is becoming more prevalent, due inter alia to reductions in salt intake and the use of (non-iodinated) sea salt (34, 35).

 

The bactericidal effects of LPO can be effectively mimicked and amplified by delivering hypothiocyanite ions directly. This technology was initially developed in France for food plant sterilisation, and subsequently to sterilise salad leaves. It is used as an antiseptic in Belgium, and has been adapted by the WHO for bulk milk sterilisation in China and Korea.

 

Clinical applications are developing rapidly. The first pilot study of hypothiocyanite ions was carried out in 2008. In this open study, 20 patients with respiratory tract, urinary tract and soft tissue infections were treated with KIB, a delivery system which utilises stabilised LPO to produce the effector ions. In all 20 patients the infections were cleared, with no treatment failures or adverse effects (36). A subsequent open study involving 200 patients will start in the autumn at a well-known clinical centre, and should report by mid-2010.

 

This is an innovative approach, but there is a folk precedent. In the northernmost areas of Sweden and Norway, lactating mothers routinely treat eye and ear infections with breast milk, which is of course a rich source of LPO (37).

 

Future Directions                                                                                                                                                                                       

There have been very interesting reports from a small number of patients with HIV/AIDS who have self-treated with KIB. The LPO system acts on the human insufficiency virus (Table 1), so this story has a degree of coherency. A larger number of MS patients have used KIB with self-reported success. If these cases can be substantiated, it would imply an infectious component in at least a sub-set of MS patients. Both the HIV and MS cases are currently being followed up, and will hopefully be reported in a subsequent article.

 

Preparation                                                                                                                                                                                                 

Hyopthiocyanite ions are unstable, so must be made up shortly before use. KIB Ltd. has produced a 4-phase mixer pack containing the enzyme, substrate and reaction stop to produce 25 mg of effector ions in 500 mls of clear, tasteless water. Given the possible effect of stomach acid on the identity of the ions, there is some reason to believe that this product may work most effectively if taken on empty stomach.

 

Safety                                                                                                                                                                                                           

Thiocyanite ions are present in all biological fluids. Humans produce between 50 and 100 mg of the ions per day, depending primarily on dietary factors. The therapeutic dose developed by KIB, and used in the pilot study above, is 25 mg, ie 25 – 50% of daily synthesis. The LD50 of thiocyanate is 50 mg/kg (38). The therapeutic dose is therefore less than 1% of the LD50.

 

Other Factors                                                                                                                                                                                             

The molecular weight of the hypothiocyanite ion is 74. To put this in context, synthetic antibiotics have molecular weights ranging from 400 to several thousand. The very small hypothiocyanite ions rapidly enter all body compartments, cross cell membranes, and reach even the most inaccessible sites in concentrations that the larger synthetic drug molecules cannot achieve. I have used this approach to cure periapical infections, much to the surprise of the attending dentists; thus precluding otherwise inevitable surgery. Finally, it seems likely that the effector ions will rapidly diffuse through caseation tissue, making this a very interesting candidate for the treatment of TB and MDR-TB.

 

 

Application                                                                                                                                                                                                  

KIB is the first system, developed by Kib Ltd, which produces hypothiocyanite ions to GMP specifications. Already available to CAM practitioners as a non-licensed supplement, it is now being developed as a licensed product with medicinal claims for use by the medical profession.

Table 1: LPO activity in vitro: preliminary results                                                                                                                                 

Bacteria 

Viruses 

 Yeasts

 

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  1. Cohen ML ’92. Epidemiology of drug resistance: implications for a post anti-microbial era. Science 257:1050-5 
  2. W.H.O. Reports 164 & 204 
  3. Czop JK, Puglisi AV, Miorandi DZ, Austen KF. Perturbation of beta-glucan receptors on human neutrophils initiates phagocytosis and leukotriene B4 production. J Immunol 1988;141:3170–6
  4. Di Renzo L, Yefenof E, Klein E. The function of human NK cells is enhanced by beta-glucan, a ligand of CR3 (CD11b/CD18). Eur J Immunol 1991;21:1755–8
  5. Wakshull E, Brunke-Reese D, Lindermuth J, et al. PGG-glucan, a soluble beta-(1,3)-glucan, enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B-like factor in               human PMN: evidence for a glycosphingolipid beta-(1,3)-glucan receptor. Immunopharmacology 1999;41:89–107
  6. Jung K, Ha Y, Ha SK, Han DU, Kim DW, Moon WK, Chae C. Antiviral effect of Saccharomyces cerevisiae beta-glucan to swine influenza virus by increased production of interferon-gamma and nitric oxide. J Vet Med B Infect              Dis Vet Public Health. 2004 Mar;51(2):72-6
  7. Beebe DP, Schreiber RD, Cooper NR. 1983. Neutralization of influenza virus by normal human sera: mechanisms involving antibody and complement. J. Immunol. 130:1317-1322
  8. Jayasekera JP, Moseman EA, Carroll MC. Natural Antibody and Complement Mediate Neutralization of Influenza Virus in the Absence of Prior Immunity. Journal of Virology, April 2007, p. 3487-3494, Vol. 81, No. 7

9. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005        Jul;19(9):1067-77.

10. Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, Packe GE, Davidson RN, Eldridge SM, Maunsell ZJ, Rainbow SJ, Berry JL, Griffiths CJ. A single dose of vitamin D enhances immunity to                         mycobacteria. Am J Respir Crit Care Med. 2007 Jul 15;176(2):208-13.

11. Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J. 2008 Feb 25;5:29. Review.

12. Sheridan PA, Zhong N, Carlson BA, Perella CM, Hatfield DL, Beck MA. Decreased selenoprotein expression alters the immune response during influenza virus infection in mice. J Nutr. 2007 Jun;137(6):1466-71.

13. Beck MA, Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, Barclay D, Levander OA. Selenium deficiency increases the pathology of an influenza virus infection. FASEB J. 2001 Jun;15(8):1481-3

14. Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, Barclay D, Levander OA, Beck MA. Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J. 2001 Aug;15(10):1846-8.

15. Beck MA, Williams-Toone D, Levander OA. Coxsackievirus B3-resistant mice become susceptible in Se/vitamin E deficiency. Free Radic Biol Med. 2003 May 15;34(10):1263-70.

16. Beck MA, Levander OA, Handy J. Selenium deficiency and viral infection. J Nutr. 2003 May;133(5 Suppl 1):1463S-7S. Review.

17. Jaspers I, Zhang W, Brighton LE, Carson JL, Styblo M, Beck MA. Selenium deficiency alters epithelial cell morphology and responses to influenza. Free Radic Biol Med. 2007 Jun 15;42(12):1826-37

18. Li W, Beck MA. Selenium deficiency induced an altered immune response and increased survival following influenza A/Puerto Rico/8/34 infection. Exp Biol Med (Maywood). 2007 Mar;232(3):412-9

19. Chan MCW, Cheung CY, Chui WH, et al. Proinflamatory cytokine responses induced by influenza A(H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6:135 2005

20. Moro JR, Iwata M, von Andriano UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008 Sep;8(9):685-98. Rev

21. Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. Markers of innate immune function are associated with vitamin a stores in men. J Nutr. 2009 Feb;139(2):377-85.

22. Clayton P, Rowbotham J. How the mid-Victorians worked, ate and died. Int J Environ Res Public Health. 2009 Mar;6(3):1235-53

23. Gerson CJ, Sabater M, Scuri A, Torbati R, Coffey JW, Abraham I, Lauredo R, Forteza A, Wanner M, Salathe WM, Abraham WM, Conner GE. 2000. The lactoperoxidase system functions in bacterial                 clearance of airways. Am. J.Respir. Cell Mol. Biol. 22:665–671. 

24. Pruitt KM, Reiter B. 1985. Biochemistry of peroxidase system: antimicrobial effects. In The Lactoperoxidase System: Chemistry and Biological Significance. K. M. Pruitt and J. O. Tenovuo, editors. Marcel Dekker, Inc. New York.        143–178.

25. Wang H, Ye X, Ng TB. First demonstration of an inhibitory activity of milk proteins against human immunodeficiency virus-1 reverse transcriptase and the effect of succinylation. Life Sci. 2000 Oct      20;67(22):2745-52

26. Fweja LW, Lewis MJ, Grandison AS. Challenge testing the lactoperoxidase system against a range of bacteria using different activation agents. J Dairy Sci. 2008 Jul;91(7):2566-74.

27. Reiter B, Perraudin J-P. 1991. Lactoperoxidase: biological functions. In Peroxidases in Chemistry and Biology, Vol. I. J. Everse, K. E. Everse and M. B. Grisham, editors. CRC Press. Boca Raton, FL. 144–180.  

28. Slungaard A, Mahoney JR Jr. Thiocyanate is the major substrate for eosinophil peroxidase in physiologic fluids. Implications for cytotoxicity. J Biol Chem. 1991 Mar 15;266(8):4903-10

29. Thomas EL, Aune TM. Lactoperoxidase, peroxide, thiocyanate antimicrobial system: correlation of sulfhydryl oxidation with antimicrobial action.  Infect Immun. 1978 May; 20(2): 456–463.

30. Mangold CM, Streeck RE. Mutational analysis of the cysteine residues in the hepatitis B virus small envelope protein. J Virol. 1993 Aug;67(8):4588-97

31. Almeida JD, Bradburne AF, Wreghitt TG. The effect of sodium thiocyanate on virus structure. J Med Virology 1979. 4(4):269-277

32. Dirix P, Nuyts S, Vander Poorten V, Delaere P, Van den Bogaert W. Efficacy of the BioXtra dry mouth care system in the treatment of radiotherapy-induced xerostomia. Support Care Cancer. 2007 Jan 18; [Epub ahead of print

33. Hinton WL. Supply & Demand for Vegetables in the UK. ISHS Acta Horticulturae 72

34. Li M, Eastman CJ, Waite KV, Ma G, Zacharin MR, Topliss DJ, Harding PE, Walsh JP, Ward LC, Mortimer RH, Mackenzie EJ, Byth K, Doyle Z. Are Australian children iodine deficient? Results of the Australian National Iodine                  Nutrition Study. Med J Aust. 2006 Feb 20;184(4):165-9

2.

35. Nawoor Z, Burns R, Smith DF, Sheehan S, O'Herlihy C, Smyth PP. Iodine intake in pregnancy in Ireland--a cause for concern? Ir J Med Sci. 2006 Apr-Jun;175(2):21-4.

36. Clayton P. 2009. Company data, to be published in 2010 in conjunction with the forthcoming clinical trial

37. Yndestad H. Personal communication ‘09

38. Registry of Toxic Effects of Chemical Substances ’77, German drug use

 

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