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Building the Immune System – The End of the Age of Antibiotics – Author Dr. Paul Clayton

16th September 2007 by Arrow Durfee Posted in Uncategorized

The End of the Age of Antibiotics – Author Dr. Paul Clayton

‘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.’ Professor George Poste, April ’05.

It would be unwise to ignore Professor Post’s alarming predictions. He heads the Biodesign Unit at the University of Arizona, and is reckoned to be one of the most influential clinical scientists on the planet. His expertise includes epidemiology, bio-terrorism and molecular biology, so he should know; but he is saying nothing new.

Back in 1992, Mitchell Cohen of the Centres for Disease Control in Atlanta published a paper in Science entitled ‘Epidemiology of drug resistance: implications for a post anti-microbial era’ (Cohen ’92). This paper, which went on to become 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. But Cohen wasn’t the first person to notice this either. Twenty three years before Cohen’s paper was published, British concerns about increasing cases of antibiotic-resistant salmonella in calf disease had lead to the setting up of the Joint Committee on the Uses of Antibiotics in Animal Husbandry and Veterinary Medicine which, in a 1969 report, was already ringing alarm bells about the dangers of inappropriate antibiotic use. This was a particularly prescient paper, and I am very proud of the fact that my father, who sat on that committee, consistently argued for more stringent antibiotic use.

The Joint Committee’s recommendations on the separation of growth-promoting and therapeutic antibiotics were timely, widely acted on, and did a great deal to slow the rise of antibiotic resistance in clinical medicine. Cohen’s paper, however, although influential in academia, was not understood or acted on by governments anywhere; and the scientific illiteracy of our political classes has lead us, inevitably, to the point where Professor Poste is now sounding the death knell for antibiotics in general.

And here, we must step back and look again at the subject through the long lens of history. Throughout recorded history – and undoubtedly throughout our pre-recorded history also – the default causes of illness and death were starvation, trauma, exposure, and above all infection. This is reflected in such folk tales as the Sleeping Beauty, where the protagonist’s unnaturally prolonged sleep actually represents death by septicaemia caused by a stick wound (the spindle); and the Pied Piper of Hammelin, in which the mass loss of children represents the death of a generation through a rat-borne epidemic.

The degenerative diseases that dominate public health today were minority issues, and it was only when the infectious diseases were beaten back by improved sanitation, vaccination and latterly the antibiotics, that the degenerative diseases assumed their modern significance.

due to the importance of the infectious and epidemic diseases, Victorians regarded death as an anticipated and a communal experience. Given that it was a more religious age, such sentiments were usually couched in terms we would not commonly use today – but the shared feeling is obvious: ‘the Lord gives strength to bear death, and how good it is to feel that we have a family to greet us in heaven’ (Balfour, 1856) This is in marked contrast to the intensely personalised perspective we have of death today, due to the recent emergence of non-communicable diseases as prime causes of death. The relative brevity of dying from infectious disease in the Victorian era compared to today, when palliative medicine typically extends the dying phase by years, also affected their view of both life and death: ‘Death came swiftly, as always in these cases of infection, and in a day the child’s life ebbed away’ (Carey, 1888)

Why waste time and space in a nutritional journal on such issues? Because we are in danger of losing the gains of the last century and reverting to a situation where, once more, infection will be the greatest killer, and patterns of dying and death in the OECD nations will no longer be distinguishable from those in the third world.

The loss of our antibiotic weapons, unhealthy population densities, mass travel and mass dysnutrition could bring this about in our life-times; and if global warming leads to even a 3 meter rise in sea levels, we will lose the bulk of our sewage processing facilities. Factor in the so-called ‘Peak Oil’ effect’ where rising oil prices will make our high energy pharmaceutical model of health care unsustainable, 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 (WHO Reports), and the pending flu pandemic which is predicted to kill up to 1.5% of humanity all on its own, and the future does indeed look green – in a gangrenous sort of way.

Nutritional therapists do not generally focus on infectious illnesses simply because these have been so amenable to antibiotic treatment; but they must now begin to consider what they can do to help reduce the risk of infection or to treat it when, as they will increasingly do, the antibiotics fail.

PREVENTION

Prevention, of course, is generally the best option; and when considering prophylaxis, innate immune priming using the 1-3, 1-6 beta glucans derived fom yeast is clearly the most effective option currently available. The only comparative data we have was generated in 2006 at the James Graham Brown Cancer Centre at the University of Louisville (Biothera data on file), and this showed that yeast-derived beta glucans considerably out-perform all other immuno-primers including Reishi and Maitake mushrooms, the mushroom-derived AHCC, and Echinacea. This is hardly surprising: humans had to evolve strong immune defences against yeast infections, whereas we are rarely infected / invaded by mushrooms! (Yeasts and fungi are members of the same family, but the beta glucans in the cell walls of mushrooms have shorter 1-6 side-chains, making them less effective at occupying CR3 receptors and priming the innate immue system.)

Prevention should also focus on general nutrition. Supplement manufacturers tell us that vitamin C, zinc, omega three fatty acids or even probiotics are essential for immune function; but the reality is that the complexity of the immune system means that almost every micro- and phytonutrient plays some role in determining overall immunity.

For example, for the immune system to function properly requires extensive cell division and the synthesis of many specific functional proteins and other macromolecules. These processes require in turn an adequate intake of the essential and conditionally essential amino acids; the conditionally essential amino sugars; at least 12 trace elements (not just iron, zinc and selenium!); vitamins A, B2, B6, B12 and folic acid, C and D; and many other dietary factors, including the carotenoids – the list goes on and on (ie Santos et al ’96, Hughes et al ‘97). It’s better not to waste time on more restricted supplements, but to concentrate on a healthy diet and /or a comprehensive micro- and phyto-nutrient support programme.

That approach, of course, is contra-indicated for virulent strains of flu, when death is paradoxically more likely to occur if the immune system is functioning well. This is due to the ability of some flu viruses to secrete a compound called Cytokine OX-40, which prevents the apoptosis of activated T-cells (Humphreys et al ‘07)and thereby precipitates an overwhelming inflammatory reaction that destroys the respiratory tract (Chan et al ‘05). In this case it would be far wiser to concentrate on the beta glucans, wich have been shown to increase resistance to infection and to reduce mortality in a rodent influenza model (Mandeville ‘04), and to reduce respiratory tract damage in a swine influenza model (Jung et al ‘04). This isn’t clinical proof, obviously, but it is the best we are likely to get.

Oral health is important, and it is worth noting that the oropharynx is known, colloquially, as ‘the ringmaster of infection’. This site is heavily colonised by many different strains of pathogens and potential pathogens, and has been implicated as the source of many auto-infections including URTI, UTI; and infections of the heart valves and prostheses.

Many of the pathogenic microorganisms which colonise the oropharynx are only able to do so are by forming biofilm, bacterial glucans which adhere to dental surfaces and provide binding sites for the bacteria so that they are not washed out of the mouth by salivary flow. This provides nutritional therapists with a potentially very powerful set of tools, because dietary factors are critical here.

A healthy diet, rich in fruits and vegetables, contains phytonutrients, which have direct antibacterial properties against many of the pathogenic species in dental plaque (Menezes et al ‘06). Other foods contain anti-adhesins which effectively remove bacterial docking sites. Flavonoids in berry fruits such as the cranberry (Weiss et al ’04, Yamanaka et al ’04) do this by inhibiting the bacterial enzymes called glucosyltransferases, which build plaque. In countries such as Japan where edible seaweeds are a staple, the sulphated polysaccharides contained in some marine algae are also highly effective in preventing plaque formation by interfering with glucan deposition (Saeki ’94, Saeki et al ’96). This approach has very recently been developed as a nutritional supplement, standardised to its funoran content and sold to dentists and vets as ‘PlaqueOff’. It is surprisingly effective at reducing and removing plaque, and this mode of action will also protect against infection at other vulnerable sites such as heart valves and prostheses, where biofilm is critically involved.

Our eyes, gastro-intestinal and respiratory tracts are also protected by a complex array of antibacterial enzymes such as lysozyme, lactoferrin and lactoperoxidase (Gerson et al 2000); antimicrobial peptides including bacteriocins produced by probiotic species such as bifidobacteria and lactobacilli (Karaolu et al ’03), and defencins, produced by our own epithelial cells (Goldman et al ’97). Backing all this up are innate immune system phagocytic cells including macrophages and neutrophil granulocytes, and a variety of immunoglobulins, complement factors and other compounds. This helps to explain why the immune system requires such a wide range of nutritional support!

Due to our historically low levels of physical activity and calorie intakes, most people today are depleted in the majority of micro- and phyto-nutrients. To make matters worse, given our historically low levels of fruit and vegetable intake, intakes of food-derived anti-bacterials and anti-adhesins are also compromised. And finally, given modern agricultural and food processing technology, levels of the critically important immuno-priming 1-3, 1-6 beta glucans (Czop ’88, DiRenzo et al ’91, Wakshull et al ‘99) are also at an all-time low. This combination of environmental and dietary factors has inevitably reduced the effectiveness of our immune system(s); and helps to explain why, for example, when we travel to less developed countries than our own, we inevitably become infected by pathogens that the locals have no problems with.

TREATMENT

Until very recently there has been no effective natural genuine antibiotic. That, however, has now changed with the arrival of the all-natural lacto-peroxidase hypothiocyanite ion delivery system. Sorry about the jargon – let me explain.

The lactoperoxidase (LPO) system is present in many secretions including tears, saliva, milk and airway surface fluid. It has an incredibly broad spectrum of antimicrobial activity against gram-positive and gram-negative bacteria, viruses and fungi (Pruitt & Reiter ‘85); and is important for the control of microorganisms in milk from lactating animals, and cell-mediated pathogen killing.

LPO utilises the commonly present thiocyanate ions as one substrate, producing hypothiocyanite ions. These ions are extremely toxic to most microorganisms; they are cell-permeable and can inhibit glycolysis as well as nicotinamide adenine dinucleotide (NADH)/nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reactions in bacteria (Reiter & Perraudin ‘91). This is an impressive mode of pathogen-killing, 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 in the inflammatory reactions mounted by the host, and is responsible for much tissue damage. By preventing hydrogen peroxide build-up, LPO is a doubly important defence mechanism.

(This explains the severe dental and gingival problems associated with xerostomia, where the LPO system is deficient; and which are exacerbated by reduced levels of other defence compounds including lactoferrin, lysozyme and the secretory immunoglobulins. In the management of xerostomia, salivary substitutes containing LPO, lactoferrin and lysozyme have been shown to be highly effective (Dirix et al ’07).)

The hypothiocyanite ions are not toxic to human cells, and have little if any effect on probiotic species, making them a near-perfect antibiotic system. And if you’re concerned about resistance issues, reflect on this: it is very difficult indeed for micro-organisms to develop resistance to LPO. We know this because of it was easy for pathogens to develop resistance to LPO we would not have survived as a species, as a key element in our immune system would have been disabled.

The bactericidal effects of LPO can be effectively amplified by delivering hypothiocyanite ions directly, either orally or by inhalation. This technology was initially developed in France for food plant sterilisation, and subsequently adopted by the WHO for bulk milk sterilisation. It has most recently been utilised as a therapeutic strategy in the UK and in Finland, where it is widely used by the dental profession in the prevention and management of periodontal disease. Marketed in the UK by Qures Ltd as ‘Kiss-It-Better’, this remarkable product has rapidly gained a reputation as an extremely effective and safe antibiotic for use in gut and systemic infections. I have included below a list of micro-organisms against which LPO has shown considerable (i.e. useful) activity:

Bacteria
• Escherichia coli (10)
• Yersinia enterocolitica (4)
• Klebsiella pneumoniae (13)
• Klebsiella oxytoca (10)
• Streptococcus agalactiae
• Streptococcus mutans
• Staphylococcus Aureus
• Salmonella species (12)
• Shigella sonnei (15)
• Listeria monocytogenes
• Acinetobacter species (40)
• Neisseria species (20)
• Haemophilus influenzae (20)
• Campylobacter jejuni (14)
• Aeromonas hydrophila (8)
• Pseudomonas aeruginosa (6)
• Capnocytophaga ochracea
• Selenomonas sputigena
• Wolinella recta
• Enterobacter cloacae (12)

Viruses
• Herpes simplex virus
• Immunodeficient virus
• Respiratory syncytial virus

Yeasts
• Candida albicans

Incidentally, LPO is a ferro-protein, and its effectiveness is therefore compromised by a lack of iron. Iron depletion and deficiency are the most commonly encountered malnutrition conditions, especially in women of childbearing age, and this fully justifies the inclusion of iron in any pharmaco-nutritional support programmes.

SUMMARY

Pharmaceutical approaches to infection control are in danger of failing; some experts say they are already failing. The growing understanding of human immune functions, and their modulation by dietary factors, opens a whole new area for nutritional and pharmaco-nutritional intervention; which may eventually take over from the antibiotics for both the prevention and treatment of infection. The LPO system developed by Qures Ltd will play a very critical role in this shift. Already available to CAM practitioners as a non-licensed supplement (without clear product claims), it is now being developed as a licensed product with medicinal claims for use by the medical profession.

REFERENCES

Balfour, CL, Present for a Maiden (Religious Tract Society, London, 1856)

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

Cohen ML ’92. Epidemiology of drug resistance: implications for a post anti-microbial era. Science 257:1050-5

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.

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.

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]

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.

Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM. 1997. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88:553–560.

Hughes DA, Wright AJ, Finglas PM, et al. The effect of beta-carotene supplementation on the immune function of blood monocytes from healthy male nonsmokers. J Lab Clin Med 1997;129:309–17.

Humphreys IR, Walzl G, Edwards L, Rae A, Hill S and Hussell T. A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection, J Exp Med 198 (8) 1237-1242

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.

Karaolu A, Aydin F, Kilic SS, Kilic AO. Antimicrobial Activity and Characteristics of Bacteriocins Produced by Vaginal Lactobacilli Turk J Med Sci 33 (2003) 7-13

Mandeville R: Biophage Pharma Inc, data on file, ‘04

Menezes SM, Cordeiro LN, Viana GS. Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother. 2006;6(2):79-92.

Murakami M, Ohtake T, Dorschner RA, Gallo RL. Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva. J Dent Res. 2002; 81(12):845-50

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.

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.

Saeki Y. Effect of seaweed extracts on Streptococcus sobrinus adsorption to saliva-coated hydroxyapatite. Bull Tokyo Dent Coll. 1994 Feb;35(1):9-15.

Saeki Y, Kato T, Naito Y, Takazoe I, Okuda K. Inhibitory effects of funoran on the adherence and colonization of mutans streptococci. Caries Res. 1996;30(2):119-25.

Santos MS, Meydani SN, Leka L, et al. Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation. Am J Clin Nutr 1996;64:772–7.

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.

Weiss EI, Kozlovsky A, Steinberg D, Lev-Dor R, Bar Ness Greenstein R, Feldman M, Sharon N, Ofek I. A high molecular mass cranberry constituent reduces mutans streptococci level in saliva and inhibits in vitro adhesion to hydroxyapatite. FEMS Microbiol Lett. 2004 Mar 12;232(1):89-92

W.H.O. 164 & 204

Yamanaka A, Kimizuka R, Kato T, Okuda K. Inhibitory effects of cranberry juice on attachment of oral streptococci and biofilm formation. Oral Microbiol Immunol. 2004 Jun;19(3):150-4.

PRODUCT REFERENCES

LPO ‘amplification’: bactericidal via HSCN
‘Kiss-It-Better’: www.kissitbetter.net

Seaweed extract
‘PlaqueOff’: info@molarltd.co.uk
11048

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One Response to “Building the Immune System – The End of the Age of Antibiotics – Author Dr. Paul Clayton”

  1. andrew Says:

    What is the chemical present in vegetables and fruits that helped humans to gain immunity against antibiotics?