Helicobacter Pylori as a Gram-negative Microaerophilic Bacterium - Coursework Example

One of the major drawbacks of conventional antibiotic treatment for infectious disease is the increased tendency to give rise to resistance in the pathogens. Since the discovery Helicobacter pylori several treatment regimen has been developed to effectively treat this fatal infection. In spite of the best available drug and improved management systems, the falling eradication rate has called for the need of newer and effective therapies. In this essay the role of probiotic in eradication of Helicobacter pylori and disease management has been reviewed. Introduction Helicobacter pylori is a Gram negative microaerophilic bacterium that infects an estimated 50% of the total human population. In 10% of the total infected population, the infection can lead to stomach adenocarcinoma and in the remaining 90% the infection can persist life long even under vigorous host immune response leading to life long colonization [1].Although the organism is now known to have infected humans for a long time, it was first identified and successfully cultured in the early 1980s by Dr. Barry J. Marshall and Dr. J. Robin Warren [2]. Triple therapy and quadruple therapy are the two most widely practiced treatment methods used against H. pylori infection [3]. However evolution has armed these gut pathogens with effective means to parry unfavorable situations. The uniqueness of these bacteria lies in the fact that they can survive the acidic environment of the host gut by neutralizing the acidic pH of the stomach by high urease activity that is present both on the surface and in the cytoplasm [4]. Acidic pH of the stomach may also contribute to the ineffectiveness of antibiotic therapy and therefore is another significant obstacle [5]. The high burden of bacteria in the stomach and their ability to form biofilms aggravates the condition. Reversible resistance of Helicobacter pylori is another challenge in its treatment. It is known that such kind of resistance in bacteria is manifested often when a non-replicating bacterial population is present that can survive until antibiotic therapy is stopped [6, 7]. As H. pylori is capable of maintaining pH lower than 6,maintaining a non-replicating stage and in the process conferring reversible resistance and increasing the local pH might restore replication. This has become the principle behind the success of dual therapy with proton pump inhibitor (PPI) and amoxicillin [8]. The treatment for H.pylori infection is widely recommended. Combination therapy forms the first line of treatment in H. pylori infection. According to the Maastricht 2-2000 Consensus Report is a 7- day triple therapy containing clarithromycin, amoxicillin and a proton pump inhibitor (PPI) [9,10]. This procedure has shown success but comes with prominent disadvantages of being expensive, causing side effects and in particular giving rise to resistance strains. These harsh antibiotic regimes also damage the normal microbiota of the gut epithelium. There is thus great interest in developing alternative therapies that can solve one or more of these problems. Treatment with probiotics in this scenario has become a tangible option and the volumes of work that has been done in this regard will be reviewed here. Probiotics in Human Health Probiotics are defined as ‘Live microorganisms which when administered in adequate amounts confer a health benefit on the host’ [11]. Dietary supplementation of probiotics not only helps in the colonization of “friendly bacteria” in the gut but also may have some favorable immunomodulatory effect. Improvement of post menopausal syndrome, reduction of cholesterol level and improvement of lactose intolerance are some other features of a good probiotics [12]. As shown in Table 1, Lactic acid fermenting bacterial strains like Lactobacillus acidophilus, L. lactis, L. helviticus, L. salivarius, L. plantrum, L. jhonsonii, Bifidobacterium bifidum, B. breve and Sachharomyces boulardii are commonly used as probiotics. [13] A probiotic may be a single bacterial strain or may be a cocktail as well. It can be in the form of powder, liquid, gel, paste, granules or capsules. The survival of probiotics in the gut depends on the colonization factors that they possess. Either immobilizing them or proliferating at a much faster rate than the rate of removal by peristalsis can bring about survival in the gut epithelium by probiotics. Probiotics has been used in controlled clinical trials of diverse clinical conditions as rotavirus infection, antibiotic associated diarrhea, irritable bowel syndrome and inflammatory bowel disease. [14, 15]. Strains Country Company Lactobacillus johnsonii Lal L. casei DN 014001 Lactobacillus casei Shirota Lactobacillus acidophilus NCFM L. casei CRL-43i Gilliland (La-Mo) Lactobacillus reuteri SD 2112 Lactobacillus plantarum 299V L. casei DN 014001 Streptococcus thermophilus 1131 Bifidobacterium longum SBT-2928 Saccharomyces boulardii Switzerland France Japan USA USA USA Sweden France Japan Japan USA Japan Nestle, Lausanne Danone Yakult, Tokyo Rhodia, Madison Chr. Hansens, Wisconsin BioGaia, North Carolina Probi, Lund Danone Meiji milk products, Tokyo Snow brand milk products, Tokyo Biocodex, Seattle Morinaga milk industry Table1: Commercially used probiotics. Modified form V.C et al. [13] The clinical effect of probiotics in humans is now intensely researched as it is evident from the increase in number of publications over the years [16] and with the emergence of drug resistant bacteria the need for new therapies against drug resistance has become imperative. Mode of action of probiotics : In a recent publication Hamilton-Miller [16] has reviewed the possible mechanism of probiotic action in view of eradicating Helicobacter pylori infection. In general probiotic after colonizing host intestine they exert several effects competing for nutrients, competitive exclusion form the gut wall to which pathogen would otherwise binds and production of inhibitory compounds like lactate, hydrogen peroxides, short chain fatty acids and bacteriocin like substances. In case of helicobacter infection, the initial onset might be hindered by competition for binding sites, as it is evident from previous works on germ free mice [17, 18]. Elimination of existing H.pylori infection was aided by lactic acid and other inhibitory metabolites that could have toxic effect on the pathogen [19]. Apart from what has been mentioned above, the immune-modulatory role is a notable effect of probiotics [20]. Study of probiotics in tissue culture models: Studies lead by Aiba et al., Kabir et al, Coconnier et al and many others have shown that Lactobacilli strains (eg: Lactobacillus acidophilus, L. casei. L. Jhonsonii) and their metabolic products has bactericidal or bacteristatic properties [17, 19, 21-24]. It has been proposed that the large amount of lactate that is catabolically produced by Lactobacillus in culture has either inhibitory or toxic effect on H. pylori [22, 23, 17]. However mediators other than lactate have also been reported to have direct bactericidal function [19, 21, 24]. Silva et al speculated that the bactericidal effect may be is due to the presence of microcin, which is commonly found to be produced by the Lactobacillus strain GG. However this killing effect was found to be specific in nature as only six out of thirteen dairy starter strains was able to inhibit Helicobacter pylori [23]. Apart from the bactericidal effects, probiotics are also capable of modulating biochemical changes in host cells. Kabir et al. reported that apart from reducing the adherence of H. pylori onto the gut wall, probiotics were also capable of reducing IL-8 secretion. [25]. It is known that IL8 plays a major role in Helicobacter mediated gastric inflammation. Tamura et al [26] showed that Lactobacillus grasseri at a much lower concentration than H.pylori in a coculture system was able to significantly suppress both mRNA and protein in the coculture indicating that LG21 was able to inhibit Helicobacter induced IL8 production in both gastric cell line and gastric mucosa. This inhibition was only accounted by live probiotics as both heat killed and ultraviolate rays treated cells failed to stop IL8 secretion. In another study Bergonzelli et. al [27] reported that the heat shock protein GroEL from Lactobacillus johnsonii La1 and other lactic acid bacteria might play role in gastrointestinal homeostasis due to their ability to bind to components the gastrointestinal mucosa and can also aggregate H. pylori. Heat resistance and protease sensitive factors elaborated by some Bifidobacteria strain have inhibitory effect on bacterial growth irrespective of their antimicrobial resistant status [28]. These reports mentioned here underline a possible mechanism of probiotic action and emphasizes the difference in response that exists among various strains of probiotics towards the treatment of the disease. Study of probiotics in animal models: Studies of probiotics in animal models have yielded significant data in curbing H. pylori mediated infection. In a controlled study conducted by Johnson-Henry et al. [29], C57BL/6 female mice that were provided with water supplemented with probiotics showed reduced growth of H.pylori on colixin nalidixic acid plates comapared to groups challenged with H.pylori orogastrically. In a similar study the reduction of bacterial colonization and amelioration in mouse stomach was shown with L. casei strain shirota [30]. Kabir et. al [25] reported that germ free animals when fed with Lactobacillus salivarius before pathogen challenge no colonization was observed and when infected mice were fed with L. salivarius, number of pathogens were reduced to less than 1% of those found in animals not supplemented with Lactobacilli. Therefore this study conclusively postulates that Lactobacilli are capable of eradicating established colony. In another study Coconnier et. al [19] found that supernatant fraction from L. acidophilus LB reduced colonization of H. felis and reduced the gastric lesion. They also found decrease in urease activity in the stomach of infected mice treated with L. acidophilus LB. Probiotics as therapeutics for human: Both in vitro and in vivo experiments in animal models have generated enough information to raise a plausible question: can probiotics as sole therapy eradicate Helicobacter pylori infection in human? Clinical trail study has revealed that probiotics have given positive outcome but they alone cannot be used as an effective single therapy in eliminating established H.pylori infection in human subjects. [31, 32]. From a clinical trial carried out at a Santiago school, 182 children were found to be infected with H.pylori. Triple therapy (lanzoprazole, clarythromycin and amoxicillin for 8 days) in these subjects were found to cure about 71.7% of the patients as compared to just 12% and 6.5 % in Saccharomyces boulardii, and Lactobacillus acidophilus. [33]. Not many formal clinical studies have been done to elucidate the role of probiotics in treating H.pylori infection in humans. Animal models shows promising results and thus investigation may prove worthwhile in this direction. Probiotics has a better and a wider response in the fields of adjunct therapy. The two main thrusts in this research is to find whether addition of probiotic results in any positive outcome when administered along with the therapeutic regimen and whether probitics were able to ameliorate any adverse effect that may have arise due to conventional therapeutic procedure. In a patient study in which triple therapy has failed, quadruple therapy with or without Lactobacillus and Bifidobacterium was performed. Of the 183 patients enrolled yogurt plus quadruple therapy group had a higher rate of H. pylori eradication than the quadruple therapy only group [34]. In a recent pilot study by Myllyluoma et al. [35], probiotics were shown effective in terms of enhancing the tolerance of the conventional anti microbial therapy. It also indicated that probiotics were capable of surviving the intensive antimicrobial therapy. These positive findings are very encouraging and might help fuel further investigations. Conclusion: Potential use of probiotics as an alternative therapy for Helicobacter infection has generated considerable amount of interest. However investigations are still in its infancy. To date probiotics has only shown desirable results on human infection as an adjunct therapy in conjunction with conventional anti-microbial regimen. More detailed investigations are needed to identify which probiotic strains to use and what the best delivery system to achieve reliable results is. Reference: 1. Clarkson S. Immune evasion: H. pylori: the plastic pathogen. Nat rev microbiol. 2004; doi:10.1038/nrmicro809 2. Go MF. Natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 2002;16(Suppl. 1):1_/15. 3. Kate V, Ananthkrishnan N. Treatment for Helicobacter pylori infection- A review, Indian J Pharmacol 2001 33: 410-416. 4. Yoshiyama H, Nakazawa T. Unique mechanism of Helicobacter pylori for colonizing the gastric mucus. Microbes Infect. 2000 Jan;2(1):55-60. 5. Durfee MA, Forsyth PS, Hale JA, Holmes KK. Ineffectiveness of erythromycin for treatment of Haemophilus vaginalis-associated vaginitis: possible relationship to acidity of vaginal secretions. Antimicrob Agents Chemother. 1979 ;16(5):635-7 6. Graham DY and Dore MP (1998) Variability in the outcome of treatment of Helicobacter pylori infection: a critical analysis. In Helicobacter pylori: Basic mechanisms to clinical cure, 426-440 (Eds Hunt RH and Tytgat GNJ) Dordrecht: Kluwer Academic Publishers . 7. Lewis K (2007) Persister cells, dormancy and infectious disease. Nat Rev Microbiol 5:48-56 8. Furuta T et al. (2001) Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics 11: 341-348 9. Malfertheiner P, Megraud F, O’Morain C, et al.; European HelicobacterPylori Study Group (EHPSG). Current concepts in the management of Helicobacter pylori infection—the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther 2002;16:167–80. 10. McLoughlin R, Racz I, Buckley M, O’Connor HJ, O’Morain C. Therapy of Helicobacter pylori. Helicobacter 2004;9:42–8 11. FAO/WHO. Guidelines for the evaluation of probiotics in food. Report of a joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food. World Health Organization, London Ontario, Canada, 2002: Page 8. ftp://ftp.fao.org/es/esn/food/wgreport2.pdf 12. Liong MT. Probiotics: A critical review of their potential role as ntihypertensives, immune modulators, hypocholesterolemics, and perimenopausal treatments.Nutrition Reviews. 2007;65:316–328 13. V.C. Suvarna , V.U Boby. Probiotics in human health: A current assessment. Current Science. 2005; 88(11): 1744-48 14. Ouwehand AC, Salminen S, Isolauri E. Probiotics: an overview of beneficial effects. Ant Leeuwenhoek 2002;82:279_/89. 15. de Vrese M, Schrezenmeir J. Probiotics and non-intestinal infectious conditions. Br J Nutr 2002;88(Suppl. 1):ss59_/66. 16. Hamilton-Miller JM. The role of probiotics in the treatment and prevention of Helicobacter pylori infection. Int J Antimicrob Agents. 2003 Oct;22(4):360-6. 17. Aiba Y, Suzuki N, Kabir AMA, Takagi A, Koga Y. Lactic acidmediated suppression of Helicobacter pylori by the oral administration of Lactobacillus salivarius as a probiotic in a gnotobiotic murine model. Am J Gastroenterol 1998;93:2097_/101. 18. 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Suppressive effect of Lactobacillus gasseri OLL 2716 (LG21) on Helicobacter pylori infection in humans . J Antimicrob Chemother 2001 ; 47 : 709 – 710 33. Gotteland M , Poliak L , Cruchet S , Brunser O . Effect of regular ingestion of Saccharomyces boulardii plus inulin or Lactobacillus acidophilus LB in children colonized by Helicobacter pylori . Acta Paediatr 2005 ; 94 : 1747 – 1751 34. Sheu B-S , Cheng H-C , Kao A-W , Wang S-T , Yang Y-J , Yang H-B , Wu J-J . Pretreatment with Lactobacillus - and Bifidobacterium -containing yogurt can improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection after failed triple therapy . Am J Clin Nutr 2006 ; 83 : 864 – 869 35. Myllyluoma E , Veijola L , Ahlroos T , et al . Probiotic supplementation improves tolerance to Helicobacter pylori eradication therapy – a placebo-controlled, double-blind randomized pilot study .Aliment Pharmacol Ther 2005 ; 21 : 1263 – 1272 Read More