h pylori and probiotics

Are probiotics useful for therapy of Helicobacter pylori diseases? - ScienceDirectWarning: The NCBI website requires JavaScript to operate. Treatment of helicobacter pylori: antibiotics or probiotics Kamila Goderska1Faculty of Food Sciences and Nutrition, Instituto de Tecnología Alimentaria de Origen Vegetal, Departamento de Fermentación y Biosintesis, Universidad Poznan de Ciencias de la Vida, Wojska Polskiego 31, 60-624 Poznan, Poland Sonia Agudo Penaego2 Alternative treatments have been proposed for the eradication of H. pylori. Some of them including novel or classic antibiotics in different combinations; these treatments are being used in regular clinical practice as new and more effective treatments. Other therapies are using probiotics associated with antibiotics to treat this infection. This article is a review of H. pylori eradication treatment, focusing on emerging approaches to avoid treatment failure, using new antimicrobial or probiotic therapies. Introduction Helicobacter pylori is a common bacteria that infects about half of the world's population, with the highest prevalence in developing countries, where H. pylori could infect up to 80% of the population (Moayyedi and Hunt ), than in developed countries. H. pylori is associated with the development of gastrointestinal disorders such as chronic gastritis, peptic ulcer and gastric adenocarcinoma (Kuipers). H. pylori is also involved in the development of other extra-gastric disorders such as lymphoma associated with mucosa (MALT), idiopathic thrombocytopenic purpura, vitamin B12 deficiency and iron deficiency (Kuipers). The eradication of H. pylori could help in managing these disorders associated with H. pylori. During the last two decades, the recommended treatment for the eradication of H. pylori is the standard triple therapy (Papastergiou et al. , ), using a proton pump inhibitor or citrate of ranitidine cookies, combined with claritromycin and amoxicillin or metronidazole. During the 1990s, because these treatments reached high eradication rates [more than 90%] along with the safety profile, these triple therapies had a very high acceptance among the clinicians (Malfertheiner et al. ). The effectiveness of these triple regimes has recently decreased at rates below 70%, due to H. pylori resistance to key antibiotics, mainly claritromycin, but also metronidazole and levofloxacin (Agudo et al. , ; De Francesco et al. ). These low rates of successful treatment are not acceptable in Maastricht's consensus, which indicates that the rates consistently below 80% per intention to treatment are not acceptable to treat H. pylori (Graham et al. ). Before establishing a treatment plan for the patient to avoid repeated treatments, information on local resistance to antibiotics should be taken into account. Several exposures to antibiotic treatments could result in more side effects and a decrease in the percentage of antibiotic resistance. For this reason, this test is an overview of H. pylori eradication focused on second-line therapies that are used as sequential therapy and quadruple therapy. However, due to increased resistance to antibiotics, some studies have begun to focus on probiotics, as a therapeutic approach. Probiotics are defined as living microbial species that may include anti-inflammatory and antioxidative mechanisms that can improve intestinal microecology and general health (Lu et al. ). Probiotics are living microorganisms, which when administered in appropriate quantities give a health benefit to the guest. The most used probiotic bacteria are Lactobacillus and Bifidobacterium (Ruggiero ). Probiotics could improve the eradication of H. pylori and reduce side effects during therapy (Kim et al. ). Part of this review will focus on the use of probiotics against H. pylori. H. Pylori resistance to antibiotics Classical treatment During the 1990s, standard triple therapy was the standard of gold in the treatment of H. pylori infections. Standard triple therapies are based on a proton pump inhibitor, claritromycin and amoxicillin or metronidazole. Increased prevalence of resistance to these antibiotics, especially to the key antibiotic, claritromycin, has decreased the effectiveness of standard regimes (Malfertheiner et al. ). In a recent systematic review, it has been reported that the global incidence of H. pylori primary resistance to claritromycin is 17.2%, demonstrating an increase worldwide (Kuipers). The prevalence of H. pylori resistance to claritromycin varies between different countries, such as 10.6 to 25% in North America, 16% in Japan and 1.7 to 23.4% in Europe (Elitsur et al.; Horiki et al.; Koletzko et al.). This disparity in resistance rates seems to be related to the national level of macrolide consumption and different policies for antibiotic consumption in different countries (Agudo et al. , ), for example, 49% of clarithromycin resistance has been reported in some Spanish areas, but only 1% in the Netherlands, reflecting a stricter policy of Northern Europe for antibiotic use than in South European countries (Sec al.) (Sec. The new macrolides were marketed in Europe in the early 90s; patients were exposed to macrolides to treat respiratory infections with antibiotics from this group. Additional aspects such as geographical characteristics, virulence factors of H. pylori strains, or some host aspects [age, place of birth] could contribute to significant variation in the prevalence of antibiotic resistance (Van Doorn et al. ). Metronidazole is a key component included in the three therapies (Malfertheiner et al. ) that is associated with a high level of resistance. It has been estimated that the prevalence of metronidazole resistance is 17 to 44% for Europe and America respectively (Ogata et al. ; De Francesco et al. ). The highest level of resistance to this antibiotic in Europe has been reported in Western Europe, where between 20 and 45% of the insulators H. pylori are resistant to metronidazol (Lopez-Brea et al. ). The percentage of metronidazole resistance in developing countries has been reported from 50 to 100 per cent, instead of up to 90 per cent in Africa (Falsafi et al.). Metronidazole resistance is so high in developing countries because this antibiotic is widely used to treat parasitic and/or gynaecological infections in female patients (John et al. ). In addition, there are some studies that describe that metronidazole resistance is linked to the pressure factors of virulence, the strains without cagA gene are more resistant (Taneike et al. ). The lowest rates related to metronidazole resistance have been reported in Japan, about 10% (De Francesco et al. Based on these publications, standard triple therapies may not be recommended more for empirical use. Due to the high level of resistance to the two key antibiotics of standard triple therapies, clarithromycin and metronidazole, and to the different resistance patterns in different populations, the standard triple therapies must adapt to the local resistance pattern, and where possible, the treatment should be based on susceptibility data obtained through stress tests after culture. Alternative strategies are being implemented in clinical practice to treat H. pylori resistant strains. This included the development and use of new and more effective treatments and the use of probiotics to improve eradication regimes and reduce antibiotic side effects. During this review, new treatment will be discussed H. pylori and probiotic therapies. Bismuth quadruple Therapy This therapy contains two antibiotics, tetracycline and metronidazole, plus bismuth and PPI for 14 days (Harb et al. ). This therapy is preferred as a first-line treatment option for areas with a high incidence of claritromycin resistance and also as a second-line therapy when the first treatment with classic triple therapy against H. pylori (Papastergiou et al. , ) was failed. This therapy works completely independent of claritromycin, the most problematic antibiotic in terms of resistance. In relation to metronidazole, the use of high doses and the duration of prolonged treatment allows to minimize the impact on strains resistant to metronidazole, providing high eradication rates even in areas with high resistance to this antibiotic (Lee et al. ).The potential toxicity of the biscuit, as well as the non-availability of polylla or tetracycline salts in some countries is the main impediment related to this therapy. In some studies, tetracycline was replaced by amoxicillin (Perri et al. ).In a meta-analysis, randomized controlled trials were analyzed in nine trials (Luther et al. ), comparing quadruple bimuth therapy and the triple clarithromycin therapy; they found that quadruple therapy of bismumine patients achieved eradication in 783%. The conclusion was that quadruple and triple therapies have similar eradication rates as primary therapy for H. pylori infection. On the other hand, the effectiveness of this therapy has been confirmed as a second-line treatment in a meta-analysis based on 30 studies showing 77% of eradication after the standard triple therapy failure (Gisbert ). Sequential therapy Sequential therapy uses the same antibiotics as standard triple therapy, but they are given sequentially: 5 days with PPI plus amoxicillin, followed by 5 days of PPI plus clarithromycin and amoxicillin (Kuipers ).Amoxicilin is given first, because amoxicillin disrupts bacterial cell walls to prevent the development of effluding channels. There were some published studies, most of them in Italy, where the result of sequential therapy was superior to standard triple therapy. The most recent research data developed in South America and Asia show below 80% eradication rates (Kuipers). In a recent meta-analysis, 36 randomized clinical trials were reviewed. The eradication rate was 84.1 per cent for sequential therapy compared to 75.1 per cent for standard triple therapy. Sequential therapy appears to be more effective against patients with single claritromycin resistant strain; eradication rates were 80.9% for sequential therapy and 40.7% for standard triple therapy (Feng et al. ). It is another therapy valid in countries with high incidence of claritromycin resistance. This therapy contains PPI [but without bismuth], claritormicin, amoxicillin and metronidazole for 10 days. The main disadvantage of this treatment is the large number of pills compared to other therapies (Papastergiou et al. , ).In a meta-analysis carried out in 2012 including randomized controlled studies comparing non-bismuth quadruple therapy and standard triple therapy, the eradication rate was 90 vs. 78%, respectively. Resistance to Clarithromycin may reduce the effectiveness of non-community quadruple therapy, although the decline in eradication rates appears to be much lower than in standard triple therapy (Gisbert and Cavet). Hybrid Therapy This therapy is based on 7 days of PPI and amoxicillin therapy, followed by 7 days of quadruple therapy with PPI, amoxicillin, clarithromycin and metronidazole. There is not much data in literature, comparing this therapy to others, standard or sequential therapies, but the results do not indicate that hybrid therapy will be superior to sequential therapy (Papastergiou et al. There is a review where five studies were identified comparing hybrid therapy and sequential therapy, and three comparing hybrid therapy and concomitant therapy. The five randomized controlled trials did not reveal significant differences between hybrid therapy and sequential therapy, and the three randomized control tests showed no significant differences between hybrid therapy and concomitant therapy (He et al. ). Due to the increased resistance to claritromycin, levofloxacin, a broad-spectrum quinolone, is used for the eradication of H. pylori in order to replace claritromycin in triple or sequential regimes. The rate of eradication of levofloxacin-containing therapies could be more than 90%, especially in areas where local resistance to levofloxacin is low [less than 10%]. As for clarithromycin and metronidazole, there is an increase in resistance to levofloxacin, because quinolones are often used for the treatment of urinary infections. The resistance to the quinolls is around 20% in Europe, 15% in America and 10% in Asia (Liang et al. Due to the rapid development of resistance to secondary quinolone, the use of first-line levofloxacin is generally discouraged, and the drug is reserved for use in second-line regimes after the failure of claritromycin and/or metronidazole-based regimens (Gisbert et albiotics). Probiotics are defined as living microorganisms that, when administered in appropriate quantities, can improve microbial balance in the intestine and exercise positive health effects in the host (FAO/WHO), including beneficial effects on the prevention of intestinal infections, cardiovascular diseases, cancer and antiallergic effects (Pianoa et al.).Probiotics may be microorganisms of the group of bacteria or yeasts. However, most of the probiotics are bacteria, including lactic acid bacteria, typically associated with the human gastrointestinal tract, which are the most used (Rodes et al. ). They include Gram (+) cocci and Lactobacillus and Bifidobacterium rods, which are the two most common species used as probiotics and are widely investigated for their beneficial effects on the host, including the promotion of ripening and intestinal integrity, antagonism against pathogens, and modulation of the immune system and tumor promotion agents. A common characteristic of these bacteria is the ability of anaerobic digestion of the saccharides and the production of lactic acid. These microorganisms are characterized by low pH resistance and tolerance to a wide range of temperatures. The natural ecosystem of lactic acid bacteria is the digestive tract, the mucous membrane of the mouth and the genital tract of humans and animals (Rodes et al.).In fact, H. pylori has been considered a difficult infection to treat mainly due to the resistance acquired to commonly used antibiotics, there is a growing interest in using probiotics along with antibiotic regimes to eradicate H. pylori. Probiotics have proven to be useful in treating several intestinal diseases such as diarrhea, in addition to the benefits of probiotic bacteria in the intestines; some beneficial effects have been reported in the stomach. Among them, the anti-Helicobacter pylori (Aiba et al.) activity has been studied.The benefits of probiotic therapy in the H. pylori case increase eradication and improve tolerability by avoiding the occurrence of treatment and related side effects. In addition, probiotics can help improve H. pylori-related diseases. The clinical result of H. pylori infection is determined by several factors, including the type of H. pylori strain, the extent of inflammation and colonization density H. pylori. It has been reported that the risk of development of peptic ulcer disease and gastric cancer increases with an increasing level of infection. Therefore, the permanent or long-term deletion of H. pylori could reduce the risk of developing H. pylori-related diseases (Yang et al. ). Various studies have been carried out to show the favorable effect of the different probiotics against H. pylori and have clarified the mechanism of action of probiotics against H.chan pylori, including the strength of the mucose barrier, immune competition for adhesion, The first line of defense against pathogenic bacteria is the stomach acidity and gastric barrier of mucosa. It was suggested that, taking probiotics, this first line of defense could be stronger due to the production of antimicrobial substances competing with H. pylori for adherent receptors, stimulating the production of mucin and stabilizing the intestinal mucous barrier. Probiotics can inhibit H. pylori growth by secreting short chain fatty acids and antibacterial substances. Short-chain fatty acids, such as acetic, ownnic and lactic acids, are produced during the metabolism of carbohydrates by probiotics and, as a result, a reduction of pH is found. In 1989, Bhatia and others () were the first group to observe an antagonistic effect of a Lactobacillus strain against H. pylori related to short-chain fatty acids. In addition, antimicrobial activity may be due to inhibition of H. pylori urease activity as shown in other publications (Sgouras et al. ).Certain Lactobacillus species synthesize antimicrobial compounds related to bacteriocin classes. Bacteriacins are protein toxins with potential anti-H. pylori activity. They are small and diabetic peptide structures with antimicrobial activities. Antimicrobial activity of bacteriocyns varied between H. pylori strains and also the type of bacteriocyns produced by Lactobacillus sp. Some bacteriocins have shown a stronger antibacterial activity against H. pylori strains than others, although both were produced by Lactobacillus spp. (Kim et al. ) There are several possible mechanisms by which probiotic bacteria can inhibit adherence to H. pylori. H. pylori's adherence to epithelial cells is important to determine the result in H. pylori-associated diseases; the ability of bacteria to establish physical contact with gastric epithelium is affected by the influence of epithelial mucosa, receptors associated with H. pylori's adherence to epithelium, and immune cells (Zhang et al. ). There are several possible mechanisms by which probiotic bacteria can inhibit the adherence of H. pylori, mainly lactic acid and bacteriocins (Lesbros-Pantoflickova et al. ). Mucous surfaces have protective strategies to defend against harmful substances and pathogens found within the intestinal lumen. Some strategies, such as mucins, large complex glycoproteins that protect the intestinal mucous surfaces of microbial pathogens by limiting the access of environmental matter to their epithelial cells (Mack et al. ). Several mucins have been identified. H. pylori is known to suppress the expression of MUCI and MUC5 genes in a line of human gastric cells (Hanisch et al. ). It has been shown that in vitro studies with probiotics such as L. plantarum and L. rhamnosus increase the expression of MUC2 and MUC3 genes and therefore extracellular secretion of mucin by cultures of colon cells can inhibit the adherence of pathogenic bacteria. This ability of these strains restores the mucous permeability of the gastric mucosa and inhibits the adherence of pathogenic bacteria such as H. pylori. The inflammatory response to the gastric The H. pylori infection is characterized by the release of several inflammatory mediators such as chemocins and cytokines. Probiotics could modify the immune response by modulating the secretion of anti-inflammatory cytokines, which would result in a reduction in gastric activity and inflammation (Wiese et al. ). Revised documents related to probiotics and H. pylori have been searched at PUBMED for the last 10 years (from January 2004 to July 2017), introducing keywords such as "revision", "probiotics", "Helicobacter" and "treatment"; 159 articles were obtained, but only 34 of them were related to probiotics and H. pylori. Based on the data found in these documents, probiotics cannot be considered as an alternative to antihH. pylori treatment, but their use in association with the standard antih treatment. pylori could improve the treatment of H. pylori by increasing the eradication rates, as well as diminishing the adverse effects of current drug therapy. This was the conclusion of the four meta-analysis related to treatment and probiotics H. pylori published between 2016 and 2017 (Lü et al. McFarland et al. Feng et al. Wang et al. ). There is a scientific report published by Nature in 2016 that described the meta-analysis including randomized controlled trials eligible to determine whether probiotic supplementation can improve the eradication of H. pylori and reduce side effects during therapy (Dang et al.). The authors investigated the effect of combining probiotics, with or without placebo, without standard therapy. Compared to the placebo group, the probiotic group was the eradication of H. pylori infection in the analysis of intent to treatment and protocol analysis, respectively. Probiotics with triple therapy plus a 14-day treatment course did not improve the eradication of H. pylori infection compared to placebo. However, probiotics improved the adverse effects of diarrhea and nausea. These common dates suggest that the use of probiotics plus standard therapy does not improve the rate of eradication of H. pylori infection compared to placebo. Some meta-analysis have reported that supplementation of probiotics can improve the rate of H. pylori eradication compared to single therapy. It may be widely accepted that probiotics can improve H. pylori eradication and reduce side effects during standard therapy, but some species from a group of probiotic bacteria can help pharmacotherapy. Consumption of fermented products in diet (f.ex. 250 g of fermented product in milk) can improve the gastrointestinal tract with good microorganism in the gastrointestinal tract. These data suggested that the use of probiotics more standard therapy does not improve the rate of eradication of H. pylori infection compared to placebo. A placebo is a simulated or otherwise medically ineffective treatment for a disease or other medical condition that aims to deceive the receiver. It is well known that physiological phenomena are closely associated with gastric diseases. In addition, the placebo effect generates alternation in the levels of systematic and intrinsic hormones and subjective effects (Dong et al. ; Lesbros-Pantoflickova et al. ; Ruggiero ; Vítor and Vale ; Patel et al. ; Sachdeva and Nagpal ; Zou et al. Franceschi et al. Zhengn et al. Patel et al. Pacifico et al. ; Sabbi ; Tong et al. Wilhelm et al. Gotteland et al. ). Metaanalysis shows that the rate of eradication of H. pylori infections in the probiotic group vs. the placebo and non-placebo groups in the analysis of the ITT and estimate the RW with covalence interval of 95% and weight percentage. ConclusionThe triple regimens containing two antimicrobial agents have been the standard anti-infection therapies for H. pylori for more than 15 years. However, the increase in the prevalence of macrolide resistance, mainly claritromycin, has reduced the effectiveness of these therapies to unacceptably low levels in most parts of the world, leading to the need to study other possible therapies to eradicate pathogen. These therapies are quadruple, sequential, and hybrid bias. Due to the rapid development of quinolone resistance, levofloxacin-based regimens should be reserved as a second-line treatment option. In relation to probiotics, probiotics could not be used as a single agent for eradication therapy. However, its use associated with standard treatment as a supplement will improve the deleted rates and decrease the side effects related to treatment. Financing This study was not funded, it is a review article. Compliance with ethical standards Ethical approval This article does not contain studies with human or animal participants performed by any of the authors. Conflict of interest The authors declare that they have no competing interests. ReferencesFormats: Share , 8600 Rockville Pike, Bethesda MD, 20894 USA

Warning: The NCBI website requires JavaScript to operate. Are the probiotics useful in the eradication of Helicobacter pylori? Correspondence to: Matjaž Homan, MD, PhD, University Children's Hospital, Bohoričeva 20, 1000 Ljubljana, Slovenia. Phone: + 386-15229276 Fax: + 386-15229206RestractHelicobacter pylori (H. pylori) is considered an etiological factor for the development of the disease of peptic ulcer, gastric adenocarcinoma and MALT lymphoma. Therapeutic schemes to eradicate bacteria are based on double antibiotic therapy and proton pump inhibitor. Despite many therapeutic improvements in the treatment of H. pylori eradication, it is still associated with a high rate of infection also in developed countries. Bacterial resistance and adverse events occur among the most common causes for the failure of anti-H. pylori treatment. Several studies have reported that certain probiotic strains may exhibit inhibitive activity against H. pylori bacteria. In addition, some probiotic strains can reduce the occurrence of side effects due to antibiotic therapy and, consequently, increase the rate of H. pylori eradication. The results of the prospective studies controlled by double-blind placebo suggest that specific probiotics, such as S. boulardii and L. johnsonni La1 may decrease the bacterial load, but not completely eradicate the H. pylori bacteria. In addition, it seems that supplementation with S. boulardii is a useful concomitant therapy in the standard treatment protocol H. pylori eradication and probably increases the eradication rate. L. reuteri is equally effective, but more positive studies are needed. Finally, the probiotic strains, such as S. boulardii, L. reuteri and L. GG, decrease the associated adverse gastrointestinal effects. Basic Council: Deficient eradication rates have been reported in the infected patients of Helicobacter pylori (H. pylori), which is mainly explained by the increase in bacterial resistance rates to antibiotics and the low compliance of these drugs. This situation needs the development of alternative treatment options for H. pylori infection in patients. The results of recent studies suggest that certain test strains complemented by standard eradication therapy decrease the frequency of gastrointestinal adverse effects and therefore increase eradication rates. HELICOBACTER PYLORIHelicobacter pylori (H. pylori) is a gram-negative microorganism. Since the original discovery of the Helicobacter genus, more than 20 species have been formally defined.[] Gastric mucosa is well protected against bacterial infection. After ingestion H. pylori must survive the bactericidal activity of gastric lumen and enter the layer of mucus. H. pylori is well suited to special conditions in the stomach. It possesses flagella, which allows the colonization of the gastric epithelium[]. In addition, the bacteria produces the urease enzyme, which hydrolyzes the urea in carbon dioxide and ammonia and elevates the pH in the environment of the bacteria. The enzyme activity is higher in low pH[]. Bacteria H. pylori usually causes chronic infection due to a complex balance between host factors and bacterial factors of virulence. Among several bacterial factors one of the main factors, which leads the Th17 inflammation, represents the prolyl cys secreted peptidil, trans-isomerase[]. In colonization and chronic infection the adherence of the bacteria to the gastric epithelium is also very important. Lipolysaccharide is a component of the bacterial wall consisted of a specific or polysaccharide chain, oligosaccharide and lipid A. The antigens similar to Lewis (Lex, Law, Lea, Leb) of H. pylori lipolysaccharide are also expressed in the epithelial cells of the gastric mucosa, so they probably play an important role in the cells About 5% of the H. pylori genome encodes external membrane proteins (OMP). WMOs are adhesins on the surface of the bacteria, which promote the union of epithelial cells in the stomach. The main WMP is the antigenous adherence of the blood group A (BabA), which means the binding of H. pylori to the antigen of the blood group of fucosylated Leb. Also mediate the union to the salivar mucin MUC5B, a proline-rich glycoprotein, and glycoprotein gp-340[]. The second most important WIPO is the adherence to the sialic acid (SabA) binding.[] Halfway the union of the bacteria to sialil-dimeric-Lex, to the salivar mucin MUC5B, and to salival glucoproteins such as MUC7 and zinc-glycoprotein[]. In gastric colonization, other WMOs such as AlpA, AlpB, HopZ and HomB are also involved. Therefore, the union of the tension of bacteria to gastric epithelial cells is also enabled with BabA2 and Saba adhesins. The H. pylori is very closely associated with the extracellular cells MUC5AC and epithelials that produce MUC5AC, therefore MUC5AC plays a role in the adherence of H. pylori to the gastric mucosa. The important receptor for bacteria is the Leb structure present in normal gastric tissue and MUC5AC is the most important carrier of Leb, with the attachment that is done through BabA[]. H. pylori infection remains one of the most common bacterial infections worldwide. H. pylori infection is very common in Eastern Europe, Africa and most Asian countries[]. In developed parts of the world prevalence has decreased and is less than 10% in children and less than 30% in adults.[] 20% of infected individuals develop symptomatic gastritis, gastric or duodenal ulcer, gastric adenocarcinoma and non-Hodgkin gastric lymphoma[]. H. pylori is also associated with iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency[]. Several bacterial, host and environmental factors have been studied to determine the clinical outcome of H. pylori infection. Among the bacterial factors, the virulence genes are more important, and the severity of the disease related to H. pylori correlates with the presence of cagA, vacA s1m1 and genotypes babA2[,]. Chronic active gastritis can lead to precancer lesions such as gastric mucous atrophy and intestinal metaplasia, and finally to the development of gastric adenocarcinoma. The results of recent studies support the beneficial effect of H. pylori eradication on the prevention of gastric cancer, as well as on the regression of mucosa atrophy and intestinal metaplasia of gastric mucosa[]. Therefore, precancer gastric lesions require the rapid detection of H. pylori and the eradication of bacteria. It is suggested that H. pylori also have beneficial properties. Several meta studies and analysis showed an inverse relationship between H. pylori infection and the appearance of asthma[,]. The association was stronger for children than adults, but more prospective studies are needed to confirm the relationship mentioned above. In addition, H. pylori infection probably decreases the prevalence of obesity in children[]. The association between H. pylori infection and gastroesophageal reflux disease is still unclear. Although it has been previously suggested that the eradication of H. pylori may cause reflux disease, the existence of such an association was not recently confirmed.[] Standard eradication therapy consists of two antibiotics and a long-lasting proton pump inhibitor for 7-14 d. The percentage of treatment failures is increasing and the main cause of this is bacterial resistance to frequently prescribed antibiotics. The frequent use of claritromycin for respiratory tract infections has led to high rates of resistance to claritromycin []. Metronidazole resistance has less clinical impact. Metronidazole resistance can be overcome partially by increasing the dose and duration of the treatment. H. pylori resistance to metronidazole has been reported between 30% and 40%.[] Eradication levels used by standard triple therapy are between 60% and 80%, the last being considered as the minimum acceptable level according to Maastricht guidelines. Therefore, there is a great interest in developing new alternatives to eradication therapy, such as quadruple therapy or sequential therapy. Another possibility is to add the additional medication to the standard therapy protocol. Several studies have examined the potential influence of probiotics as supplements to standard therapy in the H. pylori eradication rate. In addition, probiotics were studied to reduce the frequency of side effects, as adverse events related to H. pylori therapy are an important factor that influences compliance. The overall rate of adverse events was 53.3% in a multicenter study[]. The most common adverse events reported are diarrhea, nausea and vomiting, which have significant physical and social impacts, and it has been shown that side effects were significantly associated with decreased compliance and failure of treatment.[] PROBIOTICS The definition of FAO/WHO probiotics is that probiotics are living microorganisms that when administered in appropriate amounts confer a health benefit on the host[]. The most used probiotics in humans are microorganisms belonging to the genus Bififobacterium, Lactobacillus, Saccharomyces and Bacillus[]. They are used as a unique species or multispecies preparation. The beneficial effects of probiotics seem to be specific to the tension and dose-dependent. Clinical studies of human probiotics are increasing rapidly. The beneficial effect of probiotics is already confirmed in diseases such as acute diarrhea, antibiotic-related diarrhea, functional gastrointestinal disorders, intestinal inflammatory disease, etc.[]. H. pylori infection is also a field in which there is a particular interest in using probiotics. The GASTRIC MICROBIOTALactobacillus species are acid resistant and are usually present in healthy gastric microbiota. Some strains may even adhere to gastric epithelial cells so that they can stay longer than other bacteria in the stomach.[] These have been confirmed in a study where it was possible to detect L. reuteri 55730 adhering to gastric epithelial cells of healthy volunteers a few hours after oral administration[]. Elliott et al[] have observed that in a gastric ulcer rat activates the local microbiota changed into gram-negative bacteria including E. coli while the Lactobacullus species almost disappeared. In the process of healing gastric mucosa, the population of Lactobacillus resurfaced and this process was accelerated by the administration of oral lactulosa. This study suggests that normal gastric microbiota participates in the maintenance of healthy mucosa. In addition, the oral intake of probiotics can reinforce the protective functions in the stomach. DIFERENT MECHANISMS OF ANALYCTERIAL ACTION Probiotics can inhibit H. pylori by several immunological and non-inmunological mechanisms. Probiotics are able to modify the immune response of the host. Neutrophils, lymphocytes, plasma cells and macrophages are involved in the inflammatory response to H. pylori. The consequences are higher levels of pro-inflammatory cytokines, such as IL-1β, IL-2, IL-6, IL-8 and tumor necrosis factor α in the gastric mucosa[]. Probiotics such as L. salivarius WB 1004 have reduced IL-8 secretion in vitro by gastric epithelial cells[]. It seems that at least in vitro L. acidophilus can improve gastric inflammation induced by H. pylori by inactivating the Smad7 and NFκB[]. In addition, Zhou et al[] showed that L. bulgaricus inhibited the activation of the TLR4 signaling pathway and the production IL-8 induced by H. pylori lipolysaccharide in SGC-7901 cells. Gastric inflammation can be controlled at some level by different strains of Lactobacilli by inactivating JAK2 through the JAK-STAT tracks and through a greater expression of the SOCS protein family.[] H. pylori also induces the humoral response of gastric mucosa, which can contribute to gastric mucosa damage. Lactobacilli was able to increase the local concentration of IgA and decrease specific antibodies anti H. pylori IgG in animal models[,] Among non-immunological mechanisms probiotics are able to influence bacterial growth by secreting antibacterial substances such as lactic acid, short-chain fatty acids, hydrogen peroxide, and spiral bacteriocin. Metabolites can decrease the number of bacteria[] Lactic acid probably has an additional effect on H. pylori by lowering pH and inhibiting urease[]. L. acidophilus CRL 639 secrete a autolysin, a proteinaceous compound released after cell lysis, which has some antibacterial activity[]. Substances, similar to isocoumarin antibiotics, are produced by B. subtilis and can also kill H. pylori bacteria[]. L. reuteri ATCC 55730 produces unique substance called reuterine that suppresses the growth of spiral bacteria[]. Mucins are high molecular weight glycoproteins that protect the gastric epithelium. Gastric surface mucin is decreased in infected patients, because H. pylori suppresses the expression of MUC5AC and MUC1 genes[]. It has been shown that the cepa plantarum 299v increases the expression of the MUC2 gene and that L. rhamnosus GG stimulates the expression of the MUC3 gene and the subsequent extracellular secretion of the mucin by the cultures of the colon cells[,]. Therefore, the ability of some probiotic strains to increase mucin production can protect the gastric mucous barrier against the adhesion of pathogenic bacteria such as H. pylori. The adherence of H. pylori to the host tissue is of vital importance for the colonization of the gastric mucosa[]. There are several proposed anti-adherence mechanisms of probiotics. L. reuteri and W. confuse are able to compete with the H. pylori strains for the adhesion sites. For example, the strains of L. reuteri, JCM 1081 and TM 105 inhibit the union of spiral bacteria to glylipid asialo-GMI receptors and sulfatide[]. In addition, Sakarya et al[] showed that S. boulardii contains neuraminidase activity, which eliminates the sialic acid linked to the α(2-3) surface, the ligand for H. pylori adhesion that binds sialic acid. POSSIBLE ROLE OF PROBIOTICS IN H. PYLORI TREATMENT The rate of eradication failure of more than 20% and the high percentage of adverse effects of antibiotic therapy are the main problems in standard eradication therapy protocols. In addition, the fulfillment of the lover due to adverse events results in increased antibiotic resistance of bacterial strains. Studies published to date suggest that probiotics can have a double role in fighting H. pylori infection. The frequency of gastrointestinal adverse events caused by antibiotic therapy decreases and the rate of eradication increases. Probiotics have been piloted as unique therapy in eradication protocols or as a therapeutic agent used concomitantly with standard eradication therapy. Probiotics as Unique Treatment in Treatment H. pylori The first positive results in vitro were published in 1989[]. Bhatia et al[] found that H. pylori growth in vitro washibied, if L. acidophilus was present in the culture. Michetti et al[] studied for the first time the effect of probiotics [L. acidophilus (La1)] on colonization H. pylori in humans. The study showed that the density of the bacterial load decreases in the probiotic group of asymptomatic patients, while the total eradication of H. pylori was not successful. Similarly, Wang et al[] revealed that after the intake of B. lactis Bb12 and L. acidophilus La5 in H. pylori infected adults a decrease in urea breathing test values was detected. The bacterial load was evaluated by the semi-quantative breathing test 13C-urea in subjects treated with L. johnsonii La1[], L. brevis CD2 lyophilized bacteria[], B. bifidum BF-1[], L. reuteri ATCC 55730[], L. gasseri OLL 2716[], and with significant respiratory probiotics Gotteland et al[] includes 182 asymptomatic children infected with H. pylori and divided into four groups: standard triple therapy group, S. boulardii and inulin symbiotic group, probiotic group L. acidophilus LB, or control group without any therapy. Statistically significant decreases were detected in the urea breathing test values in two groups: the standard triple group and the symbiotic group of inulina S. boulardii children. The authors concluded that S. boulardii can lower the bacterial load in the gastric mucosa of children infected with H. pylori bacteria. Surprisingly, in 12% of the children of the second group treated with S. boulardii and inulin H. pylori even eradication was successful. The same author conducted a randomized and double-blind study in 295 asymptomatic children infected with H. pylori[]. The study compared eradication rates after 3 wk therapy with (1) placebo/L. johnsonii La1 juice; (2) cranberry juice /L. johnsonii La1; (3) placebo/heat-qualified juice L. johnsonii La1; and (4) cranberry juice/heated juice L. johnsonii La1. Except for the placebo group the eradication rates were higher than 14% in all tested groups, but they do not statistically differ significantly from each other. Cruchet et al[] included 326 children infected in a similar study. The children were divided into five groups. They were treated for a month either with L. johnsonii La1 or L. paracasei ST11 alive or inactive. The fifth group was the control group. Statistically significant changes were observed in the 13C-urea respiratory test only in the group of pediatric patients treated with L. johnsonii La1 living probiotics. In conclusion, there are only some studies that evaluate the effect of probiotics as monotherapy in the H. pylori eradication rate. The results of the studies suggest that specific probiotics, such as S. boulardii and L. johnsonni La1 probably decrease the bacterial load, but do not completely remove the H. pylori bacteria. Probiotics such as adjuvant therapy in standard eradication protocols Several systematic reviews and metaanalysis have been published regarding the effect of probiotics as adjuvant therapy to the standard treatment of H. pylori infection[,]. The authors suggested that the supplementation of probiotics in general would likely increase the rate of eradication and reduce the frequency of adverse effects due to dual antibiotic therapy. However, the beneficial effects of probiotics seem to be specific to the strain, so collecting data on different strains in metaanalysis can result in misleading conclusions. With regard to this, a better approach is to unite data on the tension of individual probiotics and to perform a meta-analysis. Szajewska et al[] recently published a systematic review to assess the effects of supplements with S. boulardii to the standard triple therapy protocol on the H. pylori eradication rate. Five randomized controlled trials of good methodological quality involving 1307 patients were identified. Only 90 children were included. The daily dose of S. boulardii ranged between 500 mg and 1000 mg and the duration of therapy was 2-4 wk. Since four trials, complete data on eradication rates were available. In 80% of patients treated with boulardii S together with triple therapy, the eradication was confirmed by standard diagnostic tools. The control group detected an absolute eradication rate of 9 per cent mistress (71%, 324 of the 455 patients). The authors concluded that compared to placebo or without intervention, S. boulardii given along with triple therapy significantly increased the rate of eradication [relative risk (RR) = 1.13, 95%CI: 1.05-1.21]. The side endpoints of the same metaanalysis also determined the effect of S. boulardii on the adverse effects related to therapy. About 24.3 per cent of patients experienced adverse effects in the control group treated with triple therapy, compared to 12.9 per cent of patients in probiotic group. Thus, the significant difference was found between group S. boulardi and the control group regarding the risk of general adverse effects (five randomized control tests, n = 1305, RR = 0.46, 95% CI: 0.3-0.7). The authors also analyze the specific adverse effects data. With respect to epigastric pain, impairment of taste/dry mouth, nausea or abdominal/blocker gas, no significant difference was found between the studied groups. On the other hand, the risk of diarrhea-related therapy was statistically significantly lower in the probiotic group compared to the control group treated only with antibiotics and proton pump inhibitor (5.6% vs 12.2%, RR = 0.47, 95% CI: 0.32-0.69). The findings of metaanalysis were that the concomitant use of S. boulardii with triple therapy increases moderately H. eradication rates of pylori and decreases the adverse effects related to antibiotics, especially diarrhea. However, more recent studies published by Song et al[] and Zojaji et al[] did not confirm the positive impact of S. boulardii on the eradication rate. In the Song 991 H. pylori study infected patients were recruited. The patients of group A were treated only with two antibiotics and proton pump inhibitor, in group B S. boulardii was added for a month, and in group C the same regime was used and also the D-9601 mucoprotector agent derived from asiatic Artemisia was prescribed concomitantly. Curiously, the eradication rate was significantly higher in group B and C compared to group A only if the intent was made to treat the analysis (P = 0.003), while the difference in the rate of eradication of patients by protocol was not significant. The conclusion was that supplementation with S. boulardi could be effective in improving eradication rates by reducing adverse effects, thus contributing to the termination of eradication therapy. Zojaji et al[] included 160 adult patients. In the study protocol probiotic S. boulardii was added to clarithromycin, amoxicillin and omeprazole for two weeks. The study showed that probiotics decrease the frequency of adverse events due to antibiotic therapy, but did not increase the rate of H. pylori eradication. Tong et al[] systematically evaluated the effectiveness of supplementation with different probiotics in the increase of H. pylori eradication rates. In the publication they also made subanalisi for different probiotic preparations. In eight of fourteen randomized trials a strain of individual probiotics was used. In tree trials, the species of Lactobacillus were administered to standard eradication therapy[-]. However, the increase in the eradication rate of H. pylori in the Lactobacillus group was reported in only two studies published by Sýkora et al[] and Canducci et al[]. In general, in tree studies, eradication rates were 70% in control group and 84% in complemented probiotic group, which is a statistically significant difference (RR = 2.09, 95%CI: 1.28-3.41). In addition, this meta-analysis revealed that the addition of probiotics to standard eradication protocols reduces the adverse effects during treatment (25% vs 39%, RR = 0.44, 95%CI: 0.30-0.66). The positive impact on diarrhea and taste alteration was more prominent. The efficacy of L. GG in children with H. pylori infection was studied in a Polish trial[]. Of the 83 children tested, 34 children in a group of probiotics received L. GG 109 twice a day for a week with three-fold therapy. No significant difference was found in H. pylori eradication rates between probiotic and control group (RR = 0.985%CI: 0.7-1.4). This result is consistent with adult trials. Armuzzi et al[] included 60 asymptomatic patients infected in a prospective study in which patients were treated with rabeprazole, clarithromycin tinidazole and L. GG or with the same triple therapy and placebo. Diarrhea, nausea and alteration of taste were significantly reduced in the supplemental group L. GG (relative risk = 0.1 CI of 95%: 0.1 ± 0.9; relative risk = 0.1 ± 0.9; relative risk = 0.5; 95% CI: 0.2 ± 0.9, respectively). Another Italian study included 85 asymptomatic adults, and the conclusion of the study was that supplementation L. GG to standard therapy beneficially affects the adverse effects related to treatment[]. However, it seems that L. GG has no effect on eradication rates. Demonstration that L. reuteri ATCC 55730 is able to colonize the stomach and duodenum driven studies on the effect of this strain on H. pylori eradication rates and the frequency of side effects[]. In a recent study conducted in Italy, Ojetti et al[] recruited 90 patients in his study. The supplementation of L. reuteri was used concomitantly for 14 d with second-line therapy that received esomeprazole, levofloxacin and amoxicillin in patients infected with H. pylori. Probiotic supplementation increased the rate of eradication in treated patients (group 1: 36/45, 80%; group 2: 28/45 62%; P The use of commercial yogurt containing B. animalis and L. casei combined with conventional triple therapy was investigated in two studies. Sheu et al[] proved the effectiveness of this yogurt as adjuvant for triple treatment. The difference in the rates of eradication of H. pylori infection in two groups was statistically significant in favour of the probiotic group (73/80 vs 63/80, P Effect of pretreatment with L. gasseri OLL2716 on first-line eradication therapy was studied in a trial published by Deguchi et al[]. Approximately 229 infected patients were randomized into two groups, either a week of triple therapy (rabeprazol, claritromycin, amoxicillin) or the same therapy with addition of probiotics. Overall eradication was significantly better in the studied probiotic group [intention to treatment (P = 0.018)/by protocol (P = 0.0411)], but more prospective studies are needed to evaluate the role of L. gasseri OLL2716 in treatment in H. pylori infection. The beneficial effects of adding fermented milk products containing L. casei DN-114 001 to triple therapy on the rate of eradication of H. pylori infection in children were shown in a multicenter study of the Czech Republic[]. Eighty-six symptomatic children infected with H. pylori were randomized to receive omeprazole, amoxicillin, clarithromycin or the same regime with addition of probiotics for 7 d. The eradication rate was statistically significantly higher in the probiotic group (P = 0.0045). B. claussi has also been studied as a possible complement to standard therapy for the eradication of H. pylori, but the positive effect on the eradication rate was not confirmed[]. The characteristics of the important studies in which probiotics were used as adjuvant therapy for the treatment of eradication are presented in table .Table 1Probiotics as adjuvant therapy in eradication protocols Helicobacter pylori Ref.TerapiaStudy Eradication rate Adverse effects Eradication therapy (d)Probiotic therapy (d) No. H. pylori H. pylori + probiotic therapy H. Pylori therapy H. pylori + probiotic therapyH. pyloritherapyCindoruk et al[]PPI + AC (14)S. boulardii (14)124UBT44/62137/6214/62137/62Cremonini et al[]PPI + CT (7)S. boulardii (14)43UBT 17/203/21112/20Duman et al[] 45/4834/424/48113/42Song et al[]PPI + AC (7)S. boulardii (28)661UBT264/330237/33148/330163/331Zojaji et al[]PPI + AC (14)S. boulardii (14)160UBT75/8014/80129/80Canducci et al[] RUT23/3422/3218 GI (14)85UBT16/213/20112/20Ojetti et al[]PPI + ALL. reuteri (14)90UBT36/45127/4510/45126/45Lionetti et al[]uterI + ACT (10)L/2019 Emara et al[]PPI + AC (14)L. reuteri (28)70hist, RUT26/3523/3510/35124 Therefore, the eradication of H. pylori is a primary objective in symptomatic patients. Eradication rates reached by classical triple therapy were proton pump inhibitor and double antibiotic therapy are fairly low and range between 60% and 80%, due to resistance to antibiotics and moderate patient compliance. Gastrointestinal adverse events associated with antibiotics are the main cause of minor compliance. It was therefore proposed that probiotics be a useful complement to improve the eradication rate and reduce the frequency of adverse effects. So far, most of the different types of Lactobacillus and S. boulardii were tested. The above-mentioned probiotics probably decrease the bacterial load but do not eradicate completely H. pylori in the gastric mucosa, if used as monotherapy. On the contrary, some probiotics when added to triple classical therapy can increase eradication rates. There is a reasonable amount of evidence that supplementation with S. boulardii is a useful concomitant therapy in the standard H. pylori eradication treatment protocol and probably increases the rate of eradication. L. reuteri is also a good candidate for adjunctive therapy, but more positive studies are needed. The effect of other probiotic strains is less well described. Side effects, caused by double antibiotic therapy, can be reduced with probiotics. Probiotic strains, such as S. boulardii, L. reuteri and L. GG, decrease the adverse effects associated with gastrointestinal antibiotics, especially diarrhea. The Maastricht IV/Florence Consensus Report suggests that certain probiotics and prebiotics show promising results such as adjuvant treatment to reduce side effects[]. FootnotesConflict-of-interest statement: Authors have no conflict of interest to declare. Open-Access: This article is an open access article that was selected by an internal editor and reviewed by external experts. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0), which allows others to distribute, remix, adapt, build on this non-commercial work, and license its derivative works in different terms, provided that the original work is duly cited and the use is not commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Peer-review initiated: 3 March 2015 First decision: 30 March 2015 Press article: 2 September 2015P- Comment: D'Elios MM, Eren B, Malnick S, Sakarya S- Editor: Yu J L- Editor: A E- Editor: Wang CHReferencesFormats:Share , 8600 Rockville Pike, Bethesda MD, 20894 USA

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