Helicobacter pylori infection: New pathogenetic and clinical aspects

Helicobacter pylori(H.pylori)infects more than half of the world’s human population,but only 1%to3%of infected people consequently develop gastric adenocarcinomas.The clinical outcome of the infection is determined by host genetic predisposition,bacterial virulence factors,and environmental factors.The association between H.pylori infection and chronic active gastritis,peptic ulcer disease,gastric cell carcinoma,and B cell mucosa-associated lymphoid tissue lymphoma has been well established.With the exception of unexplained iron deficiency anemia and idiopathic thrombocytopenic purpura,H.pylori infection has no proven role in extraintestinal diseases.On the other hand,there is data showing that H.pylori infection could be beneficial for some human diseases.The unpredictability of the long-term consequences of H.pylori infection and the economic challenge in eradicating it is why identification of high-risk individuals is crucial.     

Lower concentrations of clarithromycin suppress urease activity, motility, and binding to gastric epithelial cells in Helicobacter pylori isolates

Background. Our previous study showed that histological scores of gastric mucosal inflammation and Helicobacter pylori density decreased even in patients who failed to eradicate Helicobacter pylori after antimicrobial therapy including clarithromycin. This may reflect indirect suppressive effects of lower concentrations of clarithromycin on Helicobacter pylori, as suggested in other Gram-negative rod infections.Aims. To investigate whether clarithromycin suppresses virulence factors of Helicobacter pylori at sub-minimal inhibitory concentration.Methods. Six clarithromycin-susceptible Helicobacter pylori isolates and 7 clarithromycin-resistant isolates were obtained from patients with peptic ulcer disease. These isolates were analysed for urease activity, motility, and ability to bind to gastric epithelial cells after they were incubated with or without clarithromycin at sub-minimal inhibitory concentrations.Results. Incubation of Helicobacter pylori isolates with clarithromycin at sub-minimal inhibitory concentrations reduced urease activity, motility, and binding to gastric epithelial cells in a dose-dependent manner. These findings were observed both in clarithromycin-susceptible and resistant strains.Conclusions. Suppressive effects of clerithromycin on virulence factors of Helicobacter pylori at sub-minimal inhibitory concentrations may be associated with observed attenuation of gastric inflammation and Helicobacter pylori density in patients who failed in bacterial eradication after triple therapy including clarithromycin.     

Correlation between expression of MMP-9 and MMP-3 in Helicobacter pylori infected patients with different gastroduodenal diseases

Background and study aims

Helicobacter pylori (H. pylori) has been implicated in the pathogenesis of most important gastro-duodenal diseases, such as gastritis, peptic ulcer disease (PUD) and gastric cancer. H. pylori upregulates the expression and activity of several matrix metalloproteinases (MMPs) in the gastric mucosa, but the role of MMP-3 and MMP-9 in infected patients with H. pylori have not been clearly defined yet. We examined mucosal MMP-3 and MMP-9 mRNA levels in gastric mucosa of H. pylori infected patients and evaluated the effects of virulence factors cagA and vacA allelic variants on these levels. We also determined correlation between mucosal MMP-3 and MMP-9 mRNA levels and types of disease.

Diagnosis of Helicobacter pylori infection: Current options and developments

Accurate diagnosis of Helicobacter pylori (H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice, several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology, culture, rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathing test and stool antigen test are most widely used non-invasive tests, whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection, several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori, as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes.     

Medicinal plant activity on Helicobacter pylori related diseases

More than 50%of the world population is infected with Helicobacter pylori(H.pylori).The bacterium highly links to peptic ulcer diseases and duodenal ulcer,which was classified as a groupⅠcarcinogen in 1994 by the WHO.The pathogenesis of H.pylori is contributed by its virulence factors including urease,flagella,vacuolating cytotoxin A(VacA),cytotoxin-associated gene antigen(Cag A),and others.Of those virulence factors,VacA and CagA play the key roles.Infection with H.pylori vacA-positive strains can lead to vacuolation and apoptosis,whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer.Numerous medicinal plants have been reported for their anti-H.pylori activity,and the relevant active compounds including polyphenols,flavonoids,quinones,coumarins,terpenoids,and alkaloids have been studied.The anti-H.pylori action mechanisms,including inhibition of enzymatic(urease,DNA gyrase,dihydrofolate reductase,N-acetyltransferase,and myeloperoxidase)and adhesive activities,high redox potential,and hydrophilic/hydrophobic natures of compounds,have also been discussed in detail.H.pylori-induced gastric inflammation may progress to superficial gastritis,atrophic gastritis,and finally gastric cancer.Many natural products have anti-H.pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress.Anti-H.pylori induced gastric inflammatory effects of plant products,including quercetin,apigenin,carotenoids-rich algae,tea product,garlic extract,apple peel polyphenol,and finger-root extract,have been documented.In conclusion,many medicinal plant products possess anti-H.pylori activity as well as an anti-H.pylori-induced gastric inflammatory effect.Those plant products have showed great potential as pharmaceutical candidates for H.pylori eradication and H.pylori induced related gastric disease prevention.     

Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review

Since Isaacson and Wright first reported on the extranodal marginal zone B-cell lymphoma of the stomach in 1983,following studies have clarified many aspects of this disease.We now know that the stomach is the most affected organ by this disease,and approximately90% of gastric mucosa-associated lymphoid tissue(MALT) lymphomas are related to Helicobacter pylori(H.pylori) infection.This implies that approximately 10% of gastric MALT lymphomas occur independent of H.pylori infection.The pathogenesis of these H.pylori-negative gastric MALT lymphomas remains unclear.To date,there have been several speculations.One possibility is that genetic alterations result in nuclear factor-kappa B(NF-κB) activation.Among these alterations,t(11;18)(q21;q21) is more frequently observed in H.pylori-negative gastric MALT lymphomas,and such translocation results in the synthesis of fusion protein API2-MALT1,which causes canonical and noncanonical NF-κB activation.Another possibility is infection with bacteria other than H.pylori.This could explain why H.pylori eradication therapy can cure some proportions of H.pylori-negative gastric MALT lymphoma patients,although the bacteria responsible for MALT lymphomagenesis are yet to be defined.Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment.A certain proportion of H.pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence,H.pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H.pylori infection status.     

Helicobacter pylori:Does it add to risk of coronary artery disease

Helicobacter pylori(H. pylori) is a known pathogen implicated in genesis of gastritis, peptic ulcer disease, gastric carcinoma and gastric lymphoma. Beyond the stomach, the organism has also been implicated in the causation of immune thrombocytopenia and iron deficiency anemia. Although an area of active clinical research, the role of this gram negative organism in causation of atherosclerosis and coronary artery disease(CAD) remains enigmatic. CAD is a multifactorial disease which results from the atherosclerosis involving coronaryarteries. The major risk factors include age, diabetes mellitus, smoking, hypertension and dyslipidemia. The risk of coronary artery disease is believed to increase with chronic inflammation. Various organisms like Chlamydia and Helicobacter have been suspected to have a role in genesis of atherosclerosis via causation of chronic inflammation. This paper focuses on available evidence to ascertain if the role of H. pylori in CAD causation has been proven beyond doubt and if eradication may reduce the risk of CAD or improve outcomes in these patients.     

IS HELICOBACTER PYLORI‐INDUCED ENLARGED FOLD GASTRITIS A HIGH‐RISK FACTOR FOR GASTRIC CARCINOMA?

It is now a generally accepted fact that Helicobacter pylori is an important cause of gastric carcinoma. The International Agency for Research on Cancer classified H. pylori as a group 1 carcinogen. We previously reported that H. pylori‐positive subjects had enlarged folds (fold width = 5 mm); that is, ‘enlarged fold gastritis’. Helicobacter pylori‐induced enlarged fold gastritis is accompanied by a massive infiltration of inflammatory cells, profound production of interleukin‐1β (IL‐1β) and hepatocyte growth factor (HGF), which decrease gastric acid secretion and increase the proliferation rate of the gastric epithelial cells. In addition, there is increased mutagenicity of gastric juice, and mucosal 8‐hydroxydeoxyguanosine (8‐OhdG) levels. Fold width improves and these factors recover to within a normal range with the eradication of H. pylori. The odds ratio for gastric carcinoma and the prevalence of diffuse‐type early gastric carcinoma in the body region increased with an increase in fold width. Therefore, enlarged fold gastritis may be a major risk factor for gastric carcinoma among H. pylori‐infected people. We propose that H. pylori‐infected persons with enlarged fold gastritis are a potential population for the prevention of gastric carcinoma via the use of antibiotics.     

Diversidad de los genotipos vacA y cagA de Helicobacter pylori y expresión de interferón gamma en pacientes con gastritis crónica y cáncer gástrico

BackgroundHelicobacter pylori (H. pylori) is the main risk factor for the development of chronic gastritis, gastric ulcer, and gastric cancer. In H. pylori-infected individuals, the clinical result is dependent on various factors, among which are bacterial components, the immune response, and environmental influence.AimsTo compare IFN-γ expression with the H. pylori vacA and cagA genotypes in patients with chronic gastritis and patients with gastric cancer.MethodsNinety-five patients diagnosed with chronic gastritis and 20 with gastric cancer were included in the study. Three gastric biopsies were taken; one was used for the molecular detection and genotyping of H. pylori; another was fixed in absolute alcohol and histologic sections were made for determining IFN-γ expression through immunohistochemistry.ResultsNo differences were found in the cells that expressed IFN-γ between the patients with chronic gastritis (median percentage of positive cells: 82.6% in patients without H. pylori and 82% in infected persons) and those with gastric cancer (70.5% in H. pylori-negative patients and 78.5% in infected persons). IFN-γ expression was 69% in chronic gastritis patients infected with H. pylori vacAs2m2/cagA^-, it was 86.5% in patients infected with H. pylori vacAs1m2/cagA^-, 86.5% in vacAs1m1/cagA^-, and 82% in vacAs1m1/cagA⁺. Similar data were found in the patients with gastric cancer.ConclusionsIFN-γ expression varied depending on the H. pylori vacA and cagA genotype, but not in accordance with the presence of chronic gastritis or gastric cancer.     

Risk Factors for Gastric Cancer after the Eradication of Helicobacter pylori Evaluated Based on the Background Gastric Mucosa: A Propensity Score-matched Case-control Study

Objective The eradication of Helicobacter pylori (H. pylori) reduces the risk for gastric cancer (GC) development, but it cannot prevent GC completely. We investigated the risk factors of early GC development after the eradication of H. pylori, based on the histological characteristics of gastric mucosa. Methods Sixty-one patients who underwent endoscopic submucosal dissection for early GC after successful H. pylori eradication (Group A) and 122 patients without developing a gastric neoplasm over 3 years after successful H. pylori eradication (Group B) were analyzed. We compared the histological findings of the patients enrolled in Group A and Group B before and after the propensity score-matching. Results Comparing the characteristics of two the groups, Group A consisted predominantly of males, had significantly more elderly patients, and the years after successful eradication tended to be longer. We performed score matching for these three factors to reduce the influence of any confounding factors. After matching, the scores of inflammation for Group A (n=54) was significantly higher than those of Group B (n=54) at the greater curvature of the antrum, the lesser curvature of the corpus, and the greater curvature of the corpus. According to a multivariate analysis, inflammation of the greater curvature of the antrum and lesser curvature of the corpus were found to be independent risk factors. The risk ratio and 95% CI were 5.92 (2.11-16.6) (p<0.01), and 3.56 (1.05-13.2) (p=0.04), respectively. Conclusion A continuous high level of inflammation of the background gastric mucosa may be a risk factor for gastric cancer onset after H. pylori eradication.     

4 Pathogenic mechanisms

Research is asking how H. pylori causes diseases, and also why the same bacteria produces different conditions in different persons. The process involves bacterial factors and the host's response. Some bacterial factors such as urease are produced by all strains of H. pylori. This enzyme may damage the gastric epithelium by practically releasing ammonia. Other bacterial factors such as vacuolating toxin are only produced by some strains, and these strains are more likely to cause ulcers or cancer. The host's response has been studied by physiologists, immunologists, and histologists, but the separation of systems is artificial. For example, physiologists find that H. pylori stops gastric D-cells from expressing somatostatin normally, which impairs reflex inhibition of acid secretion, but the D-cell malfunction is probably due to inflammatory factors. In H. pylori gastritis, the gastric epithelial cells behave like immunocytes and express class II molecules and cytokines such as interleukin-8. The patient's histological response to H. pylori is quite closely related to the disease outcome. Patients who respond by developing gastric atrophy are more likely to get gastric ulcers or stomach cancer, but patients whose gastric corpus remains healthy tend to secrete more acid and develop duodenal ulcers, particularly if they have gastric metaplasia in their duodenum. Studies of disease mechanisms provide a valuable insight into the development of these common diseases, and may enable us to identify at-risk groups who particularly merit eradication therapy.     

Asociación de cepas de Helicobater pylori cagA+ con alta actividad de ureasa y dispepsia en adultos mexicanos

Introduction and aimsHelicobacter pylori (H. pylori) is associated with a higher risk of peptic ulcer and gastric cancer. The sole presence of the bacterium is not a determinant of clinical outcome, but rather the interaction of strain type and host factors determines the risk of disease. Our aim was to study the association between bacterial load, strain type, and gastric symptoms in H. pylori-positive subjects.Materials and methodsIn a community survey, a diagnostic ¹³C-urea breath test for H. pylori was performed on 302 volunteers that were not taking antibiotics, antacids, or proton pump inhibitors one month prior to the test. The breath test produced 25 H. pylori-positive subjects, between 25-74 years of age, who then took a gastric symptoms survey and were tested for the presence of the cagA genotype in gastric juice, using the Entero-test®. Bacterial load was determined as a measure of urease activity, utilizing the delta over baseline value, obtained in the ¹³C-urea breath test.ResultsA total of 48% of the H. pylori-positive subjects were cagA+. A positive association was found between cagA status and high gastric urease activity (P < .0001) and the latter was significantly associated with the presence of symptoms (P < .0001).ConclusionGastric urease activity was strongly associated with dyspeptic symptoms and cagA+ H. pylori. Elevated ¹³C-delta over baseline values could be used as indicators of a higher risk for gastric disease.     

Relatedness of Helicobacter pylori populations to gastric carcinogenesis

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects half of the human population. The infection is associated with chronic inflammation of the gastric mucosa and peptic ulcers. It is also a major risk factor for gastric cancer. Phylogenetic analysis of global strains reveals there are seven populations of H. pylori, including hpAfrica1, hpAfrica2, hpEastAsia, hpEurope, hpNEAfrica, hpAsia2 and hpSahul. These populations are consistent with their geographical origins, and possibly result from geographical separation of the bacterium leading to reduced bacterial recombination in some populations. For each population, H. pylori has evolved to possess genomic contents distinguishable from others. The hpEurope population is distinct in that it has the largest genome of 1.65 mbp on average, and the highest number of coding sequences. This confers its competitive advantage over other populations but at the cost of a lower infection rate. The large genomic size could be a cause of the frequent occurrence of the deletion of the cag pathogenicity island in H. pylori strains from hpEurope. The incidence of gastric cancer varies among different geographical regions. This can be attributed in part to different rates of infection of H. pylori. Recent studies found that different populations of H. pylori vary in their carcinogenic potential and contribute to the variation in incidence of gastric cancer among geographical regions. This could be related to the ancestral origin of H. pylori. Further studies are indicated to investigate the bacterial factors contributing to differential virulence and their influence on the clinical features in infected individuals.     

De-escalating therapy in gastric aggressive lymphoma

The treatment of primary gastric diffuse large B-cell lymphoma (DLBCL) has changed radically over the last 10–15 years, with the abandonment of routine gastrectomy in favor of more conservative therapies. Low-level evidence suggests that consolidation radiotherapy could be avoided in patients with limited-stage DLBCL of the stomach who achieve complete remission after rituximab-CHOP combination. Small, recent prospective trials suggest that selected patients with limited-stage Helicobacter pylori (H. pylori)-positive DLBCL of the stomach and favorable prognostic factors can be managed with antibiotics alone, with excellent disease control and cure rates, keeping chemo-radiotherapy for unresponsive patients. This recommendation should equally regard patients with mucosa-associated lymphoid tissue-related or de novo DLBCL. Future studies should be focused on the establishment of reliable variables able to distinguish the best candidates for exclusive treatment with H. pylori eradication from those who need for conventional chemo-immunotherapy.     

Helicobacter pylori infection and inflammatory bowel disease: Is there a link?

Helicobacter pylori(H.pylori)infection is one of the most widely spread infectious diseases in humans.It can cause chronic gastritis,peptic ulcer disease and gastric malignancies and has been associated with extra-gastric disorders.H.pylori elicit a chronic systemic inflammatory response which,under certain conditions,may trigger autoimmune reactions and may be implicated in the pathogenesis of autoimmune diseases.Although the pathogenesis of inflammatory bowel disease(IBD)is unknown,it is thought to result from complex interactions between environmental factors and microbiota in the gut of individuals who are genetically susceptible.Several bacterial and viral agents have been implicated in the aetiology of IBD.In theory,H.pylori infection could be involved in the pathogenesis of IBD by inducing alterations in gastric and/or intestinal permeability or by causing immunological derangements resulting in absorption of antigenic material and autoimmunity via various immunological pathways.Similar mechanisms may also be responsible for the co-existence of IBD with other autoimmune diseases and/or extra-intestinal manifestations.However,the epidemiological data fail to support this association.Infact,various studies indicate that the prevalence of H.pylori infection is low in patients with IBD,suggesting a protective role for this infection in the development of IBD.In this report,we aim to shed light on proposed mechanisms and confounding factors underlying the potential link between H.pylori infection and IBD.     

To be or not to be:The host genetic factor and beyond in Helicobacter pylori mediated gastro-duodenal diseases

Helicobacter pylori(H.pylori)have long been associated with a spectrum of disease outcomes in the gastroduodenal system.Heterogeneity in bacterial virulence factors or strains is not enough to explain the divergent disease phenotypes manifested by the infection.This review focuses on host genetic factors that are involved during infection and eventually are thought to influence the disease phenotype.We have summarizedthe different host genes that have been investigated for association studies in H.pylori mediated duodenal ulcer or gastric cancer.We discuss that as the bacteria co-evolved with the host;these host gene also show much variation across different ethnic population.We illustrate the allelic distribution of interleukin-1B,across different population which is one of the most popular candidate gene studied with respect to H.pylori infections.Further,we highlight that several polymorphisms in the pathway gene can by itself or collectively affect the acid secretion pathway axis(gastrin:somatostatin)thereby resulting in a spectrum of disease phenotype     

Enfermedades relacionadas con Helicobacter pylori: dispepsia, úlcera y cáncer gástrico

This article summarizes the main conclusions drawn from the presentations on Helicobacter pylori infection at Digestive Disease Week 2010. Antibiotic resistance is increasing in several countries. There is an inverse relationship between H. pylori and gastroesophageal reflux disease (GERD), although this association does not imply that H. pylori eradication favors the development of GERD. The benefit of eradication therapy in uninvestigated dyspepsia seems to be confirmed in the long term. H. pylori eradication improves symptoms in a subgroup of patients with functional dyspepsia. The frequency of idiopathic peptic ulcers seems to be increasing. H. pylori eradication eliminates almost all episodes of peptic ulcer rebleeding; nevertheless, the use of non-steroidal anti-inflammatory drugs (NSAIDS) or H. pylori reinfection can lead to bleeding recurrence. Diagnostic methods for H. pylori based on gastric biopsy have reduced sensitivity in patients with gastrointestinal bleeding. Even patients showing gastrointestinal hemorrhage while receiving NSAIDs are frequently infected. The phylogenetic origin of the H. pylori strain predicts the development of preneoplastic gastric lesions. The electrochemical properties of H. pylori allow these lesions to be rapidly and accurately detected in gastric biopsies. The rapid urease test, including biopsies from both antrum and body, increases sensitivity and allows results to be obtained more quickly. Although confirmation of H. pylori eradication is recommended, in clinical practice, this recommendation is frequently not carried out. Narrow-band imaging allows the change in mucous and vascular pattern after eradication to be confirmed. An association between H. pylori infection and iron deficiency anemia, arteriosclerosis, obesity and adenomas/colorectal tumors has been suggested but remains to be confirmed. The efficacy of “traditional” triple therapies currently leaves much to be desired but could be increased by the use of high-dose proton pump inhibitors and antibiotics and/or increased duration of therapy. The new single-capsule preparation combining bismuth, tetracycline and metronidazole simplifies administration of quadruple therapy. The superiority of “sequential” therapy over the standard triple therapy should be confirmed in different environments. A hybrid sequential-concomitant therapy is a potentially useful alternative. The new sustainedrelease formulation antibiotics have shown promising results. Second-line rescue therapy with levofloxacin is effective and is also simpler and better tolerated than quadruple therapy. In patients allergic to penicillin, a combination with levofloxacin and clarithromycin is a promising rescue alternative. The new-generation quinolones, such as sitafloxacin, could be useful in third-line eradication therapy. Because H. pylori infection does not confer protection, reinfection can occur more than once with the same strain, which could allow the use of this bacterium as a vector for the administration of various vaccines on multiple occasions.     

Genomic fingerprinting and genotyping of Helicobacter pylori strains from patients with duodenal ulcer or gastric cancer from different geographic regions

Continuing attempts have been made to classify pathogenic strains within bacterial populations based on DNA fingerprints and to identify virulence factors in H. pylori. We studied 287 H. pylori isolates from patients with duodenal ulcer or gastric cancer from three different geographic regions. DNA fingerprints were generated using REP-PCR and analyzed by cluster analysis. The status of three candidate virulence factors—vacA polymorphism, cagA and iceA,—were examined by PCR amplification. Cluster analysis of the REP-PCR fingerprints showed clustering by geographic region but not by disease presentation. cagA was detected in 91.3% of the isolates. Differences in vacA subtypes were observed among the three geographic regions. There was no association between iceA subtypes and clinical outcome. We conclude that geographic differences among the H. pylori strains exist in single gene allelic variants as well as in the conserved noncoding regions such as REP sequences throughout the entire bacterial genome. We did not detect any association between disease presentation and H. pylori genotypes using either DNA fingerprinting or candidate single gene virulence factors.     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection and gastric cancer: Host,bug, environment,or all three?

Helicobacter pylori is a common bacterial pathogen that colonizes the gastric mucosa of over 50% of the world’s population. All infected individuals exhibit chronic gastric inflammation, and approximately 1% of patients develop gastric cancers, including adenocarcinomas and mucosal-associated lymphoid tissue lymphomas. In 1994, the World Health Organization International Agency for Research on Cancer classified H. pylori as a type I, or definite carcinogen. Because the prevalence of gastric cancers among H. pyloriinfected patients varies between individuals, countries, and geographic areas, H. pylori disease-related outcomes are believed to be determined by an interplay between host factors, bacterial factors, and their interaction with the environment. This review highlights recent advances in our knowledge on H. pylori disease pathogenesis, focusing on the role of the host, bacteria, and environment in the development of gastric carcinoma.