Gastric campylobacter-like organisms: their role in gastric disease of laboratory animals

Campylobacter pylori, first isolated in 1982, is now recognized as a primary cause of acute gastritis in man, and there is substantial data suggesting that this organism also plays an important role in the pathogenesis of duodenal ulcers. More recently, Campylobacter-like organisms and other morphologically distinct spiral bacteria have been isolated from gastric lesions in a variety of laboratory animal species. The zoonotic significance of C. pylori and other gastric spiral bacteria isolated from man as well as laboratory and domestic animals requires further study. An appreciation of the ecological and pathological role of gastric spiral bacteria in domestic and laboratory animals is an essential first step when considering the role and proper selection of animal models in the study of C. pylori gastroduodenal disease.     

Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis

Helicobacter pylori represents a highly successful human microbial pathogen that infects the stomach of more than half of the world's population. H. pylori induces gastric inflammation, and the diseases that can follow such infection include chronic gastritis, peptic ulcers and, more rarely, gastric cancer. The reasons why a minority of patients with H. pylori develops gastric cancer could be related to differences in host susceptibility, environmental factors and the genetic diversity of the organism. This review examines the features of H. pylori-induced epithelial cell signalling in gastric diseases. Clinical studies and animal models, and also evidence for H. pylori strain-related differences in gastric epithelial cell proliferation in vivo are discussed. In addition, the mechanisms by which H. pylori triggers hyperproliferative processes and takes direct command of epithelial cell signalling, including activation of tyrosine kinase receptors, cell-cell interactions and cell motility are reviewed.     

Immunoproteomics of Helicobacter pylori infection and relation to gastric disease

The Gram negative bacterium Helicobacter pylori is a human pathogen which infects the gastric mucosa and causes an inflammatory process leading to gastritis, ulceration and cancer. A systematic, proteome based approach was chosen to detect candidate antigens of H. pylori for diagnosis, therapy and vaccine development and to investigate potential associations between specific immune responses and manifestations of disease. Sera from patients with active H. pylori infection (n = 24), a control group with unrelated gastric disorders (n = 12) and from patients with gastric cancer (n = 6) were collected and analyzed for the reactivity against proteins of the strain HP 26695 separated by two-dimensional electrophoresis. Overall, 310 antigenic protein species were recognized by H. pylori positive sera representing about 17% of all spots separated. Out of the 32 antigens most frequently recognized by H. pylori positive sera, nine were newly identified and 23 were confirmed from other studies. Three newly identified antigens which belong to the 150 most abundant protein species of H. pylori, were specifically recognized by H. pylori positive sera: the predicted coding region HP0231, serine protease HtrA (HP1019) and Cag3 (HP0522). Other antigens were recognized differently by sera from gastritis and ulcer patients, which may identify them as candidate indicators for clinical manifestations. The data from these immunoproteomic analyses are added to our public database (http://www.mpiib-berlin.mpg.de/2D-PAGE). This platform enables one to compile many protein profiles and to integrate data from other studies, an approach which will greatly assist the search for more immunogenic proteins for diagnostic assays and vaccine design.     

Effect of Helicobacter pylori Eradication on Incidence of Gastric Cancer in Human and Animal Models: Underlying Biochemical and Molecular Events

Background:  Gastric cancer remains one of the most common cancers worldwide. A strong association exists between Helicobacter pylori infection and the risk of developing noncardia gastric cancer. H. pylori eradication by antibiotic treatment is regarded as a primary chemoprevention strategy to reduce gastric cancer incidence.
Aim:  To analyze the efficacy of H. pylori eradication in preventing gastric cancer in human and animal models, and to discuss whether biochemical, genetic, and epigenetic changes associated with H. pylori infection are reversible after curing the infection.
Results:  Several intervention trials have indicated that in some patients, H. pylori eradication leads to regression and prevents the progression of precancerous lesions. The eradication therapy reduces gastric cancer incidence in patients without any precancerous lesions at the baseline and is most effective before the development of atrophic gastritis. A few recent intervention studies in Japan have demonstrated significant prophylactic effects of eradication therapy on the development of gastric cancer, suggesting the use of eradication therapy in high-risk populations as a gastric cancer reduction strategy. However, gastric cancer may still develop despite successful eradication therapy. Studies in animal models have confirmed the use of eradication therapy at an early point of infection to prevent gastric cancer development.
Conclusion:  H. pylori eradication may not completely abolish the risk of gastric cancer. However, eradication therapy may be used in high-risk populations to reduce gastric cancer incidence. It can reverse many biochemical, genetic, and epigenetic changes that H. pylori infection induces in the stomach.     

Cell envelope characteristics of Helicobacter pylori: their role in adherence to mucosal surfaces and virulence

Abstract Helicobacter pylori colonises the gastric mucosa of humans and causes both antral gastritis and duodenal ulcer disease. Exactly how H. pylori causes disease is not known but several pathogenic determinants have been proposed for the organism. These include adhesins, cytotoxins and a range of different enzymes including urease, catalase and superoxide dismutase. Surface molecules of H. pylori such as flagella, lipopolysaccharide, the urease enzyme and outer membrane proteins are putative adhesin molecules. While phosphatidylethanolamine and the Lewis^b blood group antigen have been proposed as receptor molecules for the organism the exact mechanism by which H. pylori adheres to the gastric mucosa has still to be identified. Characterisation of the adhesins of H. pylori could lead to the development of adhesin analogues for use in the inhibition of colonisation and improved therapy for ulcer disease. In vivo studies with isogenic mutants which are incapable of adhering to the gastric mucosa would greatly clarify the significance of adherence. Such mutants could possibly be useful as a vaccine against infection with wild-type organisms.     

幽门螺杆菌过氧化氢酶基因的克隆、序列测定及其生物信息学分析

幽门螺杆菌(Helicobacter pylorl,Hp)感染是慢性活动性胃炎和消化性溃疡的主要病因,与胃腺癌、胃粘膜相关淋巴样组织(MALT)淋巴瘤的发生亦密切相关。其有效抗原成份过氧化氢酶可刺激机体产生保护性的免疫反应。用高保真PCR扩增系统扩增出过氧化氢酶基因片段,将其定向插入载体pET-22b( ),对其全序列进行了测定。并以生物信息学软件分析其生物学特性。克隆的过氧化氢酶基因序列与报道的序列完全一致,并显示出良好的抗原性和疏水性。这一研究获得了序列正确的过氧化氢酶基因,为将来以过氧化氢酶分子作抗原的Hp疫苗研制工作打下了良好基础。     

幽门螺杆菌保护性抗原研究进展

幽门螺杆菌是一种与慢性胃炎、胃溃疡及胃癌的发生密切相关的致病菌。疫苗是预防和控制传染病的有效途径,筛选出幽门螺杆菌保护性抗原是设计和构建幽门螺杆菌疫苗的关键。本对与幽门螺杆菌粘附、定植及与其毒素相关的保护性抗原做一概述。     

The C-terminally encoded, MHC class II-restricted T cell antigenicity of the Helicobacter pylori virulence factor CagA promotes gastric preneoplasia

Chronic infection with the human bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to an increased gastric cancer risk. Consequently, H. pylori-specific vaccination is widely viewed as a promising strategy of gastric cancer prevention. H. pylori strains harboring the Cag pathogenicity island (PAI) are associated with particularly unfavorable disease outcomes in humans and experimental rodent models. We show in this study using a C57BL/6 mouse model of Cag-PAI(+) H. pylori infection that the only known protein substrate of the Cag-PAI-encoded type IV secretion system, the cytotoxin-associated gene A (CagA) protein, harbors MHC class II-restricted T cell epitopes. Several distinct nonoverlapping epitopes in CagA's central and C-terminal regions were predicted in silico and could be confirmed experimentally. CagA(+) infection elicits CD4(+) T cell responses in mice, which are strongly enhanced by prior mucosal or parenteral vaccination with recombinant CagA. The adoptive transfer of CagA-specific T cells to T cell-deficient, H. pylori-infected recipients is sufficient to induce the full range of preneoplastic immunopathology. Similarly, immunization with a cholera toxin-adjuvanted, CagA(+) whole-cell sonicate vaccine sensitizes mice to, rather than protects them from, H. pylori-associated gastric cancer precursor lesions. In contrast, H. pylori-specific tolerization by neonatal administration of H. pylori sonicate in conjunction with a CD40L-neutralizing Ab prevents H. pylori-specific, pathogenic T cell responses and gastric immunopathology. We conclude that active tolerization may be superior to vaccination strategies in gastric cancer prevention.     

Helicobacter pylori gastritis: a Th1 mediated disease?

Helicobacter pylori is now considered to be the main cause for most stomach diseases including ulcer, MALT lymphoma, adenocarcinoma and gastritis. The infection with this bacterium is chronic despite a local and systemic immune response towards it. Among the cellular infiltrate that arises during H. pylori-mediated gastritis, there is a considerable frequency of CD4+ Th1 cells producing IFNgamma, but not of Th2 cells producing IL-4. Since IFNgamma may induce binding of H. pylori to gastric epithelial cells followed by apoptosis of these cells, one may speculate that H. pylori-mediated diseases are in part autoimmune diseases initiated by H. pylori-specific Th1 cells infiltrating the gastric mucosa. Recent support for this hypothesis comes from an animal model in which mice are infected with H. pylori and display strongly reduced gastritis in the absence of IFNgamma.     

Subtractive hybridization analysis of gastric diseases-associated Helicobacter pylori identifies peptidyl-prolyl isomerase as a potential marker for gastric cancer

Helicobacter pylori, a microaerophilic Gram-negative bacterium, is known to cause chronic gastritis, peptic ulcer and gastric cancer. Genes that are present in certain isolates may determine strain-specific traits such as disease association and drug resistance. In order to understand the pathogenic mechanisms of gastric diseases, identify molecular markers of the diseases associated with H. pylori strains and provide clues for target treatment of H. pylori-related diseases, a subtracted DNA library was constructed from a gastric cancer-associated H. pylori strain and a superficial gastritis-associated H. pylori strain by suppression subtractive hybridization. The presence of gastric cancer-specific genes was identified by dot blot hybridization, DNA sequencing and PCR-based screening. Twelve gastric cancer-specific high-copy genes and nine low-copy genes were found in gastric cancer compared with the superficial gastritis strain. These genes were confirmed by PCR analysis of H. pylori isolates. Notably, peptidyl-prolyl cis-trans isomerase (PPIase) was detected positively in 11 out of 22 (50%) gastric cancer-associated H. pylori strains. In contrast, <24% of the H. pylori strains from superficial gastritis showed positive results. Given the potential role of PPIases in cell growth, apoptosis and oncogenic transformation, our results suggest that PPIase may represent a novel marker and potential therapeutic target for gastric cancer.     

幽门螺杆菌毒力基因分型和宿主遗传多态性与胃病关系研究进展

幽门螺杆菌(Helicobacter pylori)感染能导致慢性胃炎、消化性溃疡、胃粘膜相关的淋巴样组织(Mu-cosa-associated lymphoid tissue,MALT)淋巴瘤和胃腺癌等疾病的发生。1994年世界卫生组织国际癌症研究中心(IARC)将H.pylori列为胃癌第一级因子。H.pylori感染引起的不同临床结局主要与H.pylori致病因子和宿主遗传易感性有关,大部分重大疾病发生在特定的细菌毒力因子(如cagA,vacA)与易感宿主遗传背景共同存在时。文章综述了H.pylori菌株的毒力基因的分型和宿主的遗传多态性对胃病发生的影响。     

Experimental Helicobacter pylori infection induces antral-predominant, chronic active gastritis in hispid cotton rats (Sigmodon hispidus)

BACKGROUND: The hispid cotton rat has proven to be an excellent animal model for a variety of human infectious disease agents. This study was performed to evaluate the use of the cotton rat as a model of Helicobacter pylori infection. MATERIALS AND METHODS: Thirty-eight inbred cotton rats were orogastrically inoculated with a human strain of H. pylori. Twenty-eight control cotton rats were dosed with vehicle only. Animals were sacrificed at 2, 4, 12, 26, or 38 weeks after inoculation for bacterial and histologic and immunologic examinations. RESULTS: Helicobacter pylori was cultured from the glandular stomach of 89% of the infected cotton rats. The level of colonization was consistently high (approximately 10(4-6) colony-forming units/g tissue). Histologically, the spiral bacteria were demonstrated on the epithelial surface and in the foveolae of the gastric mucosa with highest numbers in the antrum. H. pylori infection was associated with antral-predominant, chronic active gastritis which progressively increased in severity over time. By week 26 of infection, moderate antral gastritis had developed with frequent involvement of the submucosa and formation of lymphocytic aggregates. Splenic T cells from infected cotton rats expressed mRNAs for interferon-gamma, interleukin-4, interleukin-6, and interleukin-10 following in vitro stimulation with H. pylori. Serum levels of H. pylori-specific immunoglobulin G were significantly elevated after 12 weeks of infection. CONCLUSIONS: The H. pylori-infected cotton rat represents a novel animal model that should prove useful for studies of H. pylori-induced chronic active gastritis and factors affecting gastric colonization by this pathogen.     

Helicobacter pylori modulation of gastric acid

Helicobacter pylori plays major causative roles in peptic ulcer disease and gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs) contributes to duodenal injury, and diminished acid secretion in patients with gastric cancer allows carcinogen-producing bacteria to colonize the stomach. Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU patients and hypo-secreting relatives of gastric cancer patients. Therefore, we and others have asked how H. pylori causes these disparate changes in acid secretion. H. pylori gastritis more or less restricted to the gastric antrum in DU patients is associated with increased acid secretion. This is probably because gastritis increases release of the antral acid-stimulating hormone gastrin and diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines including TNFalpha may cause these changes in endocrine function. Gastritis involving the gastric corpus tends to diminish acid secretion, probably because bacterial products and cytokines including IL-1 inhibit parietal cells. Pharmacological inhibition of acid secretion increases corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric hypo-secretion of any cause might become self-perpetuating. H. pylori-associated mucosal atrophy will also contribute to acid hypo-secretion and is more likely in when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric acid secretion in patients with esophagitis are limited but suggest that acid secretion is normal or slightly diminished. Nevertheless, H. pylori infection may be relevant to the management of esophagitis because: (i) H. pylori infection increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump inhibitors may increase the tendency of H. pylori to cause atrophic gastritis; and (iii) successful eradication of H. pylori is reported to increase the likelihood of esophagitis developing in patients who had DU disease. Points (ii) and (iii) remain controversial and more work is clearly required to elucidate the relationship between H. pylori, acid secretion, gastric mucosa atrophy and esophagitis.     

Mucosal production of antigastric autoantibodies in Helicobacter pylori gastritis

Background. Apart form bacterial virulence factors of Helicobacter pylori , certain host factors influence the pathogenesis of H. pylori gastritis. In particular, antigastric autoantibodies that are detectable in the sera of a substantial proportion of H. pylori were shown to correlate with the development of gastric atrophy. The aim of this study was to analyze the possible antigastric autoimmune response in H. pylori gastritis at the site where the action is, i.e., in the gastric mucosa.
Material and Methods. Gastric biopsy specimens from antrum and corpus mucosa of 24 H. pylori –infected and of 33 noninfected patients were cultured for 3 days, and tissue culture supernatants were analyzed for the amount of locally produced IgA and IgG. Antigastric autoantibodies were screened in the sera and in the supernatants by means of immunohistochemistry.
Results. The infected patients had significantly higher concentrations of locally produced IgA, whereas the IgG concentrations were virtually the same in infected and noninfected patients. IgG or IgA antigastric autoantibodies, or both, were detectable only in the sera (38%) and supernatants (17%) of infected patients. Interestingly, the patient with the strongest local autoimmune response showed body-predominant H. pylori gastritis, with destruction of gastric glands and atrophy of the body mucosa.
Conclusions. These results demonstrate that antigastric autoimmune reactions are detectable at the site of the disease and might be relevant for the pathogenesis of gastric mucosa atrophy in H. pylori gastritis.     

Helicobacter pylori infection as a cause of gastritis,duodenal ulcer,gastric cancer and nonulcer dyspepsia: a systematic overview.

OBJECTIVE: To evaluate current evidence for a causal relation between Helicobacter pylori infection and gastritis, duodenal ulcer, gastric cancer and nonulcer dyspepsia. DATA SOURCES: A MEDLINE search for articles published in English between January 1983 and December 1992 with the use of MeSH terms Helicobacter pylori, gastritis, duodenal ulcer, gastric cancer, dyspepsia and clinical trial; abstracts were excluded. Six journals and Current Contents were searched manually for pertinent articles published in that time frame. STUDY SELECTION: Original studies with at least 25 patients, case reports and reviews that examined the relation between H. pylori and the four gastrointestinal disorders; 350 articles were on gastritis, 122 on duodenal ulcer, 44 on gastric cancer and 96 on nonulcer dyspepsia. DATA EXTRACTION: The quality of the studies was rated independently on a four-point scale. The strength of the evidence was assessed using a six-point scale for each of the eight established guidelines for determining a causal relation. DATA SYNTHESIS: There was conclusive evidence of a causal relation between H. pylori infection and histologic gastritis. Koch''s postulates for the identification of a microorganism as the causative agent of a disease were fulfilled for H. pylori as a causative agent of gastritis. There was strong evidence that H. pylori is the main cause of duodenal ulcers not induced by nonsteroidal anti-inflammatory drugs, but all of Koch''s postulates were not fulfilled. There was moderate epidemiologic evidence of an association between chronic H. pylori infection and gastric cancer. There was a lack of convincing evidence of a causal association between H. pylori and nonulcer dyspepsia. CONCLUSIONS: The evidence supports a strong causal relation between H. pylori infection and gastritis and duodenal ulcer and a moderate relation between such infection and gastric cancer. Further studies are needed to clarify the role of H. pylori in these disorders. Thus far, there is no evidence of a causal relation between H. pylori and nonulcer dyspepsia.     

Gastric autoimmunity: the role of Helicobacter pylori and molecular mimicry

Pathogens can induce autoreactive T cells to initiate autoimmune disease by several mechanisms. Pathogen-induced inflammation results in the enhanced presentation of self antigens, which causes the expansion of the activated autoreactive T cells that are required for disease onset. Alternatively, a pathogen might express antigens with epitopes that are structurally similar to epitopes of autoantigens, resulting in a mechanism of molecular mimicry. This is the case for Helicobacter pylori-associated human autoimmune gastritis, in which the activated CD4+ Th1 cells that infiltrate the gastric mucosa cross-recognize the epitopes of self gastric parietal cell H(+)K(+)-ATPase and of various H. pylori proteins. Therefore, in genetically susceptible individuals, H. pylori infection can start or worsen gastric autoimmunity, leading to atrophic gastritis.     

IV. Helicobacter pylori strain-specific activation of signal transduction cascades related to gastric inflammation

Helicobacter pylori strains that possess the cag pathogenicity island induce more severe gastritis and augment the risk of developing peptic ulcer disease and distal gastric cancer. A specific mechanism by which cag(+) strains may enhance gastritis is strain-selective regulation of interleukin (IL)-8 production. On contact with gastric epithelial cells, H. pylori activates multiple signal transduction cascades that regulate IL-8 secretion, including nuclear factor-kappaB and mitogen-activated protein kinases, and these events are dependent on genes within the cag island. An independent effect of cag-mediated cellular contact is translocation and phosphorylation of H. pylori proteins within the host epithelial cell. The redundancy of intracellular signaling cascades activated by H. pylori and the divergent epithelial cell responses induced by components of the cag island may contribute to the ability of this organism to persist for decades within the gastric niche.     

Helicobacter pylori. One bacterium and a broad spectrum of human disease! An overview.

Since the historical rediscovery of gastric spiral Helicobacter pylori in the gastric mucosa of patients with chronic gastritis by Warren and Marshall in 1983, peptic ulcer disease has been largely viewed as being of infectious aetiology. Indeed, there is a strong association between the presence of H. pylori and chronic active gastritis in histology. The bacterium can be isolated in not less than 70% of gastric and in over 90% of duodenal ulcer patients. Eradication of the organism has been associated with histologic improvement of gastritis, lower relapse rate and less risk of bleeding from duodenal ulcer. The bacterium possesses several virulence factors enabling it to survive the strong acid milieu inside the stomach and possibly damaging host tissues. The sequence of events by which the bacterium might cause gastric or duodenal ulcer is still not fully elucidated and Koch's postulates have never been fulfilled. In the majority of individuals, H. pylori infection is largely or entirely asymptomatic and there is no convincing data to suggest an increase in the prevalence of peptic ulcer disease among these subjects. An increasingly growing body of literature suggests an association between colonization by H. pylori in the stomach and a risk for developing gastric mucosa-associated lymphoid tissue (MALT), MALT lymphoma, gastric adenocarcinoma and even pancreatic adenocarcinoma. The bacterium has been implicated also in a number of extra-gastrointestinal disorders such as ischaemic heart disease, ischaemic cerebrovascular disease, atherosclerosis, and skin diseases such as rosacea, but a causal role for the bacterium is missing. Eradication of H. pylori thus seems to be a beneficial impact on human health. Various drug regimens are in use to eradicate H. pylori involving the administration of three or four drugs including bismuth compounds, metronidazole, clarithromycin, tetracyclines, amoxycillin, ranitidine, omeprazole for 1-2 weeks. The financial burden, side effects and emergence of drug resistant strains due to an increase in the use in antibiotics for H. pylori eradication therapy need further reconsideration.     

Four modes of adhesion are used during Helicobacter pylori binding to human mucins in the oral and gastric niches

Background:  Helicobacter pylori causes peptic ulcer disease and gastric cancer, and the oral cavity is likely to serve as a reservoir for this pathogen. We investigated the binding of H. pylori to the mucins covering the mucosal surfaces in the niches along the oral to gastric infection route and during gastric disease and modeled the outcome of these interactions.
Materials and Methods:  A panel of seven H. pylori strains with defined binding properties was used to identify binding to human mucins from saliva, gastric juice, cardia, corpus, and antrum of healthy stomachs and of stomachs affected by gastritis at pH 7.4 and 3.0 using a microtiter-based method.
Results:  H. pylori binding to mucins differed substantially with the anatomic site, mucin type, pH, gastritis status, and H. pylori strain all having effect on binding. Mucins from saliva and gastric juice displayed the most diverse binding patterns, involving four modes of H. pylori adhesion and the MUC5B, MUC7, and MUC5AC mucins as well as the salivary agglutinin. Binding occurred via the blood-group antigen-binding adhesin (BabA), the sialic acid-binding adhesin (SabA), a charge/low pH-dependent mechanism, and a novel saliva-binding adhesin. In the healthy gastric mucus layer only BabA and acid/charge affect binding to the mucins, whereas in gastritis, the BabA/Le^b-dependent binding to MUC5AC remained, and SabA and low pH binding increased.
Conclusions:  The four H. pylori adhesion modes binding to mucins are likely to play different roles during colonization of the oral to gastric niches and during long-term infection.