Search

A subset of myeloid-derived suppressor cells (MDSCs) that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter-inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia. We propose that individuals with a more robust response to damage-activated molecular patterns and increased Toll-like receptor 9 (TLR9) expression are predisposed to the neoplastic complications of Helicobacter infection.A mouse or human Transwell co-culture system composed of dendritic cells (DCs), 2-dimensional gastric epithelial monolayers, and Helicobacter were used to dissect the cellular source of interferon-α (IFNα) in the stomach by flow cytometry. Conditioned media from the co-cultures polarized primary myeloid cells. MDSC activity was determined by T-cell suppression assays. In human subjects with intestinal metaplasia or gastric cancer, the rs5743836 TLR9TC variant was genotyped and linked to TLR9, IFNα, and SLFN12L expression by immunohistochemistry. Nuclear factor-κB binding to the TLR9 C allele was determined by electrophoretic mobility shift assays.Helicobacter infection induced gastric epithelial and plasmacytoid DC expression of TLR9 and IFNα. Co-culturing primary mouse or human cells with DCs and Helicobacter induced TLR9, IFNα secretion, and SLFNTLR9 plays an essential role in the production of IFNα and polarization of SLFN

Background & Aims: The MUC1 mucin is expressed on the cell surface of epithelial cells lining the gastric mucosa. Epidemiologic studies suggest that functional allelic variations in the MUC1 gene may play a role in human susceptibility to Helicobacter pylori-associated pathologies, including gastric adenocarcinoma. We have evaluated the impact of Muc1 expression on the colonization and pathogenesis of gastric Helicobacter infections. Methods: Wild-type and Muc1-deficient mice were infected with H pylori and colonization and gastritis levels determined. Primary gastric cells were used to examine the impact of Muc1 expression on bacterial adherence. Results: Mice lacking Muc1 were colonized by 5-fold more H pylori within 1 day of infection, and this difference was maintained for at least 2 months postinfection. Mice heterozygous for the null Muc1 allele developed intermediate bacterial colonization. Although wild-type mice developed only a mild gastritis when infected for 2 months with H pylori, Muc1−/− mice developed an atrophic gastritis marked by loss of parietal cells. We demonstrate H pylori adhesion to purified MUC1 and significantly increased adhesion to cultured murine Muc1 null gastric epithelial cells, suggesting that Muc1 acts as a decoy limiting binding to the cell surface. Conclusions: Muc1 provides a protective barrier, which limits both acute and chronic colonization by H pylori, as well as playing a major role in limiting the inflammation induced by Helicobacter infection. We propose that Muc1 restricts access of H pylori to the epithelial surface, hence reducing exposure of the host to proinflammatory bacterial products.

Despite the proven ability of immunization to prevent Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive.We explored the cellular events associated with Helicobacter clearance from the stomach following vaccination by flow cytometry analysis and histological and molecular studies.Kinetic studies showed that the infection is undetectable in vaccinated mice at day 5 postbacterial challenge. Flow cytometry analysis showed that the percentages of mast cells (CD3 - CD117 + ) increased in the lymphoid cells isolated from the stomach at day 4 postchallenge in urease + cholera toxin (CT)-vaccinated mice in comparison with mice administered with CT alone (9.4% +/- 4.4% and 3.1% +/- 1%, respectively, for vaccinated and CT administered, n = 5; P.01). Quantitative PCR analysis showed an increased messenger RNA (mRNA) expression of the mast cell proteases 1 and 2 at day 5 postchallenge in the stomach of vaccinated mice. In contrast to wild-type mice, mast cell-deficient mice (W/W v mice) were not protected from H felis colonization after vaccination. Indeed only 1 out of 12 vaccinated W/W v mice showed a negative urease test. Remarkably, vaccinated W/W v mice reconstituted with cultured bone marrow-derived mast cells recovered the ability to clear the infection after vaccination (8 out of 10 mast cell-reconstituted mice showed negative urease tests [ P.006 as compared with wild-type mice]).These experiments show that mast cells are, unexpectedly, critical mediators of anti- Helicobacter vaccination.

Background & Aims: Helicobacter pylori is an important etiologic factor in the development of gastric cancer. The aim of this study was to analyze the role of H. pylori infections in the induction of mutagenic events in gastric epithelial cells. The effect of a high-salt diet as a genotoxic risk factor was also investigated. Methods: Big Blue transgenic male mice (C57Bl/6) were inoculated with H. pylori (strain SS1) or Helicobacter felis (strain CS1) for 6 and 12 months. The frequency and spectrum of mutations at the stomach level were assessed. Inflammatory host response and inducible nitric oxide synthase (iNOS) expression by reverse-transcription polymerase chain reaction and immunohistochemistry analysis were also performed. Results: After 6 months, the gastric mutant frequency was 4-fold and 1.7-fold higher in mice infected with H. pylori and H. felis , respectively, than in uninfected mice. It was associated with a high frequency of transversions (AT → CG and GC → TA) known to result from oxidative damages. The Helicobacter -infected mice exhibited severe gastritis and a high level of iNOS messenger RNA expression. Hyperplasia developed 12 months after inoculation, and both the mutagenic effects and iNOS expression decreased in H. pylori - and H. felis -infected mice. No synergistic effects of a high-salt diet and Helicobacter infection were observed regarding the frequency of gastric mutation. Conclusions: A direct gastric mutagenic effect due to H. pylori infection in the Big Blue transgenic mouse model has been shown 6 months after inoculation. This genotoxicity can be attributable to oxidative DNA damage involving the inflammatory host response.

The most common primary lymphoma of the gastrointestinal tract is B-cell lymphoma arising from mucosa-associated lymphoid tissue known as MALT lymphoma. Although the majority of these lesions affect the stomach and are associated with Helicobacter pylori organisms, sites other than the gastrointestinal tract may be affected. This case report describes a patient with concomitant laryngeal MALT lymphoma and Helicobacter pylori-related gastric MALT lymphoma derived from the same clone as confirmed by PCR. Treatment of Helicobacter pylori infection in this patient using antibiotics led to regression of both lesions. This patient remains in remission at 46-month follow-up. This is the first case report on the regression of a laryngeal MALT lymphoma after Helicobacter pylori eradication. We suggest that all patients presenting with extragastric MALT lymphoma should undergo upper gastrointestinal endoscopy with gastric biopsies for the determination of Helicobacter pylori status and presence of concomitant gastric MALT lymphoma, followed by a course of anti-Helicobacter pylori antibiotic therapy. Nonresponders may subsequently be considered for surgery and/or chemo/radiation therapy.

Background & Aims: Recently, a number of animal models for different aspects of inflammatory bowel disease (IBD) have been developed. The aim of this study was to use one of these to determine whether particular, ostensibly innocuous, intestinal bacteria could provoke or exacerbate IBD. Methods: Conventionally reared C.B17 SCID mice were compared with germ-free and gnotobiotic mice, monoassociated with 1 of 5 intestinal bacteria, after transfer of CD45RBhigh CD4+ T cells from conventionally reared congenic BALB/c mice. Recipient mice were monitored over 7–12 weeks for clinical signs of IBD, and tissues were analyzed by histology/flow cytometry for abnormal inflammation and CD4+ T cell outgrowth. Results: Neither germ-free mice nor mice monoassociated with segmented filamentous bacteria, Ochrobactrum anthropi, a nonpathogenic mutant of Listeria monocytogenes, or Morganella morganii developed any signs of IBD. In contrast, mice monoassociated with Helicobacter muridarum displayed an accelerated development of IBD in 5–6 weeks compared with 8–12 weeks observed in conventionally reared mice. The outgrowth of CD4+ T cells in spleen and large intestine of H. muridarum monoassociated mice, as well as in conventionally reared mice was significantly higher than that in the other monoassociated mice. Conclusions: Among the intestinal bacteria tested, H. muridarum can serve as a provocateur of IBD in this model. GASTROENTEROLOGY 2002;122:1346-1354

Background & Aims: Cure of Helicobacter pylori infection may lead to complete remission of associated low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in stage EI. This study investigated whether Helicobacter heilmannii infection–associated primary gastric MALT lymphoma will regress after cure of the infection. Methods: H. heilmannii–induced gastritis was diagnosed histologically, by a new specific immunoglobulin G enzyme-linked immunosorbent assay, and with 16S ribosomal RNA amplification and sequencing in 5 consecutive patients with primary gastric MALT lymphoma clinical stage EI. Patients received 40 mg omeprazole and 750 mg amoxicillin 3 times per day for 14 days. Polymerase chain reaction (PCR) was used to detect rearrangement of immunoglobulin heavy-chain genes before treatment and during follow-up. Results: Five patients (3 men, 2 women; mean age, 65 years; range, 42–79 years) were studied. H. pylori was not detected by culture, histology, serology, or PCR. Treatment resulted in the cure of H. heilmannii infection in each case and complete histological and endoscopic remission of the tumors. Three of 5 patients showed monoclonal B cells before treatment, 2 of whom remained PCR positive. Within a median follow-up period of 24 months, no relapse of the lymphoma or reinfection with H. heilmannii occurred. Conclusions: These data suggest that gastric MALT lymphoma may arise in patients with H. heilmannii infection. Cure of this infection may lead to complete remission of the MALT lymphoma. GASTROENTEROLOGY 2000;118:821-828

Background & Aims: Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined. Methods: The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice. Results: INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor α. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (≤8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P ≤ 0.05). Conclusions: These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer. GASTROENTEROLOGY 2000;118:36-47

The gastric transitional zones are the junctional zones between the different types of mucosa: antral-body, body-cardia, and antrum-duodenum. In this article, the importance of the transitional zone in determining disease outcome, specifically duodenal ulcer, gastric ulcer, and possibly gastric cancer, is reviewed. Both gastric ulcers and duodenal ulcers are located immediately adjacent to the transitional zones. The transitional zones are dynamic rather than static areas. Local acid levels determine the behavior of Helicobacter pylori at the antral-body transitional zone and, as a consequence, the geographic distribution of gastritis in the stomach and the formation of duodenal ulcer and gastric ulcer. This review also explains that diffuse antral gastritis and multifocal atrophic gastritis are part of the same disease and not separate entities.

Background & Aims: Oral immunization with Helicobacter pylori urease can cure Helicobacter infection in animals. As a step toward therapeutic immunization in humans, the safety and immunogenicity of oral immunization with recombinant H. pylori urease were tested in H. pylori –infected adults. Methods: Twenty-six H. pylori –infected volunteers were randomized in a double-blind study to four weekly oral doses of 180, 60, or 20 mg of urease with 5 μg heat-labile enterotoxin of Escherichia coli (LT), LT alone, or placebo. Side effects and immune responses were evaluated weekly after immunization, and gastric biopsy specimens were obtained after 1 month and 6 months for histology and quantitative cultures. Results: Diarrhea was noted in 16 of 24 (66%) of the volunteers who completed the study. Antiurease serum immunoglobulin A titers increased 1.58-fold ± 0.37-fold and 3.66-fold ± 1.5-fold (mean ± SEM) after immunization with 60 and 180 mg urease, respectively, whereas no change occurred in the placebo ± LT groups ( P = 0.005). Circulating antiurease immunoglobulin A–producing cells increased in volunteers exposed to urease compared with placebo (38.9 ± 13.6/10 6 vs. 5.4 ± 3.1; P = 0.018). Eradication of H. pylori infection was not observed, but urease immunization induced a significant decrease in gastric H. pylori density. Conclusions: H. pylori urease with LT is well tolerated and immunogenic in H. pylori –infected individuals. An improved vaccine formulation may induce curative immunity. GASTROENTEROLOGY 1999;116:804-812

Background & Aims: Cancer of the gallbladder is the number one cause of cancer mortality in Chilean women. Incidence rates for this tumor vary widely on a worldwide basis, being approximately 30 times higher in high-risk than in low-risk populations, suggesting that environmental factors such as infectious microorganisms, carcinogens, and nutrition play a role in its pathogenesis. Because several Helicobacter sp. colonize the livers of animals and induce hepatitis, the aim of this study was to determine whether Helicobacter infection was associated with cholecystitis in humans. Methods: Bile or resected gallbladder tissue from 46 Chileans with chronic cholecystitis undergoing cholecystectomy were cultured for Helicobacter sp. and subjected to polymerase chain reaction (PCR) analysis using Helicobacter -specific 16S ribosomal RNA primers. Results: Recovery of Helicobacter sp. from frozen specimens was unsuccessful. However, by PCR analysis, 13 of 23 bile samples and 9 of 23 gallbladder tissues were positive for Helicobacter . Eight of the Helicobacter -specific PCR amplicons were sequenced and subjected to phylogenetic analysis. Five sequences represented strains of H. bilis , two strains of " Flexispira rappini " (ATCC 49317), and one strain of H. pullorum . Conclusions: These data support an association of bile-resistant Helicobacter sp. with gallbladder disease. Further studies are needed to ascertain whether similar Helicobacter sp. play a causative role in the development of gallbladder cancer. GASTROENTEROLOGY 1998;114:755-763

Background & Aims: Infection with Helicobacter pylori uniformly leads to a chronic superficial gastritis that may progress to atrophic gastritis, a premalignant process. A mouse model of Helicobacter felis infection was used to study possible genetic determinants of the response to infection. Methods: Three inbred mouse strains with known secretory phospholipase A 2 (sPLA 2 ) genotypes [BALB/c (+/+), C3H/HeJ (+/+), and C57BL/6 (−/−)] were orally infected with H. felis and examined longitudinally using routine histology, immunocytochemistry, electron microscopy, proliferating cell nuclear antigen, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, and Northern and Western blot studies. Results: Only the C57BL/6 strain showed increased gastric fundic proliferation and apoptosis in response to infection. In addition, the C57BL/6 mouse showed a marked loss of parietal and chief cells, along with a marked expansion of an aberrant gastric mucous cell lineage that stained positive for spasmolytic polypeptide. In contrast, no significant change in these cell types was observed in BALB/c and C3H/HeJ strains. Increased expression of sPLA 2 was observed in BALB/c and C3H/HeJ after H. felis infection, whereas sPLA 2 expression was absent in C57BL/6 mice. Conclusions: H. felis infection leads to increased apoptosis and altered cellular differentiation in the C57BL/6 mouse, a strain that lacks gastric sPLA 2 expression. Because sPLA 2 has been identified recently as the MOM1 (modifier of MIN) locus that influences polyp formation in the colon, these studies suggest that sPLA 2 may also influence the gastric epithelial response to Helicobacter infection. GASTROENTEROLOGY 1998;114:675-689

Much of what is currently accepted on the natural history of Helicobacter pylori-induced gastritis and its relationship with gastric adenocarcinoma rests on the assumption that atrophic gastritis can be correctly identified and reproducibly recognized. Recently, several studies have indicated that pathologists have a low level of agreement on this topic, and the terms "gastric atrophy" and "atrophic gastritis" remain imprecisely defined and, therefore, poorly understood. Furthermore, the genesis and progression of the atrophic changes taking place in the gastric mucosa of some, but not all, subjects infected with H. pylori are incompletely characterized. This review has three aims: (1) to briefly reexamine our current knowledge of the mechanisms involved in the injury and repair of gastric glands; (2) to present a hypothesis on the development of gastric atrophy; and (3) to propose a new, stringent definition of gastric atrophy that may be usefully applied in the clinical research arena.

BACKGROUND & AIMS: Orogastric immunization of mice with Helicobacter antigens, together with a mucosal adjuvant (cholera toxin), has been shown to confer immunity in the Helicobacter felis infection model. The aim of the study was to investigate the humoral immune responses associated with immunity and to compare these with responses in H. felis-infected mice. METHODS: Enzyme-linked immunoassays were used to characterize the antibody-secreting cells and antibodies present at mucosal and systemic sites in mice. Animals were immunized orally with either whole-cell H. felis sonicates or Helicobacter pylon urease or heat-shock proteins. RESULTS: Infection of mice with H. felis preferentially induced the recruitment of plasma cells committed to immunoglobulin (Ig) A synthesis in salivary gland and gastric tissues. Antigen-specific IgA was the major antibody class detected in mucosal secretions recovered from these tissues. In contrast, immunization of mice against H. felis infection induced the proliferation of large numbers of IgG-secreting cells, as well as the synthesis of local IgG antibodies, in the gastric mucosa of the animals. Protection against H. felis infection occurred in the absence of gastric IgA responses in sonicate-immunized mice. CONCLUSIONS: It is proposed that locally synthesized specific IgG antibodies contribute to immunity against gastric Helicobacter infection. (Gastroenterology 1997 Jul;113(1):185-94)

BACKGROUND & AIMS: Gastric histology is not well studied in patients with Crohn's disease. The aim of this study was to analyze the histological appearance of gastric mucosa in patients with Crohn's disease. METHODS: In a prospective study, biopsy specimens taken from the antrum and body of 75 patients with known Crohn's disease of the large and/or small bowel and 200 Crohn's disease-free controls were evaluated by histology and immunohistochemistry. RESULTS: Helicobacter pylori-associated gastritis was found in 25 patients with Crohn's disease (33.3%) and 78 controls (39%). In H. pylori-negative patients with Crohn's disease, a characteristic type of gastritis was found in antral biopsy specimens of 36 patients (48%) and in body biopsy specimens of 18 patients (24%). It was characterized by a focal infiltration of CD3+ lymphocytes, CD68R+ histiocytes, and, in 80% of cases, of granulocytes. Granulomas were found in 11 patients. Overall, granulomas and/or focally enhanced gastritis were observed in 76% of H. pylori-negative patients with Crohn's disease and in 0.8% of controls. There were no correlations between the occurrence of focally enhanced gastritis and clinical and laboratory findings. CONCLUSIONS: Focally enhanced gastritis is common in Crohn's disease. Its recognition should guide the clinician into further investigations in patients not yet known to have Crohn's disease. (Gastroenterology 1997 Mar;112(3):698-706)

BACKGROUND & AIMS: Swine present spontaneously peptic ulcer in the gastric pars esophagea and are frequently colonized by a spiral bacterium that is of the same species as Helicobacter heilmannii type 1. This organism is also observed in the gastric mucosa of patients with gastric symptoms and who present with gastritis at histology. The aim of this study was to investigate the association between the presence of H. heilmannii type 1 and lesions of the pars esophagea. METHODS: H. heilmannii type 1 infection was investigated by mouse inoculation, urease test, and carbolfuchsin stain in 20 stomachs with ulcer, 30 stomachs with preulcer lesions, and 20 stomachs with a macroscopically normal pars esophagea. RESULTS: The microorganism was more frequently found in the stomachs with ulcer (100%) and in those with preulcer lesions (90%) than in stomachs with macroscopically normal pars esophagea (35%). Histological alterations were observed in the pars esophagea and in the glandular regions of bacterium-positive stomachs. CONCLUSIONS: It has been shown that the microorganism is strongly associated with naturally occurring ulcer and preulcer lesions of the pars esophagea of swine, which raises the possibility that the bacterium is an important factor in the pathogenesis of these lesions. (Gastroenterology 1996 Jul;111(1):19-27)

BACKGROUND & AIMS: Helicobacter infection of the gastric antrum is responsible for a number of gastric disorders. Antibiotic therapy is lengthy and is not always effective. It has been shown previously that oral immunization against Helicobacter felis in mice can prevent colonization after challenge. The aim of this study was to investigate the efficacy of therapeutic immunization in eradicating an established Helicobacter infection and in reducing gastritis. METHODS: Domestic ferrets, confirmed to be infected with Helicobacter mustelae by gastric endoscopy, were orally immunized with varying doses of purified Helicobacter pylori urease in combination with the mucosal adjuvant cholera toxin. Ferrets were assessed 1 week and 6 weeks after treatment for infection and pathology. RESULTS: Therapeutic immunization eradicated Helicobacter colonization in 30% of all immunized ferrets, although there was no difference in efficacy between the varying doses of antigen tested. The difference was statistically significant when compared with animals administered cholera toxin alone or buffer (P = 0.04). The intensity of inflammation was also significantly reduced in immunized animals (P = 0.0003). CONCLUSIONS: Oral immunization with purified H. pylori urease and cholera toxin can eradicate H. mustelae in a natural host pathogen model. Oral immunization of chronically infected animals markedly reduced gastric inflammation. (Gastroenterology 1996 Jun;110(6):1770-5)

BACKGROUND & AIMS: Helicobacter pylori infection causes gastritis and peptic ulcers and is linked epidemiologically to gastric cancer. To analyze host genetic factors and the influence of Helicobacter on cell proliferation, we used an inbred and p53 hemizygous mouse model of Helicobacter felis-induced gastritis. METHODS: H. felis was inoculated by gastric intubation into SPF C57BL/6 wild-type and p53 hemizygous mice that were followed up for 1 year and compared with uninfected controls of the same genotype using histology, proliferating cell nuclear antigen (PCNA) staining, and 5-bromo-2'-deoxyuridine (BrdU) analysis. RESULTS: Infected animalls developed sustained anti-H. felis serum immunoglobulin G antibody responses. Six months after infection, both wild-type and p53 hemizygous mice showed active chronic inflammation and marked mucosal hyperplasia compared with uninfected controls. One year after infection with H. felis, the wild-type and p53 hemizygous mice showed severe adenomatous and cystic hyperplasia of the surface foveolar epithelium. BrdU uptake and PCNA staining were markedly increased in both sets of infected mice compared with controls. Infected p53 hemizygous mice had a higher proliferative index than the infected wild-type mice. CONCLUSIONS: H. felis can induce a hypertrophic gastropathy in the C57BL/6 genotype; loss of one p53 allele, although insufficient to initiate carcinogenesis at 1 year, enhances the proliferative index, which may lead to an increased risk of cancer induction. (Gastroenterology 1996 Jan;110(1):155-66)

Bacterial adhesion to mucosal surfaces is an important pathogenic mechanism for Helicobacter-induced gastritis. The aims of this study were to compare binding of selected Helicobacter mustelae and Helicobacter pylori strains to lipids extracted from HEp-2, Chinese hamster ovary, human embryonic lung cells, and ferret gastrointestinal tissues as well as to intact tissue culture cells and to analyze the fatty acids of the receptor.Thin-layer chromatography overlay binding and a receptor-based immunoassay detected adhesion of bacteria to commercial lipids and to individual species within the lipid extracts. H. mustelae binding to tissue culture cells was performed by whole cell bacterial adhesion assay.H. mustelae and H. pylori both bound to phosphatidylethanolamine and lysophosphatidylethanolamine. Adhesion of H. mustelae to intact eukaryotic cells correlated with the amount of phosphatidylethanolamine. Binding of helicobacters was greater to lipids derived from ferret antrum compared with colon (P0.05). Biochemical analysis suggested that heterogeneity in fatty acid composition of phosphatidylethanolamine could influence the degree of Helicobacter binding.Adhesion of Helicobacter strains correlates with the quantity of phosphatidylethanolamine present in the epithelial cell and with the differences in the fatty acid profile of the lipid.

Background: Helicobacter mustelae colonizes the gastric mucosa of ferrets and causes persistent chronic gastritis. Methods: Hypochlorhydria, as measured by gastric pH probe, was induced by administering oral omeprazole, a proton pump inhibitor of the parietal cell, to adult ferrets in two separate experiments. Feces of ferrets were cultured for H. mustelae before, during, and after omeprazole therapy. Results: H. mustelae was isolated in 23 of 55 (41.8%) sequential fecal samples collected during omeprazole therapy. The same ferrets with acidic gastric pH had H. mustelae isolated in 6 of 62 (9.7%) of the fecal cultures ( P H. mustelae probe confirmed the presence of the organism in both the stomach and feces of all 5 ferrets. In 4 of 5 ferrets restriction enzyme patterns of the gastric H. mustelae were identical to those of the fecal H. mustelae strains. Conclusions: Hypochlorhydria promotes fecal transmission of a gastric Helicobacter organism. The H. mustelae -colonized ferret provides an ideal model to study the epidemiology and pathogenesis of Helicobacter pylori -induced gastritis.

BACKGROUND 38; AIMS Protective immunization limits Helicobacter infection of mice by undetermined mechanisms. Protease activated receptor 2 (PAR2) signaling is believed to regulate immune and inflammatory responses. We investigated the role of PAR2 in vaccine induced immunity against Helicobacter infection. METHODS Immune responses against Helicobacter infection were compared between vaccinated PAR2 / and wild type (WT) mice. Bacterial persistence gastric pathology and inflammatory and cellular responses were assessed using the rapid urease test (RUT) histologic analyses quantitative polymerase chain reaction and flow cytometry respectively. RESULTS Following vaccination PAR2 / mice did not have reductions in Helicobacter felis infection (RUT values were 0.01±0.01 for WT mice and 0.11±0.13 for PAR2 / mice; P

Background & Aims Helicobacter pylori infection results in a diversity of pathologies, from asymptomatic gastritis to adenocarcinoma. The reason for these diverse outcomes is multifactorial and includes host factors that regulate severity of Helicobacter -induced gastritis. Protease-activated receptors (PAR) are environmental sensors that can detect tissue damage and pathogens. Whereas PAR-2 has proinflammatory activity and PAR-1 can protect the gastric mucosa against chemical damage, neither has previously been examined for their potential roles in regulating Helicobacter pathogenesis. Methods PAR-1 −/− , PAR-2 −/− , and wild-type mice were infected with H pylori for up to 2 months then colonization levels determined by colony-forming assay, gastritis by histology, and serum antibody levels by enzyme-linked immunosorbent assay. Responsiveness of primary epithelial cells to PAR-1 activation was assessed by calcium mobilization assay. Primary epithelial cells, macrophages, and dendritic cells were cocultured with H pylori and nuclear factor (NF)-κB, and cytokine secretion was determined by enzyme-linked immunosorbent assay. Results Two months postinfection, H pylori levels were significantly reduced in PAR-1 −/− and increased in PAR-2 −/− mice. This effect on colonization was inversely correlated with inflammation severity. Infection of PAR-1 −/− mice induced an increased serum antibody response. Primary epithelial cells were activated by a PAR-1-activating peptide. H pylori stimulation of primary epithelial cells, but not macrophages or dendritic cells, from PAR-1 −/− mice induced increased levels of NF-κB and the proinflammatory cytokine macrophage-inflammatory protein (MIP)-2. PAR-1 also down-regulated MIP-2 secretion in response to cag pathogenicity island activity. Conclusions PAR-1 protects the host against severe Helicobacter -induced gastritis. This may be mediated by suppressing the production of proinflammatory cytokines such as MIP-2.

A causative role is now accepted for Helicobacter (formerly Campylobacter ) pylori in type B gastritis, and evidence is accumulating that H. pylori infection plays a major contributory role in peptic ulcer disease. Preliminary studies have reported that the prevalence of H pylori infection increases with age, but detailed information on the prevalence of the bacteria in any defined population and on the factors that may influence the pattern of distribution remains scanty. In the present study, a sensitive enzyme-linked immunosorbent assay and a [ 13 C] urea breath test were used to investigate the prevalence of H. pylori infection among 485 healthy asymptomatic volunteers between the ages of 15 and 80 residing in the Houston metropolitan area. H. pylori infection was present in 52%. The prevalence of H. pylori infection increased rapidly with age at 1%/yr for the overall population. The frequency of H. pylori infection was higher in blacks (70%) than whites (34%) ( P H. pylori infection was independent of gender but was closely correlated with socioeconomic class. There were significant inverse correlations between age-adjusted frequency of H. pylori infection and income and between educational level and H. pylori infection. There was no association between H. pylori infection and consumption of alcohol or nonsteroidal antiinflammatory drug use or smoking. Having pets was associated with a lower frequency of H. pylori infection, but this was highly associated with higher socioeconomic status. The mode(s) of transmission of H. pylori is unknown, but the social patterns of H. pylori infection are consistent with fecal-oral transmission as one important pathway. Socioeconomic factors seem to determine the age of acquisition.

Helicobacter infection is the leading cause of gastric cancer worldwide. Infection with this ubiquitous bacterium incites a chronic active immune response that persists for the life of the host, in the absence of antibiotic-induced eradication. It is the combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer. Although it may seem intuitively obvious that removing the offending organism would negate the cancer risk, this approach is neither feasible (half of the world harbors this infection) nor is it straightforward. Most patients are infected in childhood, and present with various degrees of mucosal damage before any therapy. This review outlines the histologic progression of human Helicobacter infection from the early stages of inflammation through the development of metaplasia, dysplasia, and, finally, cancer. The effects of dietary and bacterial eradication therapy on disease progression and lesion reversibility are reviewed within the context of population studies and compared between study designs and populations tested. Eradication studies in the mouse model of infection prevents the formation of gastric cancer, and allows regression of established lesions, providing a useful model to study interaction between bacterium, environment, and host, without the difficulties inherent in human population studies. Recent advances in identifying the bone marrow-derived stem cell as the cell of origin of Helicobacter-induced gastric cancer in the murine model are discussed and interpreted in the context of human disease, and implications for future treatment are discussed.

Objective of the study: Since 2013, H. pylori eradication therapy for atrophic gastritis associated with H. pylori became available for coverage by insurance in Japan. For first-line therapy, triple eradication therapy (proton pump inhibitor (PPI) + amoxicillin (AMPC) + clarithromycin (CAM) is available for H. pylori eradication, in Japan. The resistance of H. pylori strains to CAM accounts for the majority of eradication failures, the incidence of which is currently increasing and it affects H. pylori eradication rate in Japan. Another matter is recurrence of H. pylori infection after eradication. H. pylori infection sometimes recurs after successful eradication. The rate of recurrence after successful eradication is reported to be 0.5% to 2.0% in the western countries. In this study, we investigated about the long term transition of primary drug susceptibility ofH. pylori strains to CAM, and the rate of recurrence after successful eradication in Japan.Methods: Three hundred sixty six patients after successful eradication of H. pylori were followed up by culture, histological examination and urea breath tests. In 22 patients in whom H. pylori recurred during follow-up, the susceptibility of the H. pylori strains to clarithromycin was investigated. And in 17 recurrent patients, H. pylori strains isolated initially and after recurrence were compared using PCR-based restriction fragment length polymorphism (RFLP) analysis. Results: The primary resistance of H. pylori to CAM is increasing, especially in these 6 years, its rate is very high at 35%. Ten of 22 (45.5%) recurrences appeared at 6 months after successful eradication of H. pylori, and after 1 year, the annual recurrence rate of H. pylori infection was 0.29% per patient year. In recurrent cases, 50.0% (5/10) of the strains detected 6 months after successful eradication were found to be susceptible to clarithromycin. And 58.3% (7/12) of the strains detected at 12 months or later were found to be susceptible to clarithromycin. In the 10 patients who showed a recurrence of H. pylori after 12 months, all the patients showed different DNA profiles, and 5 of 7 (71.4%) patients showed different DNA profiles at 6 months after eradication Conclusions: The rate of CAM-resistant H. pylori strains is very high in Japan. Because of that, for the recurrence cases, it occurs with low frequency (0.29% per patient year), drug sensitivity examination may be necessary in Japan.

and found that parietal cells in the infected stomach expressed IFNα/β protein in response to Helicobacter infection and that gastric IFNβ mRNA peaked 2 months after the infection while IFNα and IRF7 expression peaked at 2 to 4 months, followed by the peak in Slfn4 mRNA. Ex vivo IFNα11 (800U/ml) treatment of cultured peritoneal myeloid cells induced a phenotypic shift from Gr1-/Slfn4to Gr1+/Slfn4+ cells correlating with a robust increase in Slfn4 expression in vivo. Conclusion: Hedgehog signaling synergizes with Helicobacter infection to induce acquisition of Slfn4+ MDSCs in the stomach.

Introduction Helicobacter felisinfection of C57BL/6 mice is an established model of human gastric carcinogenesis. Mice infected with H. felisby orogastric gavage show acute gastritis, and subsequently develop pre-neoplastic pathology. The acute component of this model mimics the pathology that has been identified in cases of acute Helicobacter pylori infection in humans, however most of these reports describe the consequences of ingestion of large H. pyloriinocula. It is not clear how this reflects the natural acquisition of H. pyloriwhich is usually a subclinical event. Previous studies have reported that co-housing H. felisinfected mice with uninfected littermates did not lead to H. felistransmission, but these experiments were performed before molecular diagnostic tests for bacterial colonisation were available. Method A C57BL/6 mouse, conventionally infected withH. felis, was co-housed with 9 uninfected littermates. Prokaryotic DNA was extracted from stool samples collected from individual mice at regular intervals. Mice were culled at week 7.Gastric mucosal samples were collected for nucleic acid and histological assessment. H. felistransmission was assessed by H+E, modified Giemsa and Warthin-Starry stains and by quantitative PCR (qPCR) for the H. felisgene flaA. Longitudinal changes in faecal microbiota were assessed by qPCR for selected bacterial phyla. Results FlaA was identified by qPCR in gastric and stool samples from the actively infected mouse. All 3 histological stains identified H. felisin the gastric antrum of this mouse, its gastric corpus exhibited early atrophy and inflammation. qPCR of stool samples from the other 9 mice did not identify flaA DNA. In keeping with previous studies, H. felis was not detected histologically in the gastric antral mucosa of these mice and the gastric corpus mucosa wasmorphologically normal. However flaA template DNA was identified in gastric mucosal samples from 2 of the 9 mice.Selected bacterial phyla were quantified from stool samples taken longitudinally from each mouse. PCA analysis demonstrated that the colonic microbiota of mice converged over time. A particular shift in faecal microbiota was observed in the actively infected mouse. No differences were identified in the mice that had been passively colonised with H. feliscompared to uninfected mice. Conclusion H. feliswas transmitted between co-housed mice in SPF conditions. Passive colonisation led to little inflammation and no gross shift in faecal microbiotal composition was seen. This may represent a model of asymptomatic human H. pyloriacquisition. Further investigation using larger cohorts of animals maintained for longer times will address whether the mode of acquisition of H. felis influences eventual pathological outcome. Disclosure of interest None Declared.