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Timothy C. Wang - One of the best experts on this subject based on the ideXlab platform.

  • A Distinctive Set of Genes Is Upregulated During the Inflammation-Carcinoma Sequence in Mouse Stomach Infected by Helicobacter Felis
    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 2006
    Co-Authors: Motohiro Kobayashi, Timothy C. Wang, Heeseob Lee, Lana Schaffer, Tim Gilmartin, Steven R. Head, Shigeo Takaishi, Jun Nakayama, Minoru Fukuda
    Abstract:

    Helicobacter pylori infects over half the population worldwide and is a leading cause of chronic gastritis and gastric cancer. However, the mechanism by which this organism induces inflammation and carcinogenesis is not fully understood. In the present study we used insulin-gastrin (INS-GAS) transgenic mice that fully develop gastric adenocarcinoma after infection of H. pylori-related Helicobacter Felis. Histological examination revealed that more than half of those mice developed invasive adenocarcinoma after 8 months of infection. These carcinomas were stained by NCC-ST-439 and HECA-452 that recognize 6-sulfated and non-sulfated sialyl Lewis X. Lymphocytic infiltration predominantly to submucosa was observed in most H. Felis-infected mice, and this was associated with the formation of peripheral lymph node addressin (PNAd) on high endothelial venule (HEV)-like vessels detected by MECA-79. Time-course analysis of gene expression by using gene microarray revealed upregulation of several inflammation-associated genes including chemokines, adhesion molecules, surfactant protein D (SP-D), and CD74 in the infected stomach. Immunohistochemical analysis demonstrated that SP-D is expressed in hyperplasia and adenocarcinoma whereas CD74 is expressed in adenocarcinoma in situ and invasive carcinoma. These results as a whole indicate that H. Felis induces HEV-like vessels and inflammation-associated chemokines and chemokine receptors, followed by adenocarcinoma formation.

  • Helicobacter Felis eradication restores normal architecture and inhibits gastric cancer progression in c57bl 6 mice
    Gastroenterology, 2005
    Co-Authors: Xun Cai, Calin Stoicov, Timothy C. Wang, Jane E. Carlson, Jeanmarie Houghton
    Abstract:

    Background & Aims: The impact of Helicobacter eradication therapy on the progression or regression of gastric lesions is poorly defined. This study examined the effects of eradication therapy on inflammation, atrophy, metaplasia, dysplasia, and cancer progression. Methods: C57BL/6 mice were infected with Helicobacter Felis and received bacterial eradication therapy after 2, 6, or 12 months of infection. The gastric mucosa was examined at early, mid, and late intervals after eradication and graded for histology, expression pattern of α-catenin and β-catenin, and IQGAP1. Results: Eradication of Helicobacter infection after 2 or 6 months of infection led to a regression of inflammation, restoration of parietal cell mass, and reestablishment of normal architecture. Progression to adenocarcinoma was prevented. Bacterial eradication at 1 year was associated with the reappearance of parietal cells, partial regression of inflammation, and restoration of architecture. Hyperplasia scores significantly improved, and dysplasia did not progress. Infected mice developed antral adenocarcinoma and gastric outlet obstruction by 24 months. Only 30% of the mice receiving bacterial eradication therapy at 12 months developed antral carcinoma. Bacterial eradication at any time during the first year of infection prevented death due to gastric outlet obstruction. The expression pattern of α-catenin, β-catenin, and IQGAP1 varied with cell type and paralleled histologic changes. Conclusions: Inflammation, metaplasia, and dysplasia are reversible with early eradication therapy; progression of dysplasia was arrested with eradication therapy given as late as 1 year and prevented gastric cancer-related deaths.

  • Helicobacter Felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice.
    Gastroenterology, 2005
    Co-Authors: Xun Cai, Calin Stoicov, Timothy C. Wang, Jane E. Carlson, Jeanmarie Houghton
    Abstract:

    Background & Aims: The impact of Helicobacter eradication therapy on the progression or regression of gastric lesions is poorly defined. This study examined the effects of eradication therapy on inflammation, atrophy, metaplasia, dysplasia, and cancer progression. Methods: C57BL/6 mice were infected with Helicobacter Felis and received bacterial eradication therapy after 2, 6, or 12 months of infection. The gastric mucosa was examined at early, mid, and late intervals after eradication and graded for histology, expression pattern of α-catenin and β-catenin, and IQGAP1. Results: Eradication of Helicobacter infection after 2 or 6 months of infection led to a regression of inflammation, restoration of parietal cell mass, and reestablishment of normal architecture. Progression to adenocarcinoma was prevented. Bacterial eradication at 1 year was associated with the reappearance of parietal cells, partial regression of inflammation, and restoration of architecture. Hyperplasia scores significantly improved, and dysplasia did not progress. Infected mice developed antral adenocarcinoma and gastric outlet obstruction by 24 months. Only 30% of the mice receiving bacterial eradication therapy at 12 months developed antral carcinoma. Bacterial eradication at any time during the first year of infection prevented death due to gastric outlet obstruction. The expression pattern of α-catenin, β-catenin, and IQGAP1 varied with cell type and paralleled histologic changes. Conclusions: Inflammation, metaplasia, and dysplasia are reversible with early eradication therapy; progression of dysplasia was arrested with eradication therapy given as late as 1 year and prevented gastric cancer-related deaths.

  • Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter Felis infection
    Gastroenterology, 1998
    Co-Authors: Timothy C. Wang, James R. Goldenring, Charles A. Dangler, Susumu Ito, Annegret Mueller, Woo Kyu Jeon, Theodore J. Koh, James G. Fox
    Abstract:

    Abstract 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

  • Mice Carrying a Truncated Apc Gene Have Diminished Gastric Epithelial Proliferation, Gastric Inflammation, and Humoral Immunity in Response to Helicobacter Felis Infection
    Cancer research, 1997
    Co-Authors: James G. Fox, Mark T. Whary, Charles A. Dangler, Winfried Edelman, Raju Kucherlapati, Timothy C. Wang
    Abstract:

    Abstract Helicobacter pylori infection and adenomatous polyposis coli ( Apc ) gene mutations have been linked to gastric cancer in humans, but possible synergistic interaction(s) between these risk factors have not been examined. Fourteen C57BL/6 wild-type and 14 Apc 1638 heterozygous mice were inoculated with Helicobacter Felis at 6 weeks of age and compared at various time points with a similar number of uninfected control mice of the same genotype. Both infected and uninfected Apc 1638 mice had a limited incidence of atypical proliferation foci in the mucosa of the antrum and pyloric junction at 4.5 and 6 months of age, whereas polyps of the antrum and pylorus were present in all mice, regardless of infection status, at 7.5 months. In contrast, no altered gastric mucosal foci were observed in control or infected C57BL/6 mice at any time point. Interestingly, the infected Apc 1638 mice had less epithelial proliferation and inflammation in the body of the stomach, lower anti- H. Felis serum IgG antibody responses (although both the wild-type and Apc mutant mice had a Th1-like immune response, based on a predominantly IgG2a immunoglobulin response), and higher bacteria and urease scores than did infected wild-type C57BL/6 mice. In conclusion, the Apc 1638 truncating mutation leads to gastric dysplasia and polyposis of the antrum and pyloric junction, but H. Felis infection of the Apc mutant mouse does not lead to an increased rate of gastric neoplasia. In addition, our data suggest this Apc mutation may actually lead to decreased immune, inflammatory, and gastric hyperplastic responses to Helicobacter infection, suggesting the possibility of a novel role for this tumor suppressor gene in the immune and local tissue responses to gastric bacterial infection.

James G. Fox - One of the best experts on this subject based on the ideXlab platform.

  • Altered gastrin regulation in mice infected with Helicobacter Felis
    Digestive diseases and sciences, 2000
    Co-Authors: Elizabeth J. Dial, Jimmy J. Romero, Lori R. Hall, Juan Lechago, James G. Fox, Lenard M. Lichtenberger
    Abstract:

    Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter Felis and examined after 4–21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. Felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. Felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. Felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.

  • Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter Felis infection
    Gastroenterology, 1998
    Co-Authors: Timothy C. Wang, James R. Goldenring, Charles A. Dangler, Susumu Ito, Annegret Mueller, Woo Kyu Jeon, Theodore J. Koh, James G. Fox
    Abstract:

    Abstract 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

  • Mice Carrying a Truncated Apc Gene Have Diminished Gastric Epithelial Proliferation, Gastric Inflammation, and Humoral Immunity in Response to Helicobacter Felis Infection
    Cancer research, 1997
    Co-Authors: James G. Fox, Mark T. Whary, Charles A. Dangler, Winfried Edelman, Raju Kucherlapati, Timothy C. Wang
    Abstract:

    Abstract Helicobacter pylori infection and adenomatous polyposis coli ( Apc ) gene mutations have been linked to gastric cancer in humans, but possible synergistic interaction(s) between these risk factors have not been examined. Fourteen C57BL/6 wild-type and 14 Apc 1638 heterozygous mice were inoculated with Helicobacter Felis at 6 weeks of age and compared at various time points with a similar number of uninfected control mice of the same genotype. Both infected and uninfected Apc 1638 mice had a limited incidence of atypical proliferation foci in the mucosa of the antrum and pyloric junction at 4.5 and 6 months of age, whereas polyps of the antrum and pylorus were present in all mice, regardless of infection status, at 7.5 months. In contrast, no altered gastric mucosal foci were observed in control or infected C57BL/6 mice at any time point. Interestingly, the infected Apc 1638 mice had less epithelial proliferation and inflammation in the body of the stomach, lower anti- H. Felis serum IgG antibody responses (although both the wild-type and Apc mutant mice had a Th1-like immune response, based on a predominantly IgG2a immunoglobulin response), and higher bacteria and urease scores than did infected wild-type C57BL/6 mice. In conclusion, the Apc 1638 truncating mutation leads to gastric dysplasia and polyposis of the antrum and pyloric junction, but H. Felis infection of the Apc mutant mouse does not lead to an increased rate of gastric neoplasia. In addition, our data suggest this Apc mutation may actually lead to decreased immune, inflammatory, and gastric hyperplastic responses to Helicobacter infection, suggesting the possibility of a novel role for this tumor suppressor gene in the immune and local tissue responses to gastric bacterial infection.

  • Hypertrophic gastropathy in Helicobacter Felis-infected wild-type C57BL/6 mice and p53 hemizygous transgenic mice
    Gastroenterology, 1996
    Co-Authors: James G. Fox, Li X, R J Cahill, Karl Andrutis, Anil K Rustgi, Robert D. Odze, Timothy C. Wang
    Abstract:

    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)

  • hypertrophic gastropathy in Helicobacter Felis infected wild type c57bl 6 mice and p53 hemizygous transgenic mice
    Gastroenterology, 1996
    Co-Authors: James G. Fox, R J Cahill, Karl Andrutis, Anil K Rustgi, Robert D. Odze, Timothy C. Wang
    Abstract:

    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)

Marja-liisa Hänninen - One of the best experts on this subject based on the ideXlab platform.

  • Multiplex PCR Assay for Differentiation of Helicobacter Felis, H. bizzozeronii, and H. salomonis
    Journal of clinical microbiology, 2004
    Co-Authors: Margo Baele, Annemie Decostere, Richard Ducatelle, Peter Vandamme, Marja-liisa Hänninen, K. Van Den Bulck, Freddy Haesebrouck
    Abstract:

    Helicobacter Felis, Helicobacter bizzozeronii, and Helicobacter salomonis are frequently found in the gastric mucous membrane of dogs and cats. These large spiral organisms are phylogenetically highly related to each other. Their fastidious nature makes it difficult to cultivate them in vitro, hampering traditional identification methods. We describe here a multiplex PCR test based on the tRNA intergenic spacers and on the urease gene, combined with capillary electrophoresis, that allows discrimination of these three species. In combination with previously described 16S ribosomal DNA-based primers specific for the nonculturable “Candidatus Helicobacter suis,” our procedure was shown to be very useful in determining the species identity of “Helicobacter heilmannii”-like organisms observed in human stomachs and will facilitate research concerning their possible zoonotic importance.

  • Prevention and suppression of Helicobacter Felis infection in mice using colostral preparation with specific antibodies.
    Helicobacter, 2003
    Co-Authors: Pertti Marnila, Marja-liisa Hänninen, Päivi Kärkkäinen, Timo U. Kosunen, Susanna Rokka, Leena Rehnberg-laiho, Hilpi Rautelin, Eeva-liisa Syväoja, Hannu Korhonen
    Abstract:

    Background. Specific antibodies against Helicobacter were enriched from the colostra of hyperimmunized cows. Efficacies of colostral control preparation and immune preparation containing specific antibodies against Helicobacter Felis were studied in the prevention and treatment of experimental H. Felis infection in mice. Materials and Methods.H. Felis-infected mice were given either immune or control preparation with or without complement or amoxicillin orally in four different trials. H. Felis status was assessed on the basis of bacterial stainings, gastric histology and serum antibodies. Results. Immune, but not control preparation, prevented H. Felis infection (p > 0.01), the efficacy being dependent on the presence of specific antibodies. In the trial on infected Balb/c mice treatment with immune preparation (p = 0.029) but not control preparation decreased the colonization of gastric antrum by H. Felis. In the further trials with infected SJL-mice, treatments with colostral preparations did not decrease colonization. Amoxicillin treatment decreased the colonization with trend-setting significance (p = 0.056; infected mice as controls), whereas amoxicillin combined with immune preparation had a significant effect (p < 0.0005). Conclusions. Specific colostral antibodies were useful in the prevention of Helicobacter infection in a mouse model. The results of the treatment trials were controversial but a similar colostral immune preparation against H. pylori could be effective and useful in preventing infections in humans and during antibiotic treatment.

  • Characterization of Helicobacter Felis by pulsed-field gel electrophoresis, plasmid profiling and ribotyping.
    Helicobacter, 1999
    Co-Authors: Katri Jalava, Jani O'rourke, Adrian Lee, Maria Corazon A. De Ungria, Urszula Hirvi, Marja-liisa Hänninen
    Abstract:

    Background. Helicobacter Felis, an organism naturally infecting both canine and feline gastric mucosa, has been largely used as in animal models to study the ecology and treatment of human Helicobacter pylori infections. H. Felis has not yet been studied at the genetic level. Methods. The aims of this study were to modify an in situ DNA isolation method suitable for H. Felis and, by the use of pulsed-field gel electrophoresis (PFGE), plasmid profiling, and ribotyping, to determine the degree of genetic variation among H. Felis strains isolated from cats and dogs from various geographic locations, and to determine the genome size of H. Felis. Furthermore, the ability of these new H. Felis strains to colonize mice was tested. Results. Most H. Felis strains were distinguishable from each other, and 20 distinct PFGE types were detected. Four pairs of strains within a country and animal species produced identical patterns. All strains tested were found to carry several plasmids and plasmid profiling was equally discriminatory to PFGE. Ribotyping was not able to discriminate all the strains. Conclusions. The genome size of H. Felis was found to be ≈ 1.6 Mb.

  • Helicobacter salomonis sp. nov., a Canine Gastric Helicobacter sp. Related to Helicobacter Felis and Helicobacter bizzozeronii
    International Journal of Systematic and Evolutionary Microbiology, 1997
    Co-Authors: Katri Jalava, M. Utriainen, Irmeli Happonen, Matti Kaartinen, Marja-liisa Hänninen
    Abstract:

    During a study of the prevalence and distribution of gastric Helicobacters in domestic pets, a novel group of Helicobacter-like organisms were identified. These “Helicobacter group 2 strains were initially distinguished from the species Helicobacter Felis and Helicobacter bizzozeronii by their cellular morphology and the type of motility exhibited. Bacterial cells were only slightly spiral, 5 to 7 μm long, and 0.8 to 1.2 μm wide and showed an unusual slow wavelike motion. Each cell had tufts of sheathed flagella at one or both ends. Phylogenetic analysis by 16S ribosomal DNA sequence comparison revealed that H. Felis, H. bizzozeronii, “Gastrospirillum hominis” 2, and the new group of Helicobacters formed a distinct cluster with intraspecies similarity values of more than 98%. These taxa were clearly separated from all other known Helicobacter species. Dot blot DNA-DNA hybridization studies indicated that the Helicobacter group 2 strains are genetically homogeneous and distinct from other canine and feline gastric Helicobacters. Quantitative DNA-DNA hybridization experiments showed that Helicobacter group 2 strains exhibit >;90% DNA homology to each other, but

  • Helicobacter salomonis sp nov a canine gastric Helicobacter sp related to Helicobacter Felis and Helicobacter bizzozeronii
    International Journal of Systematic and Evolutionary Microbiology, 1997
    Co-Authors: Katri Jalava, M. Utriainen, Irmeli Happonen, Matti Kaartinen, Marja-liisa Hänninen
    Abstract:

    During a study of the prevalence and distribution of gastric Helicobacters in domestic pets, a novel group of Helicobacter-like organisms were identified. These “Helicobacter group 2 strains were initially distinguished from the species Helicobacter Felis and Helicobacter bizzozeronii by their cellular morphology and the type of motility exhibited. Bacterial cells were only slightly spiral, 5 to 7 μm long, and 0.8 to 1.2 μm wide and showed an unusual slow wavelike motion. Each cell had tufts of sheathed flagella at one or both ends. Phylogenetic analysis by 16S ribosomal DNA sequence comparison revealed that H. Felis, H. bizzozeronii, “Gastrospirillum hominis” 2, and the new group of Helicobacters formed a distinct cluster with intraspecies similarity values of more than 98%. These taxa were clearly separated from all other known Helicobacter species. Dot blot DNA-DNA hybridization studies indicated that the Helicobacter group 2 strains are genetically homogeneous and distinct from other canine and feline gastric Helicobacters. Quantitative DNA-DNA hybridization experiments showed that Helicobacter group 2 strains exhibit >;90% DNA homology to each other, but <39% homology to the phylogenetically related taxa H. Felis and H. bizzozeronii. We propose the name Helicobacter salomonis for the novel Helicobacter group 2 strains. The type strain is H. salomonis Inkinen (= CCUG 37845).

Michael D. Burkitt - One of the best experts on this subject based on the ideXlab platform.

  • Hexane Extracts of Calophyllum brasiliense Inhibit the Development of Gastric Preneoplasia in Helicobacter Felis Infected INS-Gas Mice.
    Frontiers in pharmacology, 2017
    Co-Authors: Larissa M. S. Lemos, D. Mark Pritchard, Fabio Miyajima, Geovane Roberto De Campos Castilho, Domingos Tabajara De Oliveira Martins, Michael D. Burkitt
    Abstract:

    Objectives: Indigenous Latin American populations have used extracts from Calophyllum brasiliense, a native hardwood, to treat gastrointestinal symptoms for generations. The hexane extract of Calophyllum brasiliense stem bark (HECb) protects against ethanol-mediated gastric ulceration in Swiss-Webster mice. We investigated whether HECb inhibits the development of gastric epithelial pathology following Helicobacter Felis infection of INS-Gas mice. Methods: Groups of 5 male, 6-week-old INS-Gas mice were colonised with H. Felis by gavage. From 2 weeks after colonisation their drinking water was supplemented with 2% Tween20 (vehicle), low dose HECb (33 mg/L, lHECb) or high dose HECb (133 mg/L, hHECb). Equivalent uninfected groups were studied. Animals were culled 6 weeks after H. Felis colonisation. Preneoplastic pathology was quantified using established histological criteria. Gastric epithelial cell turnover was quantified by immunohistochemistry for Ki67 and active-caspase 3. Cytokines were quantified using an electrochemiluminescence assay. Results: Vehicle-treated H. Felis infected mice exhibited higher gastric atrophy scores than similarly treated uninfected mice (mean atrophy score 5.6 ± 0.87 SEM vs 2.2 ± 0.58, p

  • hexane extracts of calophyllum brasiliense inhibit the development of gastric preneoplasia in Helicobacter Felis infected ins gas mice
    Frontiers in Pharmacology, 2017
    Co-Authors: Larissa M. S. Lemos, Fabio Miyajima, Geovane Roberto De Campos Castilho, Domingos Tabajara De Oliveira Martins, Mark D Pritchard, Michael D. Burkitt
    Abstract:

    Objectives: Indigenous Latin American populations have used extracts from Calophyllum brasiliense, a native hardwood, to treat gastrointestinal symptoms for generations. The hexane extract of Calophyllum brasiliense stem bark (HECb) protects against ethanol-mediated gastric ulceration in Swiss-Webster mice. We investigated whether HECb inhibits the development of gastric epithelial pathology following Helicobacter Felis infection of INS-Gas mice. Methods: Groups of 5 male, 6-week-old INS-Gas mice were colonised with H. Felis by gavage. From 2 weeks after colonisation their drinking water was supplemented with 2% Tween20 (vehicle), low dose HECb (33 mg/L, lHECb) or high dose HECb (133 mg/L, hHECb). Equivalent uninfected groups were studied. Animals were culled 6 weeks after H. Felis colonisation. Preneoplastic pathology was quantified using established histological criteria. Gastric epithelial cell turnover was quantified by immunohistochemistry for Ki67 and active-caspase 3. Cytokines were quantified using an electrochemiluminescence assay. Results: Vehicle-treated H. Felis infected mice exhibited higher gastric atrophy scores than similarly treated uninfected mice (mean atrophy score 5.6 ± 0.87 SEM vs 2.2 ± 0.58, p<.01). The same pattern was observed following lHECb. Following hHECb treatment, H. Felis status did not significantly alter atrophy scores. Gastric epithelial apoptosis was not altered by H. Felis or HECb administration. Amongst vehicle-treated mice, gastric epithelial cell proliferation was increased 2.8 fold in infected compared to uninfected animals (p<.01). Administration of either lHECb or hHECb reduced proliferation in infected mice to levels similar to uninfected mice. A Th17 polarised response to H. Felis infection was observed in all infected groups. hHECb attenuated IFN-γ, IL-6 and TNF production following H.Felis infection (70% (p<.01), 67% (p<.01) and 41 % (p<.05) reduction vs vehicle respectively). Conclusions: HECb modulates gastric epithelial pathology following H. Felis infection of INS-Gas mice. Further studies are indicated to confirm the mechanisms underlying these observations.

  • Su1927 Passive Transmission of Helicobacter Felis Occurs in a Specific Pathogen Free (SPF) Laboratory Environment
    Gastroenterology, 2015
    Co-Authors: Joseph M. Tang, Bryony N. Parsons, Jonathan M. Williams, David M. Pritchard, Michael D. Burkitt
    Abstract:

    Introduction Helicobacter Felis infection of C57BL/6 mice is an established model of human gastric carcinogenesis. Mice infected with H. Felis by 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. pylori inocula. It is not clear how this reflects the natural acquisition of H. pylori which is usually a subclinical event. Previous studies have reported that co-housing H. Felis infected mice with uninfected littermates did not lead to H. Felis transmission, but these experiments were performed before molecular diagnostic tests for bacterial colonisation were available. Method A C57BL/6 mouse, conventionally infected with H. 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. Felis transmission was assessed by H+E, modified Giemsa and Warthin-Starry stains and by quantitative PCR (qPCR) for the H. Felis gene 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. Felis in 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. Felis compared to uninfected mice. Conclusion H. Felis was 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. pylori acquisition. 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.

  • Effect of Helicobacter Felis infection and somatic deletion of NFκB family members on the murine gastric microbiome
    The Lancet, 2014
    Co-Authors: Michael D. Burkitt, Sarah L. Burgess, D. Mark Pritchard
    Abstract:

    Abstract Background The development of gastric atrophy in C57BL/6 mice infected with Helicobacter Felis is differentially regulated by signalling involving NFκB1 and NFκB2. After infection, more severe atrophy develops in Nfkb1-/- mice than in wild-type (wt) mice, whereas Nfkb2-/- mice are protected from atrophic gastritis. In addition, the development of pathological changes induced by Helicobacter pylori is delayed in INS-Gas mice maintained in germ-free conditons compared with those in conventional animal house conditions. Inflammasome-deficient mice have altered immunological responses that can lead to development of a dominant dysbiosis, which is sufficient to alter the outcome of dextran sodium sulphate induced colitis. We hypothesised that the different phenotypes observed in H Felis infected mice lacking specific NFκB proteins could be influenced by altered gastric microbiota. We have therefore quantified the abundance of specific bacterial phyla in Nfkb1-/-, Nfkb2-/-, and C57BL/6 mice with and without H Felis infection. Methods We used C57BL/6, Nfkb1-/-, and Nfkb2-/- mice aged 6 weeks. Three mice of each type were infected with H Felis by gavage, humanely killed at 12 weeks, and gastric antral DNA extracted. Total bacterial load and relative abundance of α-proteobacteria, γ-proteobacteria, Bacteriodetes, Firmicutes, and Actinobacteria were measured by quantitative PCR (qPCR) of 16S rDNA. Colonisation by H Felis was assessed with qPCR for FlaA; samples were normalised to murine Gapdh. Findings Untreated wt mice had 3·4 times and 2·6 times greater universal bacterial transcripts than did Nfkb1-/- and Nfkb2-/- mice, respectively. Actinobacteria abundance was 6·0 times greater in untreated Nfkb1-/- mice and 7·0 times greater in Nfkb2-/- mice than in wt mice. α-proteobacteria were 9·0 times more abundant in untreated Nfkb1-/- mice than in wt mice. H Felis infection of wt mice resulted in increases of 5·6 times and 16·7 times in α-proteobacteria and γ-proteobacteria, respectively, compared with uninfected mice. γ-proteobacteria were more abundant in all infected groups, but significantly more so in Nfkb2-/- mice than in others (p H Felis (phylum γ-Proteobacteria) in infected Nfkb2-/- than in wt mice. Infected Nfkb2-/- mice also had a 3·3-times greater abundance of actinobacteria than did infected wt mice. No statistically significant differences were observed in the abundance of Firmicutes or Bacteroidetes. Interpretation The constitution of the murine gastric antral microbiome is affected both by H Felis infection and by somatic deletion of NFκB family members. Since deletion of NFκB1 and NFκB2 alter susceptibility to H Felis induced gastric atrophy, our data support the hypothesis that specific differences in microbiota could cause or signal this altered susceptibility. Further studies are needed to determine whether specific organisms influence the development of gastric disease either individually or within complex communities. Funding Wellcome Trust.

  • Signaling mediated by the NF-κB sub-units NF-κB1, NF-κB2 and c-Rel differentially regulate Helicobacter Felis-induced gastric carcinogenesis in C57BL/6 mice
    Oncogene, 2013
    Co-Authors: Michael D. Burkitt, Jorge Caamaño, Carrie A. Duckworth, A Hanedi, A Hara, J M Williams, András Varró, D M Pritchard
    Abstract:

    The classical nuclear factor-kappaB (NF-κB) signaling pathway has been shown to be important in a number of models of inflammation-associated cancer. In a mouse model of Helicobacter -induced gastric cancer, impairment of classical NF-κB signaling in the gastric epithelium led to the development of increased preneoplastic pathology, however the role of specific NF-κB proteins in Helicobacter- associated gastric cancer development remains poorly understood. To investigate this C57BL/6, Nfkb1 ^ −/− , Nfkb2 ^ −/− and c-Rel ^ −/− mice were infected with Helicobacter Felis for 6 weeks or 12 months. Bacterial colonization, gastric atrophy and preneoplastic changes were assessed histologically and cytokine expression was assessed by qPCR. Nfkb1 ^ −/− mice developed spontaneous gastric atrophy when maintained for 12 months in conventional animal house conditions. They also developed more pronounced gastric atrophy after short-term H. Felis colonization with a similar extent of preneoplasia to wild-type (WT) mice after 12 months. c-Rel ^ −/− mice developed a similar degree of gastric atrophy to WT mice; 3 of 6 of these animals also developed lymphoproliferative lesions after 12 months of infection. Nfkb2 ^ −/− mice developed minimal gastric epithelial pathology even 12 months after H. Felis infection. These findings demonstrate that NF-κB1- and NF-κB2-mediated signaling pathways differentially regulate the epithelial consequences of H. Felis infection in the stomach, while c-Rel-mediated signaling also appears to modulate the risk of lymphomagenesis in gastric mucosa-associated lymphoid tissue.

Adrian Lee - One of the best experts on this subject based on the ideXlab platform.

  • Immunisation against Helicobacter Felis infection protects against the development of gastric MALT Lymphoma.
    Vaccine, 2004
    Co-Authors: Philip Sutton, Jani O'rourke, John Wilson, Michael F. Dixon, Adrian Lee
    Abstract:

    The formation of mucosa-associated lymphoid tissue (MALT) in response to Helicobacter pylori infection is closely associated with the development of primary gastric MALT lymphoma. Aim: To examine whether immunisation against Helicobacter Felis can protect against development of MALT lymphoma. Results: The majority of control infected mice demonstrated MALT formation (13/15) and five developed lymphoma. Fifteen immunised mice were protected against bacterial challenge, of which only five had evidence of MALT formation and none developed lymphoma. Interestingly, of the four mice in which immunisation failed, all developed MALT and two of these had lymphoma. Conclusion: Effective immunisation against Helicobacter infection can protect against gastric MALT lymphoma. To our knowledge this is the first demonstration of vaccination protecting against a bacteria-induced malignancy.

  • Helicobacter Felis does not stimulate human neutrophil oxidative burst in contrast to ‘Gastrospirillum hominis’ and Helicobacter pylori
    FEMS immunology and medical microbiology, 2001
    Co-Authors: Tina Ken Hansen, Adrian Lee, Per Syrak Hansen, Annette Nørgaard, Henrik Nielsen, Leif P. Andersen
    Abstract:

    Helicobacte pylori is a human pathogen, whereas the natural hosts for ‘Gastrospirillum hominis’ and Helicobacter Felis are animals. ‘G. hominis’ is occasionally found to cause infection in humans, whereas H. Felis only rarely infects humans. The pathogenesis of H. pylori infection is not completely understood and in order to reveal differences in immune response to the three Helicobacter species, the upregulation of adherence molecule CD11b/CD18, chemotactic activity and oxidative burst response of neutrophils after stimulation with H. pylori, ‘G. hominis’ and H. Felis sonicates, were compared. Like H. pylori, ‘G. hominis’ and H. Felis induced upregulation of CD11b/CD18 and chemotaxis of neutrophils. ‘G. hominis’ demonstrated a more pronounced upregulation of CD11b/CD18, whereas H. Felis was the strongest stimulant of neutrophil chemotaxis. H. Felis was unable to stimulate neutrophils to oxidative burst response, whereas ‘G. hominis’ activated neutrophils in a dose-dependent way similar to H. pylori. ‘G. hominis’ and H. Felis were both able to prime neutrophils for oxidative burst response similar to H. pylori. In conclusion, we observed clear differences in neutrophil responses to different Helicobacter species, which indicates that bacterial virulence factors may be important for the diversity in the pathogenetic outcome of Helicobacter infections.

  • Helicobacter Felis does not stimulate human neutrophil oxidative burst in contrast to gastrospirillum hominis and Helicobacter pylori
    Fems Immunology and Medical Microbiology, 2001
    Co-Authors: Tina Ken Hansen, Adrian Lee, Per Syrak Hansen, Annette Nørgaard, Henrik Nielsen, Leif P. Andersen
    Abstract:

    Helicobacte pylori is a human pathogen, whereas the natural hosts for ‘Gastrospirillum hominis’ and Helicobacter Felis are animals. ‘G. hominis’ is occasionally found to cause infection in humans, whereas H. Felis only rarely infects humans. The pathogenesis of H. pylori infection is not completely understood and in order to reveal differences in immune response to the three Helicobacter species, the upregulation of adherence molecule CD11b/CD18, chemotactic activity and oxidative burst response of neutrophils after stimulation with H. pylori, ‘G. hominis’ and H. Felis sonicates, were compared. Like H. pylori, ‘G. hominis’ and H. Felis induced upregulation of CD11b/CD18 and chemotaxis of neutrophils. ‘G. hominis’ demonstrated a more pronounced upregulation of CD11b/CD18, whereas H. Felis was the strongest stimulant of neutrophil chemotaxis. H. Felis was unable to stimulate neutrophils to oxidative burst response, whereas ‘G. hominis’ activated neutrophils in a dose-dependent way similar to H. pylori. ‘G. hominis’ and H. Felis were both able to prime neutrophils for oxidative burst response similar to H. pylori. In conclusion, we observed clear differences in neutrophil responses to different Helicobacter species, which indicates that bacterial virulence factors may be important for the diversity in the pathogenetic outcome of Helicobacter infections.

  • Characterization of Helicobacter Felis by pulsed-field gel electrophoresis, plasmid profiling and ribotyping.
    Helicobacter, 1999
    Co-Authors: Katri Jalava, Jani O'rourke, Adrian Lee, Maria Corazon A. De Ungria, Urszula Hirvi, Marja-liisa Hänninen
    Abstract:

    Background. Helicobacter Felis, an organism naturally infecting both canine and feline gastric mucosa, has been largely used as in animal models to study the ecology and treatment of human Helicobacter pylori infections. H. Felis has not yet been studied at the genetic level. Methods. The aims of this study were to modify an in situ DNA isolation method suitable for H. Felis and, by the use of pulsed-field gel electrophoresis (PFGE), plasmid profiling, and ribotyping, to determine the degree of genetic variation among H. Felis strains isolated from cats and dogs from various geographic locations, and to determine the genome size of H. Felis. Furthermore, the ability of these new H. Felis strains to colonize mice was tested. Results. Most H. Felis strains were distinguishable from each other, and 20 distinct PFGE types were detected. Four pairs of strains within a country and animal species produced identical patterns. All strains tested were found to carry several plasmids and plasmid profiling was equally discriminatory to PFGE. Ribotyping was not able to discriminate all the strains. Conclusions. The genome size of H. Felis was found to be ≈ 1.6 Mb.

  • Atrophic gastric changes in both Helicobacter Felis and Helicobacter pylori infected mice are host dependent and separate from antral gastritis.
    Gut, 1996
    Co-Authors: T Sakagami, Jani O'rourke, Michael F. Dixon, R Howlett, Frank Alderuccio, J Vella, Takashi Shimoyama, Adrian Lee
    Abstract:

    BACKGROUND/AIMS: The role of host factors has been neglected in studies of the pathogenesis of Helicobacter associated disease. The aim of this study was to assess the response of different mouse strains to infection with a single strain of Helicobacter Felis. METHOD: Six strains of inbred mice were infected with the identical H Felis culture and were killed at one month, two months, and six months after infection to assess histopathological changes. In addition, two strains of mice were infected with a mouse adapted strain of H pylori and examined at six months after infection. RESULTS: In SJL, C3H/He, DBA/2, and C57BL/6 infected mice, severe to moderate chronic active gastritis was observed only in the body of the stomach, which increased in severity over time with specialised cells in the body glands being replaced. As the severity of this damage in the body increased and atrophic changes were seen, the level of bacterial colonisation of the antrum decreased. In contrast, in BALB/c and CBA mice, there was only mild gastritis in the antrum, no remarkable changes were detected in their body mucosa, and no atrophy was seen over time. In both these strains of mice, heavy bacterial colonisation was seen, which tended to increase over the period of the experiment. Of particular importance in this experiment was that bacterial colonisation was mainly restricted to the antrum yet the atrophy, when present, was only observed in the body of the stomach. H pylori infected C3H/He mice showed moderate colonisation of the antrum, which persisted up to six months with little development of atrophy. In contrast, H pylori in C57BL/6 mice showed excellent colonisation of the antrum at two months but six months after infection there was moderate to severe body atrophy, which was associated with a loss of bacteria from the antrum. CONCLUSIONS: These findings challenge current concepts of the development of Helicobacter induced atrophy in that active chronic gastritis of antrum or the body mucosa, or both, is not a prerequisite. They also suggest an autoimmune basis for the pathology although no autoantibody or antibody to the H+/K+ ATPase was detected. Loss of infecting Helicobacters from the stomach together with development of an atrophic gastritis in the body of the stomach is similar to the pattern found in certain H pylori infected human subjects.