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

  • Helicobacter Hepaticus cytolethal distending toxin promotes intestinal carcinogenesis in 129rag2 deficient mice
    Cellular Microbiology, 2017
    Co-Authors: Yan Feng, Sureshkumar Muthupalani, Nicola Parry, James G. Fox
    Abstract:

    Summary Multiple pathogenic Gram-negative bacteria produce the cytolethal distending toxin (CDT) with activity of DNase I; CDT can induce DNA double strand breaks (DSBs), G2/M cell cycle arrest and apoptosis in cultured mammalian cells. However, the link of CDT to in vivo tumorigenesis is not fully understood. In this study, 129/SvEv Rag2-/- mice were gavaged with wild-type Helicobacter hepatics 3B1( Hh) and its isogenic cdtB mutant HhcdtBm7, followed by infection for 10 and 20 weeks (WPI). HhCDT-deficiency did not affect cecal colonization levels of HhcdtBm7, but attenuated severity of cecal pathology in HhcdtBm7-infected mice. Of importance, preneoplasic dysplasia was progressed to cancer from 10 WPI to 20 WPI in the Hh-infected mice but not in the HhcdtBm7-infected mice. In addition, the loss of HhCDT significantly dampened transcriptional upregulation of cecal Tnfα and Il-6, but elevated Il-10 mRNA levels when compared to Hh at 10 WPI. Furthermore, the presence of HhCDT increased numbers of lower bowel intestinal γH2AX-positive epithelial cells (a marker of DSBs) at both 10 WPI and 20 WPI, and augmented phospho-Stat3 foci+ intestinal crypts (activation of Stat3) at 20 WPI. Our findings suggest that CDT promoted Hh carcinogenesis by enhancing DSBs and activation of the Tnfα /Il-6-Stat3 signaling pathway.

  • Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice. PLoS
    2016
    Co-Authors: Theofilos Poutahidis, James G. Fox, Tatiana Levkovich, Chung-wei Lee, Michael Doulberis, Bruce H. Horwitz, Susan E. Erdman
    Abstract:

    A role for microbes has been suspected in prostate cancer but difficult to confirm in human patients. We show here that a gastrointestinal (GI) tract bacterial infection is sufficient to enhance prostate intraepithelial neoplasia (PIN) and microinvasive carcinoma in a mouse model. We found that animals with a genetic predilection for dysregulation of wnt signaling, ApcMin/+ mutant mice, were significantly susceptible to prostate cancer in an inflammation-dependent manner following infection with Helicobacter Hepaticus. Further, early neoplasia observed in infected ApcMin/+ mice was transmissible to uninfected mice by intraperitoneal injection of mesenteric lymph node (MLN) cells alone from H. Hepaticus-infected mutant mice. Transmissibility of neoplasia was preventable by prior neutralization of inflammation using anti-TNF-α antibody in infected MLN donor mice. Taken together, these data confirm that systemic inflammation triggered by GI tract bacteria plays a pivotal role in tumorigenesis of the prostate gland

  • infection with Helicobacter bilis but not Helicobacter Hepaticus was associated with extrahepatic cholangiocarcinoma
    Helicobacter, 2015
    Co-Authors: Fany Karina Seguralopez, James G. Fox, Francisco Avilesjimenez, Alfredo Guitroncantu, Hilda A Valdezsalazar, Samuel Leoncarballo, Leoncio Guerreroperez, Javier Torres
    Abstract:

    Background and Aims: The biliary tract cancer or cholangiocarcinoma (CCA) represents the sixth leading cause of gastrointestinal tumors in the Western world, and mortality varies across the world, with regions such as Chile, Thailand, Japan, and northeastern India presenting the highest rates. CCA may develop in the bile duct, gallbladder, or ampulla of Vater; and risk factors include obesity, parity, genetic background, geographical and environmental factors. Inflammation induced by bacterial infections might play a role in the pathogenesis of CCA. In this work, we investigated whether there is an association between extrahepatic cholangiocarcinoma (ECCA) and infection with S. typhi, H. Hepaticus, or H. bilis in a Mexican population. Methods: A total of 194 patients were included and divided into 91 patients with benign biliary pathology (controls) and 103 with ECCA (cases). Tumor samples were taken during endoscopic retrograde cholangiopancreatography by biliary brushing, followed by DNA extraction and PCR testing for infections. Results: We found that 44/103 cases were positive for H. bilis, compared with 19/91 controls (p = 0.002; OR 2.83, 95% CI 1.49–5.32), and when analyzed by sub-site, H. bilis infection was significantly more associated with cancer in the common bile duct (p = 0.0005; OR 3.56, 95% CI 1.77–7.17). In contrast, H. Hepaticus infection was not different between cases (17/103) and controls (13/91) (p = 0.82; OR 1.19, 95% CI 0.54–2.60). None of the samples were positive for S. typhi infection. Conclusion: In conclusion, infection with H. bilis but neither H. Hepaticus nor S. typhi was significantly associated with ECCA, particularly with tumors located in the common bile duct.

  • spatial and temporal colonization dynamics of segmented filamentous bacteria is influenced by gender age and experimental infection with Helicobacter Hepaticus in swiss webster mice
    PMC, 2014
    Co-Authors: Stephanie E Woods, James G. Fox
    Abstract:

    In this study, we examined colonization dynamics of segmented filamentous bacteria (SFB) in intestine of Swiss Webster (SW) mice infected with Helicobacter Hepaticus (Hh). At 8 weeks post-inoculation with Hh (WPI), cecal and colonic SFB levels in the control males were significantly lower compared to those at 16 WPI. Hh infection in both genders did not alter SFB levels in the jejunum and ileum, but increased SFB levels in the cecum and colon of males compared to the controls (P < 0.05) at 8 WPI. At 16 WPI, the Hh-infected females contained lower levels of SFB in the jejunum, cecum and colon compared to the female controls. Irrespective of gender, aging and Hh infection, the Il-17A mRNA levels decreased from the small intestine to the cecum and then to the colon, whereas the Foxp3 mRNA levels were comparable in these intestinal regions. There were significant differences in Il-17A mRNA levels in the ileum (P < 0.05, R(2) = 0.31), with females having greater Il-17A mRNA levels than males, and higher SFB colonization levels related to more Il-17A mRNA. These results indicate that aging and gender play an important role in colonization dynamics of intestinal SFB and ileal SFB-associated Th17 response.

  • Helicobacter Hepaticus cholesterol α glucosyltransferase is essential for establishing colonization in male a jcr mice
    Helicobacter, 2014
    Co-Authors: Yan Feng, Sureshkumar Muthupalani, Mark T. Whary, James Versalovic, James G. Fox
    Abstract:

    Background Helicobacter pylori cholesterol-α-glucosyltransferase (cgt) is essential for survival of H. pylori in mice. Enterohepatic H. Hepaticus, the cause of colonic and hepatocellular carcinoma in susceptible mouse strains, contains an ortholog of the H. pylori cgt. However, the role of cgt in the pathogenesis of H. Hepaticus has not been investigated. Materials and Methods Two cgt-deficient isogenic mutants of wild-type H. Hepaticus (WT) 3B1 were generated and used to inoculate male A/JCr mice. Cecal and hepatic colonization levels of the mutants and WT 3B1 as well as select inflammation-associated cytokines were measured by qPCR at 4 months postinoculation. Results Both mutants were undetectable in the cecum of any inoculated mice (10 per mutant) but were detected in two livers (one for each mutant); by contrast, 9 and 7 of 10 mice inoculated with WT 3B1 were qPCR positive in the ceca and livers, respectively. The mice inoculated with the mutants developed significantly less severe hepatic inflammation (p < .05) and also produced significantly lower hepatic mRNA levels of proinflammatory cytokines Ifn-γ (p < .01) and Tnf-α (p ≤ .02) as well as anti-inflammatory factors Il10 and Foxp3 compared with the WT 3B1-inoculated mice. Additionally, the WT 3B1-inoculated mice developed significantly higher Th1-associated IgG2a (p < .0001) and Th2-associated IgG1 responses (p < .0001) to H. Hepaticus infection than mice dosed with isogenic cgt mutants. Conclusion Our data indicate that the cholesterol-α-glucosyltransferase is required for establishing colonization of the intestine and liver and therefore plays a critical role in the pathogenesis of H. Hepaticus.

David B Schauer - One of the best experts on this subject based on the ideXlab platform.

  • in vivo virulence properties of bacterial cytolethal distending toxin
    Cellular Microbiology, 2008
    Co-Authors: David B Schauer, James G. Fox
    Abstract:

    Summary Multiple pathogenic Gram-negative bacteria produce cytolethal-distending toxins (CDTs). CDT is typically composed of three subunits: the catalytic subunit CdtB has DNase I-like activity, whereas CdtA and CdtC are binding proteins for delivering CdtB into target cells. Translocation of CdtB to the nucleus induces genotoxic effects on host DNA, triggering DNA repair cascades that lead to cell cycle arrest and eventual cell death. Several lines of evidence indicate that this toxin contributes to the pathogenicity of CDT-producing bacteria in vivo. Helicobacter Hepaticus and Campylobacter jejuni CDTs are essential for persistent infection of the gastrointestinal tract and increase the severity of mucosal inflammation or liver disease in susceptible mouse strains. Haemophilus ducreyi CDT may contribute to the pathogenesis of chancroid in rabbits. Recently, H. Hepaticus CDT has been shown to play a crucial role in promoting the progression of infectious hepatitis to pre-malignant, dysplastic lesions via activation of a pro-inflammatory NF-κB pathway and increased proliferation of hepatocytes, providing the first evidence that CDT has carcinogenic potential in vivo. Thus, both in vitro and in vivo data indicate that CDT is a bacterial virulence factor.

  • Helicobacter Hepaticus promotes azoxymethane initiated colon tumorigenesis in balb c il10 deficient mice
    International Journal of Cancer, 2008
    Co-Authors: Claude M Nagamine, Arlin B. Rogers, James G. Fox, David B Schauer
    Abstract:

    The BALB/c-IL10 null mouse strain develops colitis and colitis-associated adenocarcinomas, and is a model for idiopathic inflammatory bowel disease. We tested the hypotheses that (i) azoxymethane (AOM), a carcinogen that targets the colon, synergizes with the colonic inflammation inherent in the BALB/c-IL10 null mouse resulting in an increase in incidence, multiplicity and/or progression of AOM-induced tumors or colitis-associated adenocarcinomas; and (ii) prior infection with Helicobacter Hepaticus, a common enterohepatic bacterial pathogen in many research mouse colonies, increases the incidence, multiplicity and/or progression of AOM-induced colon tumors or colitis-associated adenocarcinomas in the BALB/c-IL10 null mouse. We show that, within the timeframe examined, AOM-induced colon tumors in the BALB/c-IL10 null mouse were grossly and microscopically similar in appearance to AOM-induced colon tumors in the wild type BALB/cJ mouse. No colitis-associated adenocarcinomas were identified. Infection with H. Hepaticus prior to AOM-treatment also did not result in colitis-associated adenocarcinomas but did result in a significant increase in the incidence of AOM-induced colon tumors relative to AOM treatment alone. The AOM-induced adenomas were predominantly exophytic and nodular or polypoid and localized to the distal colon. These results suggest that H. Hepaticus promotes AOM-induced tumorigenesis in the BALB/c-IL10 null mouse.

  • colonization dynamics of altered schaedler flora is influenced by gender aging and Helicobacter Hepaticus infection in the intestines of swiss webster mice
    Applied and Environmental Microbiology, 2006
    Co-Authors: Zhongming Ge, Masahiro Ohtani, Nancy S. Taylor, Martin F Polz, Yang Qi-feng, David B Schauer
    Abstract:

    The distribution and colonization levels of the altered Schaedler flora (ASF) in their natural hosts are poorly understood. Intestinal colonization levels of the eight ASF strains in outbred Swiss Webster mice with or without Helicobacter Hepaticus infection were characterized by real-time quantitative PCR. All ASF strains were detected in the cecum and colon, but some strains displayed significant variation in colonization levels with host age, gender, and H. Hepaticus infection status.

  • in vitro and in vivo characterization of Helicobacter Hepaticus cytolethal distending toxin mutants
    Infection and Immunity, 2004
    Co-Authors: Vincent B Young, James G. Fox, Arlin B. Rogers, Kimberly A Knox, Jason S Pratt, Jennifer S Cortez, Linda S Mansfield, David B Schauer
    Abstract:

    Helicobacter Hepaticus expresses a member of the cytolethal distending toxin (CDT) family of bacterial cytotoxins. To investigate the role of CDT in the pathogenesis of H. Hepaticus, transposon mutagenesis was used to generate a series of isogenic mutants in and around the cdtABC gene cluster. An H. Hepaticus transposon mutant with a disrupted cdtABC coding region no longer produced CDT activity. Conversely, a transposon insertion outside of the cluster did not affect the CDT activity. An examination of these mutants demonstrated that CDT represents the previously described granulating cytotoxin in H. Hepaticus. Challenge of C57BL/6 interleukin 10−/− mice with isogenic H. Hepaticus mutants revealed that CDT expression is not required for colonization of the murine gut. However, a CDT-negative H. Hepaticus mutant had a significantly diminished capacity to induce lesions in this murine model of inflammatory bowel disease.

  • genomic characterization of Helicobacter Hepaticus ordered cosmid library and comparative sequence analysis
    Fems Microbiology Letters, 2001
    Co-Authors: Zhongming Ge, Deborah A White, Yan Feng, David B Schauer
    Abstract:

    Helicobacter Hepaticus is an important pathogen in laboratory mice and induces the development of liver tumors and gastrointestinal disease in susceptible strains of mice. In this study, a miniset of 36 cosmid clones from a genomic library of H. Hepaticus was ordered and grouped into four large contigs representing approximately 1 Mb of the H. Hepaticus genome using PCR, DNA sequencing, Southern and dot-blot hybridization and pulsed-field gel electrophoresis. From the 200–300 terminal nucleotide sequences of 38 cosmid clones, 56 coding regions were predicted, of which 51 were found to have orthologs in the public databases and five appeared to be unique to H. Hepaticus. Of these 51 genes, 36 have orthologs in Helicobacter pylori and 25 display the highest sequence similarity to H. pylori. However, chromosomal positions of these genes are not conserved between these two Helicobacters. In addition, 10 H. Hepaticus genes had the highest sequence similarity to orthologs in Campylobacter jejuni. The GC content in a randomly selected 21-kb H. Hepaticus genomic sequence was 35.8%, which approximates the average between H. pylori (39%) and C. jejuni (30.6%). These results demonstrate that: (1) H. Hepaticus is more closely related to H. pylori than C. jejuni; (2) significant genomic alterations exist between H. Hepaticus and H. pylori, including gene organization, protein sequences and GC content, probably in part due to specific adaptation to distinct ecological niches.

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

  • Multi-Omics Characterization of Inflammatory Bowel Disease-Induced Hyperplasia/Dysplasia in the Rag2−/−/Il10−/− Mouse Model
    'MDPI AG', 2021
    Co-Authors: Han Qiyuan, Fox, James G., Kono, Thomas J. Y., Knutson, Charles G., Parry, Nicola M., Seiler, Christopher L., Tannenbaum, Steven R., Tretyakova, Natalia Y.
    Abstract:

    Epigenetic dysregulation is hypothesized to play a role in the observed association between inflammatory bowel disease (IBD) and colon tumor development. In the present work, DNA methylome, hydroxymethylome, and transcriptome analyses were conducted in proximal colon tissues harvested from the Helicobacter Hepaticus (H. Hepaticus)-infected murine model of IBD. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (oxRRBS) analyses identified 1606 differentially methylated regions (DMR) and 3011 differentially hydroxymethylated regions (DhMR). These DMR/DhMR overlapped with genes that are associated with gastrointestinal disease, inflammatory disease, and cancer. RNA-seq revealed pronounced expression changes of a number of genes associated with inflammation and cancer. Several genes including Duox2, Tgm2, Cdhr5, and Hk2 exhibited changes in both DNA methylation/hydroxymethylation and gene expression levels. Overall, our results suggest that chronic inflammation triggers changes in methylation and hydroxymethylation patterns in the genome, altering the expression of key tumorigenesis genes and potentially contributing to the initiation of colorectal cancer

  • Multi-Omics Characterization of Inflammatory Bowel Disease-Induced Hyperplasia/Dysplasia in the Rag2−/−/Il10−/− Mouse Model
    'MDPI AG', 2021
    Co-Authors: Han Qiyuan, Fox, James G., Knutson, Charles G., Parry, Nicola M., Seiler, Christopher L., Tannenbaum, Steven R., Thomas Jy Kono, Tretyakova, Natalia Y.
    Abstract:

    © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Epigenetic dysregulation is hypothesized to play a role in the observed association between inflammatory bowel disease (IBD) and colon tumor development. In the present work, DNA methylome, hydroxymethylome, and transcriptome analyses were conducted in proximal colon tissues harvested from the Helicobacter Hepaticus (H. Hepaticus)-infected murine model of IBD. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (oxRRBS) analyses identified 1606 differentially methylated regions (DMR) and 3011 differentially hydroxymethylated regions (DhMR). These DMR/DhMR overlapped with genes that are associated with gastrointestinal disease, inflammatory disease, and cancer. RNA-seq revealed pronounced expression changes of a number of genes associated with inflammation and cancer. Several genes including Duox2, Tgm2, Cdhr5, and Hk2 exhibited changes in both DNA methylation/hydroxymethylation and gene expression levels. Overall, our results suggest that chronic inflammation triggers changes in methylation and hydroxymethylation patterns in the genome, altering the expression of key tumorigenesis genes and potentially contributing to the initiation of colorectal cancer

  • Male-Dependent Promotion of Colitis in 129 Rag2−/− Mice Co-Infected with Helicobacter pylori and Helicobacter Hepaticus
    'MDPI AG', 2020
    Co-Authors: Ge Zhongming, Ge Lili, Muthupalani Sureshkumar, Feng Yan, Fox, James G.
    Abstract:

    The prevalence of gastric Helicobacter pylori (Hp) infection is ~50% of the world population. However, how Hp infection influences inflammatory bowel disease in humans is not fully defined. In this study, we examined whether co-infection with Hp influenced Helicobacter Hepaticus (Hh)–induced intestinal pathology in Rag2−/− mice. Rag2−/− mice of both sexes were infected with Hh, of which a subgroup was followed by infection with Hp two weeks later. Co-infected males, but not females, had significantly higher total colitis index scores in the colon at both 10 and 21 weeks post-Hh infection (WPI) and developed more severe dysplasia at 21 WPI compared with mono-Hh males. There were no significant differences in colonization levels of gastric Hp and colonic Hh between sexes or time-points. In addition, mRNA levels of colonic Il-1β, Ifnγ, Tnfα, Il-17A, Il-17F, Il-18, and Il-23, which play important roles in the development and function of proinflammatory innate lymphoid cell groups 1 and 3, were significantly up-regulated in the dually infected males compared with mono-Hh males at 21 WPI. These data suggest that concomitant Hp infection enhances the inflammatory responses in the colon of-Hh-infected Rag2−/− males, which results in more severe colitis and dysplasia.National Institutes of Health (Grants P30-ES002109, P01 CA28842, R01OD11141 and R01CA093405

  • Mutagenicity of Helicobacter Hepaticus infection in the lower bowel mucosa of 129/SvEv Rag2−/−Il10−/−gpt delta mice is influenced by sex
    'Wiley', 2020
    Co-Authors: Ge Zhongming, Muthupalani Sureshkumar, Feng Yan, Sheh Alexander, Gong Guanyu, Chawanthayatham Supawadee, Essigmann, John M., Fox, James G.
    Abstract:

    Inflammatory bowel disease and colonic tumors induced by Helicobacter Hepaticus (Hh) infection in susceptible mouse strains are utilized to dissect the mechanisms underlying similar human diseases. In our study, infection with genotoxic cytolethal distending toxin-producing Hh in 129/SvEv Rag2−/-Il10−/− gpt delta (RagIl10gpt) mice of both sexes for 21 weeks induced significantly more severe cecal and colonic pathology compared to uninfected controls. The mutation frequencies in the infected RagIl10gpt males were 2.1-fold higher for the cecum and 1.7-fold higher for the colon than male RagIl10gpt controls. In addition, there was a 12.5-fold increase of G:C-to-T:A transversions in the colon of Hh-infected males compared to controls. In contrast, there was no statistical significance in mutation frequencies between infected female Rag2Il10gpt mice and controls. Moreover, Hh infection in RagIl10gpt males significantly up-regulated transcription of Tnfα and iNos, and decreased mRNA levels of cecal Atm compared to the infected females; there was no significant difference in mRNA levels of Il-22, Il-17A, Ifnγ and Atr between the infected males and females. Significantly higher levels of cecal and colonic iNos expression and γH2AX-positive epithelial cells (a biomarker for double-strand DNA breaks [DSB]) in Hh-infected Rag2Il10gpt males vs. Hh-infected females were noted. Finally, Hh infection and associated inflammation increased levels of intestinal mucosa-associated genotoxic colibactin-producing pks+ Escherichia coli. Elevated Tnfα and iNos responses and bacterial genotoxins, in concert with suppression of the DSB repair responses, may have promoted mutagenesis in the lower bowel mucosa of Hh-infected male RagIl10gpt mice.National Institutes of Health (U.S.) (Grant R01–0D01141)National Institutes of Health (U.S.) (Grant T32–0D010978)National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant P01-CA26731)National Institutes of Health (U.S.) (Grant R01-CA080024

  • Spatial and temporal colonization dynamics of segmented filamentous bacteria is influenced by gender, age and experimental infection with Helicobacter Hepaticus in Swiss Webster mice
    'Elsevier BV', 2014
    Co-Authors: Ge Zhongming, Feng Yan, Woods Stephanie, Fox, James G.
    Abstract:

    In this study, we examined colonization dynamics of segmented filamentous bacteria (SFB) in intestine of Swiss Webster (SW) mice infected with Helicobacter Hepaticus (Hh). At 8 weeks post-inoculation with Hh (WPI), cecal and colonic SFB levels in the control males were significantly lower compared to those at 16 WPI. Hh infection in both genders did not alter SFB levels in the jejunum and ileum, but increased SFB levels in the cecum and colon of males compared to the controls (P < 0.05) at 8 WPI. At 16 WPI, the Hh-infected females contained lower levels of SFB in the jejunum, cecum and colon compared to the female controls. Irrespective of gender, aging and Hh infection, the Il-17A mRNA levels decreased from the small intestine to the cecum and then to the colon, whereas the Foxp3 mRNA levels were comparable in these intestinal regions. There were significant differences in Il-17A mRNA levels in the ileum (P < 0.05, R2 = 0.31), with females having greater Il-17A mRNA levels than males, and higher SFB colonization levels related to more Il-17A mRNA. These results indicate that aging and gender play an important role in colonization dynamics of intestinal SFB and ileal SFB-associated Th17 response.United States. National Institutes of Health (P30-ES002109)United States. National Institutes of Health (R01OD11141)United States. National Institutes of Health (R01-CA067529

Sureshkumar Muthupalani - One of the best experts on this subject based on the ideXlab platform.

  • Helicobacter Hepaticus cytolethal distending toxin promotes intestinal carcinogenesis in 129rag2 deficient mice
    Cellular Microbiology, 2017
    Co-Authors: Yan Feng, Sureshkumar Muthupalani, Nicola Parry, James G. Fox
    Abstract:

    Summary Multiple pathogenic Gram-negative bacteria produce the cytolethal distending toxin (CDT) with activity of DNase I; CDT can induce DNA double strand breaks (DSBs), G2/M cell cycle arrest and apoptosis in cultured mammalian cells. However, the link of CDT to in vivo tumorigenesis is not fully understood. In this study, 129/SvEv Rag2-/- mice were gavaged with wild-type Helicobacter hepatics 3B1( Hh) and its isogenic cdtB mutant HhcdtBm7, followed by infection for 10 and 20 weeks (WPI). HhCDT-deficiency did not affect cecal colonization levels of HhcdtBm7, but attenuated severity of cecal pathology in HhcdtBm7-infected mice. Of importance, preneoplasic dysplasia was progressed to cancer from 10 WPI to 20 WPI in the Hh-infected mice but not in the HhcdtBm7-infected mice. In addition, the loss of HhCDT significantly dampened transcriptional upregulation of cecal Tnfα and Il-6, but elevated Il-10 mRNA levels when compared to Hh at 10 WPI. Furthermore, the presence of HhCDT increased numbers of lower bowel intestinal γH2AX-positive epithelial cells (a marker of DSBs) at both 10 WPI and 20 WPI, and augmented phospho-Stat3 foci+ intestinal crypts (activation of Stat3) at 20 WPI. Our findings suggest that CDT promoted Hh carcinogenesis by enhancing DSBs and activation of the Tnfα /Il-6-Stat3 signaling pathway.

  • Helicobacter Hepaticus cholesterol α glucosyltransferase is essential for establishing colonization in male a jcr mice
    Helicobacter, 2014
    Co-Authors: Yan Feng, Sureshkumar Muthupalani, Mark T. Whary, James Versalovic, James G. Fox
    Abstract:

    Background Helicobacter pylori cholesterol-α-glucosyltransferase (cgt) is essential for survival of H. pylori in mice. Enterohepatic H. Hepaticus, the cause of colonic and hepatocellular carcinoma in susceptible mouse strains, contains an ortholog of the H. pylori cgt. However, the role of cgt in the pathogenesis of H. Hepaticus has not been investigated. Materials and Methods Two cgt-deficient isogenic mutants of wild-type H. Hepaticus (WT) 3B1 were generated and used to inoculate male A/JCr mice. Cecal and hepatic colonization levels of the mutants and WT 3B1 as well as select inflammation-associated cytokines were measured by qPCR at 4 months postinoculation. Results Both mutants were undetectable in the cecum of any inoculated mice (10 per mutant) but were detected in two livers (one for each mutant); by contrast, 9 and 7 of 10 mice inoculated with WT 3B1 were qPCR positive in the ceca and livers, respectively. The mice inoculated with the mutants developed significantly less severe hepatic inflammation (p < .05) and also produced significantly lower hepatic mRNA levels of proinflammatory cytokines Ifn-γ (p < .01) and Tnf-α (p ≤ .02) as well as anti-inflammatory factors Il10 and Foxp3 compared with the WT 3B1-inoculated mice. Additionally, the WT 3B1-inoculated mice developed significantly higher Th1-associated IgG2a (p < .0001) and Th2-associated IgG1 responses (p < .0001) to H. Hepaticus infection than mice dosed with isogenic cgt mutants. Conclusion Our data indicate that the cholesterol-α-glucosyltransferase is required for establishing colonization of the intestine and liver and therefore plays a critical role in the pathogenesis of H. Hepaticus.

  • Helicobacter Hepaticus Infection Promotes Hepatitis and Preneoplastic Foci in Farnesoid X Receptor (FXR) Deficient Mice
    2014
    Co-Authors: Alton G. Swennes, Sureshkumar Muthupalani, Alexis Garcia, Alexander Sheh, Nicola M. A. Parry, Kvin Lertpiriyapong, James G. Fox
    Abstract:

    Farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid metabolism and transport. Mice lacking expression of FXR (FXR KO) have a high incidence of foci of cellular alterations (FCA) and liver tumors. Here, we report that Helicobacter Hepaticus infection is necessary for the development of increased hepatitis scores and FCA in previously Helicobacter-free FXR KO mice. FXR KO and wild-type (WT) mice were sham-treated or orally inoculated with H. Hepaticus. At 12 months post-infection, mice were euthanized and liver pathology, gene expression, and the cecal microbiome were analyzed. H. Hepaticus induced significant increases hepatitis scores and FCA numbers in FXR KO mice (P

  • Helicobacter Hepaticus Infection Promotes Hepatitis and Preneoplastic Foci in Farnesoid X Receptor (FXR) Deficient Mice
    2014
    Co-Authors: Alton G. Swennes&quot, Sureshkumar Muthupalani, Nicola M. A. Parry, Er Sheh, James G. Fox
    Abstract:

    Farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid metabolism and transport. Mice lacking expression of FXR (FXR KO) have a high incidence of foci of cellular alterations (FCA) and liver tumors. Here, we report that Helicobacter Hepaticus infection is necessary for the development of increased hepatitis scores and FCA in previously Helicobacter-free FXR KO mice. FXR KO and wild-type (WT) mice were sham-treated or orally inoculated with H. Hepaticus. At 12 months post-infection, mice were euthanized and liver pathology, gene expression, and the cecal microbiome were analyzed. H. Hepaticus induced significant increases hepatitis scores and FCA numbers in FXR KO mice (P,0.01 and P,0.05, respectively). H. Hepaticus altered the beta diversity of cecal microbiome in both WT and FXR KO mice compared to uninfected mice (P, 0.05). Significant upregulation of b-catenin, Rela, Slc10a1, Tlr2, Nos2, Vdr, and Cyp3a11 was observed in all FXR KO mice compared to controls (P,0.05). Importantly, H. Hepaticus and FXR deficiency were necessary to significantly upregulate Cyp2b10 (P,0.01). FXR deficiency was also a potent modulator of the cecal microbiota, as observed by a strong decrease in alpha diversity. A significant decrease in Firmicutes, particularly members of the order Clostridiales, was observed in FXR KO mice (P,0.05 and FDR,5%, ANOVA). While FXR deficiency strongly affects expression of genes related to immunity and bile acid metabolism, as well as the composition of the microbiome; however, its deficiency was not able to produce significan

  • Absence of FXR promotes hepatomegaly and increased serum bile acids.
    2014
    Co-Authors: Alton G. Swennes, Sureshkumar Muthupalani, Alexis Garcia, Alexander Sheh, Nicola M. A. Parry, Kvin Lertpiriyapong, James G. Fox
    Abstract:

    A) Experimental group mean cecal Helicobacter Hepaticus colonization levels ± SD determined by probe-based qPCR and expressed relative to cecal DNA quantity. B) Mean mouse liver weight – body weight ratio ± SD and C) median serum bile acid levels ± IQR are shown for each experimental group. *P

Yan Feng - One of the best experts on this subject based on the ideXlab platform.

  • Helicobacter Hepaticus cytolethal distending toxin promotes intestinal carcinogenesis in 129rag2 deficient mice
    Cellular Microbiology, 2017
    Co-Authors: Yan Feng, Sureshkumar Muthupalani, Nicola Parry, James G. Fox
    Abstract:

    Summary Multiple pathogenic Gram-negative bacteria produce the cytolethal distending toxin (CDT) with activity of DNase I; CDT can induce DNA double strand breaks (DSBs), G2/M cell cycle arrest and apoptosis in cultured mammalian cells. However, the link of CDT to in vivo tumorigenesis is not fully understood. In this study, 129/SvEv Rag2-/- mice were gavaged with wild-type Helicobacter hepatics 3B1( Hh) and its isogenic cdtB mutant HhcdtBm7, followed by infection for 10 and 20 weeks (WPI). HhCDT-deficiency did not affect cecal colonization levels of HhcdtBm7, but attenuated severity of cecal pathology in HhcdtBm7-infected mice. Of importance, preneoplasic dysplasia was progressed to cancer from 10 WPI to 20 WPI in the Hh-infected mice but not in the HhcdtBm7-infected mice. In addition, the loss of HhCDT significantly dampened transcriptional upregulation of cecal Tnfα and Il-6, but elevated Il-10 mRNA levels when compared to Hh at 10 WPI. Furthermore, the presence of HhCDT increased numbers of lower bowel intestinal γH2AX-positive epithelial cells (a marker of DSBs) at both 10 WPI and 20 WPI, and augmented phospho-Stat3 foci+ intestinal crypts (activation of Stat3) at 20 WPI. Our findings suggest that CDT promoted Hh carcinogenesis by enhancing DSBs and activation of the Tnfα /Il-6-Stat3 signaling pathway.

  • Helicobacter Hepaticus cholesterol α glucosyltransferase is essential for establishing colonization in male a jcr mice
    Helicobacter, 2014
    Co-Authors: Yan Feng, Sureshkumar Muthupalani, Mark T. Whary, James Versalovic, James G. Fox
    Abstract:

    Background Helicobacter pylori cholesterol-α-glucosyltransferase (cgt) is essential for survival of H. pylori in mice. Enterohepatic H. Hepaticus, the cause of colonic and hepatocellular carcinoma in susceptible mouse strains, contains an ortholog of the H. pylori cgt. However, the role of cgt in the pathogenesis of H. Hepaticus has not been investigated. Materials and Methods Two cgt-deficient isogenic mutants of wild-type H. Hepaticus (WT) 3B1 were generated and used to inoculate male A/JCr mice. Cecal and hepatic colonization levels of the mutants and WT 3B1 as well as select inflammation-associated cytokines were measured by qPCR at 4 months postinoculation. Results Both mutants were undetectable in the cecum of any inoculated mice (10 per mutant) but were detected in two livers (one for each mutant); by contrast, 9 and 7 of 10 mice inoculated with WT 3B1 were qPCR positive in the ceca and livers, respectively. The mice inoculated with the mutants developed significantly less severe hepatic inflammation (p < .05) and also produced significantly lower hepatic mRNA levels of proinflammatory cytokines Ifn-γ (p < .01) and Tnf-α (p ≤ .02) as well as anti-inflammatory factors Il10 and Foxp3 compared with the WT 3B1-inoculated mice. Additionally, the WT 3B1-inoculated mice developed significantly higher Th1-associated IgG2a (p < .0001) and Th2-associated IgG1 responses (p < .0001) to H. Hepaticus infection than mice dosed with isogenic cgt mutants. Conclusion Our data indicate that the cholesterol-α-glucosyltransferase is required for establishing colonization of the intestine and liver and therefore plays a critical role in the pathogenesis of H. Hepaticus.

  • Helicobacter Hepaticus induced liver tumor promotion is associated with increased serum bile acid and a persistent microbial induced immune response
    Cancer Research, 2011
    Co-Authors: Alexis Garcia, Sureshkumar Muthupalani, Yan Feng, Yu Zeng, Amanda Potter, Melissa W Mobley, Chakib Boussahmain, John S Wishnok, James G. Fox
    Abstract:

    Chronic microbial infection influence cancer progression but the mechanisms that link them remain unclear. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates enzymes involved in endobiotic and xenobiotic metabolism. CAR activation is a mechanism of xenobiotic tumor promotion, however, the effects of chronic microbial infection on tumor promotion have not been studied in the context of CAR function. Here we report that CAR limits the effects of chronic infection-associated progression of liver cancer. CAR knockout (KO) and wild-type (WT) male mice were treated or not with the tumor initiator diethylnitrosamine (DEN) at 5 weeks of age and then orally inoculated with Helicobacter Hepaticus (Hh) or sterile media at 8 weeks of age. At 50 weeks postinoculation mice were euthanized for histopathological, microbiological, molecular, and metabolomic analyses. Hh infection induced comparable hepatitis in WT and KO mice with or without DEN that correlated with significant upregulation of Tnfα and toll receptor Tlr2. Notably, DEN-treated Hh-infected KO mice exhibited increased numbers of liver lobes with dysplasia and neoplasia, as well as increased multiplicity of neoplasia, relative to similarly treated WT mice. Enhanced tumor promotion was associated with decreased hepatic expression of P450 enzymes Cyp2b10 and Cyp3a11, increased expression of Camp, and increased serum concentrations of chenodeoxycholic acid. Together, our findings suggest that liver tumor promotion is enhanced by an impaired metabolic detoxification of endobiotics and a persistent microbial-induced immune response.

  • cytolethal distending toxin is essential for Helicobacter Hepaticus colonization in outbred swiss webster mice
    Infection and Immunity, 2005
    Co-Authors: Yan Feng, Nancy S. Taylor, Mark T. Whary, Prashant R Nambiar, James G. Fox
    Abstract:

    Helicobacter Hepaticus, which induces chronic hepatitis and typhlocolitis in susceptible mouse strains, produces a cytolethal distending toxin (CDT) consisting of CdtA, CdtB, and CdtC. A cdtB-deficient H. Hepaticus isogenic mutant (HhcdtBm7) was generated and characterized for colonization parameters in four intestinal regions (jejunum, ileum, cecum, and colon) of outbred Swiss Webster (SW) mice. Inactivation of the cdtB gene abolished the ability of HhcdtBm7 to colonize female mice at both 8 and 16 weeks postinfection (wpi), whereas HhcdtBm7 colonized all of four intestinal regions of three of five males at 8 wpi and then was eliminated by 16 wpi. Wild-type (WT) H. Hepaticus was detected in the corresponding intestinal regions of both male and female mice at 8 and 16 wpi; however, colonization levels of WT H. Hepaticus in the cecum and colon of male mice were approximately 1,000-fold higher than in females (P < 0.0079) at 16 wpi. Infection with WT H. Hepaticus, but not HhcdtBm7, at 8 wpi was associated with significantly increased mRNA level of ileal and cecal gamma interferon (IFN-γ) in females (P < 0.016 and 0.031 between WT H. Hepaticus-infected and sham-dosed females, respectively). In contrast, the mRNA levels of IFN-γ were significantly higher in the colon (P < 0.0079) and trended to be higher in the cecum (P < 0.15) in the HhcdtBm7-colonized male mice versus the sham-dosed controls at 8 wpi. In addition, mRNA levels of ileal IFN-γ were significantly higher in the control females than males at 8 wpi (P < 0.016). There were significantly higher Th1-associated immunoglobulin G2a (IgG2a), Th2-associated IgG1 and mucosal IgA (P < 0.002, 0.002, 0.002, respectively) responses in the mice infected with WT H. Hepaticus when compared to HhcdtBm7 at 16 wpi. Colonic interleukin-10 (IL-10) expressions at 16 wpi were significantly lower in both female and male mice colonized by WT H. Hepaticus or in males transiently colonized through 8 wpi by HhcdtBm7 versus control mice (P < 0.0159). These lines of evidence indicate that (i) H. Hepaticus CDT plays a crucial role in the persistent colonization of H. Hepaticus in SW mice; (ii) SW female mice are more resistant to H. Hepaticus colonization than male mice; (iii) there was persistent colonization of WT H. Hepaticus in cecum, colon, and jejunum but only transient colonization of H. Hepaticus in the ileum of female mice; (iv) H. Hepaticus colonization was associated with down-regulation of colonic IL-10 production.

  • genomic characterization of Helicobacter Hepaticus ordered cosmid library and comparative sequence analysis
    Fems Microbiology Letters, 2001
    Co-Authors: Zhongming Ge, Deborah A White, Yan Feng, David B Schauer
    Abstract:

    Helicobacter Hepaticus is an important pathogen in laboratory mice and induces the development of liver tumors and gastrointestinal disease in susceptible strains of mice. In this study, a miniset of 36 cosmid clones from a genomic library of H. Hepaticus was ordered and grouped into four large contigs representing approximately 1 Mb of the H. Hepaticus genome using PCR, DNA sequencing, Southern and dot-blot hybridization and pulsed-field gel electrophoresis. From the 200–300 terminal nucleotide sequences of 38 cosmid clones, 56 coding regions were predicted, of which 51 were found to have orthologs in the public databases and five appeared to be unique to H. Hepaticus. Of these 51 genes, 36 have orthologs in Helicobacter pylori and 25 display the highest sequence similarity to H. pylori. However, chromosomal positions of these genes are not conserved between these two Helicobacters. In addition, 10 H. Hepaticus genes had the highest sequence similarity to orthologs in Campylobacter jejuni. The GC content in a randomly selected 21-kb H. Hepaticus genomic sequence was 35.8%, which approximates the average between H. pylori (39%) and C. jejuni (30.6%). These results demonstrate that: (1) H. Hepaticus is more closely related to H. pylori than C. jejuni; (2) significant genomic alterations exist between H. Hepaticus and H. pylori, including gene organization, protein sequences and GC content, probably in part due to specific adaptation to distinct ecological niches.