Helicobacter bilis Colonization Enhances Susceptibility to Typhlocolitis Following an Inflammatory Trigger

ABSTRACT Helicobacter bilis is a bacterial pathogen associated with multifocal hepatitis and inflammatory bowel disease in certain strains of mice. This bacterium colonizes the liver, bile, and lower intestine in mice and has also been isolated from a wide spectrum of laboratory animals. In this study, proteins present in the outer membrane preparation (OMP) of four H. bilis strains isolated from a mouse, a dog, a rat, and a gerbil were characterized and compared with that of Helicobacter pylori, a human gastric pathogen. All four H. bilis strains had similar OMP protein profiles that were distinct from those of H. pylori. Immunoblotting demonstrated that OMP proteins fromH. bilis and H. pylori have little cross-reactivity, except for their flagellins. Nine major immunogenic polypeptides were present in the H. bilis OMPs. By using two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, five heat-modifiable proteins with molecular masses of 82, 66, 52, 47 and 37 kDa were identified. The N-terminal sequences of the 46- and 47-kDa OMP proteins had no homology with protein sequences available in public databases. These results indicate that H. bilis has a conserved, unique OMP protein profile that is distinct from those of H. pylori.

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W1200 An Oral Prophylactic Vaccine Comprised of Helicobacter bilis Antigens Encapsulated in a Self Assembled Tris Cationic Lipid Prevents IBD-Like Disease in IL-10 Deficient Mice

Gastroenterology ◽

10.1016/s0016-5085(08)63050-4 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-653

Author(s):

Stephen J. Danon ◽

Minoo J. Moghaddam ◽

Vanessa Stebbings

Keyword(s):

Cationic Lipid ◽

Prophylactic Vaccine ◽

Helicobacter Bilis ◽

Self Assembled ◽

Deficient Mice

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Cross-Reactivity between Immune Responses to Helicobacter bilis and Helicobacter pylori in a Population in Thailand at High Risk of Developing Cholangiocarcinoma

Clinical and Vaccine Immunology ◽

10.1128/cvi.00132-08 ◽

2008 ◽

Vol 15 (9) ◽

pp. 1363-1368 ◽

Cited By ~ 15

Author(s):

Paola Pisani ◽

Mark T. Whary ◽

Ingrid Nilsson ◽

Supannee Sriamporn ◽

Torkel Wadström ◽

...

Keyword(s):

High Risk ◽

Immune Responses ◽

Cross Reactivity ◽

Surface Proteins ◽

Massachusetts Institute Of Technology ◽

Whole Cell ◽

Serologic Tests ◽

Helicobacter Bilis ◽

Institute Of Technology ◽

H Pylori

ABSTRACT Helicobacter bilis DNA has been detected in human tissue and is a candidate for etiologic investigations on the causes of hepatic and biliary tract diseases, but reliable serologic tests need to be developed in order to pursue such investigations. The scope of this study was to assess the specificity of two assays for H. bilis immune response allowing for H. pylori, and their cross-reactivity in a population in Thailand at high risk for cholangiocarcinoma. Plasma samples from 92 Thai volunteers were independently tested in two laboratories (Massachusetts Institute of Technology [MIT] and Lund). MIT performed three analyses of H. pylori and H. bilis based either on (i) outer membrane protein (OMP) with no preabsorption or on antigens derived from whole-cell sonicate before (ii) or after (iii) preabsorption with H. pylori sonicate protein. Lund used cell surface proteins from H. pylori and H. bilis as antigens. Testing for H. bilis was preabsorbed with a whole-cell lysate of H. pylori. More than 80% of the samples were positive for H. pylori in both laboratories. As tested by MIT, 58.7% (95% confidence interval, 47.9 to 68.9%) were positive for H. bilis by OMP and 44.5% (34.1 to 55.3%) were positive for H. bilis sonicate protein, but only 15.2% (8.6 to 24.2%) remained positive after preabsorption with H. pylori sonicate protein. Lund found 34.5% of the samples positive for H. bilis (22.0 to 41.0%), which was statistically compatible with all three MIT results. Serologic responses to OMPs of the two bacteria coincided in 66 and 45% of the samples in the MIT and Lund assays, respectively. We found high cross-reactivity between the immune responses to H. pylori and H. bilis antigens. More-specific H. bilis antigens need to be isolated to develop serologic tests suitable for epidemiological studies.

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Inflammatory Large Bowel Disease in Immunodeficient Rats Naturally and Experimentally Infected with Helicobacter bilis

Veterinary Pathology ◽

10.1177/030098589803500305 ◽

1998 ◽

Vol 35 (3) ◽

pp. 202-208 ◽

Cited By ~ 49

Author(s):

D. C. Haines ◽

P. L. Gorelick ◽

J. K. Battles ◽

K. M. Pike ◽

R. J. Anderson ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Animal Model ◽

Bowel Disease ◽

Large Bowel ◽

Chain Reaction ◽

Breeding Colony ◽

Silver Stain ◽

Helicobacter Bilis ◽

Potential Pathogen ◽

Polymerase Chain

Proliferative and ulcerative typhlitis, colitis, and proctitis were found incidentally in a breeding colony of male athymic nude (Cr:NIH-rnu) rats. Within the crypts of the large intestine, modified Steiner's silver stain revealed spiral organisms that were identified by culture, polymerase chain reaction, and sequencing to be Helicobacter bilis. The large bowel disease was reproduced in H. bilis-free male athymic nude rats that were injected intraperitoneally with a culture of H. bilis from the affected colony. The organism was isolated from the feces and cecum of the experimentally infected rats. H. bilis should be considered a potential pathogen in immunocompromised rats. The infection in immunocompromised rats may serve as an animal model for inflammatory large bowel disease.

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Concurrent Helicobacter bilis Infection in C57BL/6 Mice Attenuates Proinflammatory H. pylori-Induced Gastric Pathology

Infection and Immunity ◽

10.1128/iai.01395-08 ◽

2009 ◽

Vol 77 (5) ◽

pp. 2147-2158 ◽

Cited By ~ 46

Author(s):

Laura B. Lemke ◽

Zhongming Ge ◽

Mark T. Whary ◽

Yan Feng ◽

Arlin B. Rogers ◽

...

Keyword(s):

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Premalignant Lesions ◽

Mrna Levels ◽

Necrosis Factor Alpha ◽

Lower Bowel ◽

Mucous Metaplasia ◽

Helicobacter Bilis ◽

Factor Alpha ◽

H Pylori

ABSTRACT Because coinfections can alter helicobacter gastritis, we investigated whether enterohepatic Helicobacter bilis modulates Helicobacter pylori gastritis in C57BL/6 mice. Thirty mice per group were sham dosed, H. bilis or H. pylori infected, or H. bilis infected followed in 2 weeks by H. pylori and then evaluated at 6 and 11 months postinfection (mpi) for gastritis and premalignant lesions. Compared to H. pylori-infected mice, H. bilis/H. pylori-infected mice at 6 and 11 mpi had less severe gastritis, atrophy, mucous metaplasia and hyperplasia (P < 0.01) and, additionally, at 11 mpi, less severe intestinal metaplasia and dysplasia (P < 0.05). H. bilis/H. pylori-infected mice at 11 mpi exhibited less Ki67 labeling of proliferating epithelial cells, reduced numbers of FoxP3+ T-regulatory (TREG) cells, and lower FoxP3+ mRNA levels than did H. pylori-infected mice (P < 0.05). Proinflammatory interleukin-1β (IL-1β), gamma interferon, and tumor necrosis factor alpha mRNA levels were attenuated in H. bilis/H. pylori-infected mice at 6 and 11 mpi (P < 0.01), although anti-inflammatory IL-10, IL-13, and transforming growth factor β1 mRNA levels were not consistently impacted by H. bilis coinfection. Decreased pathology in H. bilis/H. pylori-infected mice correlated with higher gastric H. pylori colonization at 6 mpi (P < 0.001) and lower Th1-associated immunoglobulin G2c responses to H. pylori at 6 and 10 mpi (P < 0.05). We hypothesized that reduced pathology in H. bilis/H. pylori-infected mice was due to H. bilis-primed TREG cells in the lower bowel that migrated to the gastric compartment and inhibited Th1 responses to subsequent H. pylori infection. Thus, H. pylori-induced gastric lesions may vary in mouse models of unknown enteric helicobacter infection status and, importantly, variable sequelae to human H. pylori infection, particularly in developing countries, may occur where coinfection with lower bowel helicobacters and H. pylori may be common.

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Systemic Macrophage Depletion Inhibits Helicobacter bilis-Induced Proinflammatory Cytokine-Mediated Typhlocolitis and Impairs Bacterial Colonization Dynamics in a BALB/cRag2−/−Mouse Model of Inflammatory Bowel Disease

Infection and Immunity ◽

10.1128/iai.00530-12 ◽

2012 ◽

Vol 80 (12) ◽

pp. 4388-4397 ◽

Cited By ~ 14

Author(s):

Sureshkumar Muthupalani ◽

Zhongming Ge ◽

Yan Feng ◽

Barry Rickman ◽

Melissa Mobley ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Quantitative Pcr ◽

Bowel Disease ◽

Bacterial Colonization ◽

Inbred Mice ◽

Saline Control ◽

Content Type ◽

Immunodeficient Mice ◽

Helicobacter Bilis ◽

Inflammatory Bowel

ABSTRACTHelicobacter bilis, an enterohepatic helicobacter, is associated with chronic hepatitis in aged immunocompetent inbred mice and inflammatory bowel disease (IBD) in immunodeficient mice. To evaluate the role of macrophages inH. bilis-induced IBD,Rag2−/−BALB/c or wild-type (WT) BALB/c mice were either sham dosed or infected withH. bilisMissouri strain under specific-pathogen-free conditions, followed by an intravenous injection of a 0.2-ml suspension of liposomes coated with either phosphate-buffered saline (control) or clodronate (a macrophage depleting drug) at 15 weeks postinfection (wpi). At 16 wpi, the ceca ofH. bilis-infectedRag2−/−mice treated with control liposomes had significantly higher histopathological lesional scores (for cumulative typhlitis index, inflammation, edema, epithelial defects, and hyperplasia) and higher counts of F4/80+macrophages and MPO+neutrophils compared toH. bilis-infectedRag2−/−mice treated with clodronate liposomes. In addition, cecal quantitative PCR analyses revealed a significant suppression in the expression of macrophage-related cytokine genes, namely,Tnfa,Il-1β,Il-10,Cxcl1, andiNos, in the clodronate-treatedH. bilis-infectedRag2−/−mice compared to theH. bilis-infectedRag2−/−control mice. Finally, cecal quantitative PCR analyses also revealed a significant reduction in bacterial colonization in the clodronate-treatedRag2−/−mice. Taken together, our results suggest that macrophages are critical inflammatory cellular mediators for promotingH. bilis-induced typhlocolitis in mice.

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