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. 1997 Nov;65(11):4858–4864. doi: 10.1128/iai.65.11.4858-4864.1997

Helicobacter bilis-induced inflammatory bowel disease in scid mice with defined flora.

N H Shomer 1, C A Dangler 1, M D Schrenzel 1, J G Fox 1
PMCID: PMC175697  PMID: 9353076

Abstract

Helicobacter bilis has been isolated from aged inbred mice with multifocal chronic hepatitis and from scid mice with diarrhea, proliferative typhlitis, and colitis. To determine the pathogenic potential of H. bilis, we inoculated 4-week-old female Tac:Icr:Ha(ICR)-scidfDF mice by intraperitoneal injection of approximately 10(8) CFU of H. bilis in phosphate-buffered saline (PBS) (n = 15) or PBS alone (n = 10) and necropsied them at 7 weeks postinfection. Sham-inoculated mice had no significant gross or histopathological findings. In contrast, all 15 experimentally inoculated mice (confirmed to be H. bilis-colonized by culture and PCR of cecal contents) exhibited varying degrees of inflammatory bowel disease (IBD). Proliferative typhlocolitis was characterized by focal to segmental areas of crypt hyperplasia and a predominantly histiocytic inflammatory cell infiltrate. Labeling indices for 5-bromo-2'-deoxyuridine incorporation were increased approximately 2.5-fold in the ceca and colons of H. bilis-inoculated mice. This is the first study to demonstrate experimentally that infection with H. bilis causes IBD in scid mice with defined flora. This result both confirms a pathogenic role for H. bilis in mice and provides a new model relating a specific microbial agent and IBD.

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Selected References

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  1. Andrutis K. A., Fox J. G., Schauer D. B., Marini R. P., Murphy J. C., Yan L., Solnick J. V. Inability of an isogenic urease-negative mutant stain of Helicobacter mustelae to colonize the ferret stomach. Infect Immun. 1995 Sep;63(9):3722–3725. doi: 10.1128/iai.63.9.3722-3725.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brenes F., Ruiz B., Correa P., Hunter F., Rhamakrishnan T., Fontham E., Shi T. Y. Helicobacter pylori causes hyperproliferation of the gastric epithelium: pre- and post-eradication indices of proliferating cell nuclear antigen. Am J Gastroenterol. 1993 Nov;88(11):1870–1875. [PubMed] [Google Scholar]
  3. Cahill R. J., Foltz C. J., Fox J. G., Dangler C. A., Powrie F., Schauer D. B. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect Immun. 1997 Aug;65(8):3126–3131. doi: 10.1128/iai.65.8.3126-3131.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Correa P., Fox J., Fontham E., Ruiz B., Lin Y. P., Zavala D., Taylor N., Mackinley D., de Lima E., Portilla H. Helicobacter pylori and gastric carcinoma. Serum antibody prevalence in populations with contrasting cancer risks. Cancer. 1990 Dec 15;66(12):2569–2574. doi: 10.1002/1097-0142(19901215)66:12<2569::aid-cncr2820661220>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  5. Cover T. L., Glupczynski Y., Lage A. P., Burette A., Tummuru M. K., Perez-Perez G. I., Blaser M. J. Serologic detection of infection with cagA+ Helicobacter pylori strains. J Clin Microbiol. 1995 Jun;33(6):1496–1500. doi: 10.1128/jcm.33.6.1496-1500.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Duchmann R., Kaiser I., Hermann E., Mayet W., Ewe K., Meyer zum Büschenfelde K. H. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD) Clin Exp Immunol. 1995 Dec;102(3):448–455. doi: 10.1111/j.1365-2249.1995.tb03836.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Duchmann R., Märker-Hermann E., Meyer zum Büschenfelde K. H. Bacteria-specific T-cell clones are selective in their reactivity towards different enterobacteria or H. pylori and increased in inflammatory bowel disease. Scand J Immunol. 1996 Jul;44(1):71–79. doi: 10.1046/j.1365-3083.1996.d01-273.x. [DOI] [PubMed] [Google Scholar]
  8. Figura N., Guglielmetti P., Rossolini A., Barberi A., Cusi G., Musmanno R. A., Russi M., Quaranta S. Cytotoxin production by Campylobacter pylori strains isolated from patients with peptic ulcers and from patients with chronic gastritis only. J Clin Microbiol. 1989 Jan;27(1):225–226. doi: 10.1128/jcm.27.1.225-226.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fox J. G., Batchelder M., Marini R., Yan L., Handt L., Li X., Shames B., Hayward A., Campbell J., Murphy J. C. Helicobacter pylori-induced gastritis in the domestic cat. Infect Immun. 1995 Jul;63(7):2674–2681. doi: 10.1128/iai.63.7.2674-2681.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fox J. G., Correa P., Taylor N. S., Lee A., Otto G., Murphy J. C., Rose R. Helicobacter mustelae-associated gastritis in ferrets. An animal model of Helicobacter pylori gastritis in humans. Gastroenterology. 1990 Aug;99(2):352–361. doi: 10.1016/0016-5085(90)91016-y. [DOI] [PubMed] [Google Scholar]
  11. Fox J. G., Dewhirst F. E., Tully J. G., Paster B. J., Yan L., Taylor N. S., Collins M. J., Jr, Gorelick P. L., Ward J. M. Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. J Clin Microbiol. 1994 May;32(5):1238–1245. doi: 10.1128/jcm.32.5.1238-1245.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fox J. G., Li X., Cahill R. J., Andrutis K., Rustgi A. K., Odze R., Wang T. C. Hypertrophic gastropathy in Helicobacter felis-infected wild-type C57BL/6 mice and p53 hemizygous transgenic mice. Gastroenterology. 1996 Jan;110(1):155–166. doi: 10.1053/gast.1996.v110.pm8536852. [DOI] [PubMed] [Google Scholar]
  13. Fox J. G., Li X., Yan L., Cahill R. J., Hurley R., Lewis R., Murphy J. C. Chronic proliferative hepatitis in A/JCr mice associated with persistent Helicobacter hepaticus infection: a model of helicobacter-induced carcinogenesis. Infect Immun. 1996 May;64(5):1548–1558. doi: 10.1128/iai.64.5.1548-1558.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fox J. G., Yan L. L., Dewhirst F. E., Paster B. J., Shames B., Murphy J. C., Hayward A., Belcher J. C., Mendes E. N. Helicobacter bilis sp. nov., a novel Helicobacter species isolated from bile, livers, and intestines of aged, inbred mice. J Clin Microbiol. 1995 Feb;33(2):445–454. doi: 10.1128/jcm.33.2.445-454.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fox J. G., Yan L., Shames B., Campbell J., Murphy J. C., Li X. Persistent hepatitis and enterocolitis in germfree mice infected with Helicobacter hepaticus. Infect Immun. 1996 Sep;64(9):3673–3681. doi: 10.1128/iai.64.9.3673-3681.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gebhart C. J., Fennell C. L., Murtaugh M. P., Stamm W. E. Campylobacter cinaedi is normal intestinal flora in hamsters. J Clin Microbiol. 1989 Jul;27(7):1692–1694. doi: 10.1128/jcm.27.7.1692-1694.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Leach M. W., Bean A. G., Mauze S., Coffman R. L., Powrie F. Inflammatory bowel disease in C.B-17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T cells. Am J Pathol. 1996 May;148(5):1503–1515. [PMC free article] [PubMed] [Google Scholar]
  18. Lee A., Hazell S. L., O'Rourke J., Kouprach S. Isolation of a spiral-shaped bacterium from the cat stomach. Infect Immun. 1988 Nov;56(11):2843–2850. doi: 10.1128/iai.56.11.2843-2850.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lee A., Krakowka S., Fox J. G., Otto G., Eaton K. A., Murphy J. C. Role of Helicobacter felis in chronic canine gastritis. Vet Pathol. 1992 Nov;29(6):487–494. doi: 10.1177/030098589202900601. [DOI] [PubMed] [Google Scholar]
  20. Mannick E. E., Bravo L. E., Zarama G., Realpe J. L., Zhang X. J., Ruiz B., Fontham E. T., Mera R., Miller M. J., Correa P. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res. 1996 Jul 15;56(14):3238–3243. [PubMed] [Google Scholar]
  21. Marshall B. J., Armstrong J. A., McGechie D. B., Glancy R. J. Attempt to fulfil Koch's postulates for pyloric Campylobacter. Med J Aust. 1985 Apr 15;142(8):436–439. doi: 10.5694/j.1326-5377.1985.tb113443.x. [DOI] [PubMed] [Google Scholar]
  22. Nonoyama S., Smith F. O., Bernstein I. D., Ochs H. D. Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol. 1993 May 1;150(9):3817–3824. [PubMed] [Google Scholar]
  23. Podolsky D. K. Inflammatory bowel disease (1) N Engl J Med. 1991 Sep 26;325(13):928–937. doi: 10.1056/NEJM199109263251306. [DOI] [PubMed] [Google Scholar]
  24. Powrie F., Leach M. W., Mauze S., Caddle L. B., Coffman R. L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol. 1993 Nov;5(11):1461–1471. doi: 10.1093/intimm/5.11.1461. [DOI] [PubMed] [Google Scholar]
  25. Powrie F., Leach M. W., Mauze S., Menon S., Caddle L. B., Coffman R. L. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1994 Oct;1(7):553–562. doi: 10.1016/1074-7613(94)90045-0. [DOI] [PubMed] [Google Scholar]
  26. Rudolphi A., Bonhagen K., Reimann J. Polyclonal expansion of adoptively transferred CD4+ alpha beta T cells in the colonic lamina propria of scid mice with colitis. Eur J Immunol. 1996 May;26(5):1156–1163. doi: 10.1002/eji.1830260529. [DOI] [PubMed] [Google Scholar]
  27. Shames B., Fox J. G., Dewhirst F., Yan L., Shen Z., Taylor N. S. Identification of widespread Helicobacter hepaticus infection in feces in commercial mouse colonies by culture and PCR assay. J Clin Microbiol. 1995 Nov;33(11):2968–2972. doi: 10.1128/jcm.33.11.2968-2972.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shen Z., Fox J. G., Dewhirst F. E., Paster B. J., Foltz C. J., Yan L., Shames B., Perry L. Helicobacter rodentium sp. nov., a urease-negative Helicobacter species isolated from laboratory mice. Int J Syst Bacteriol. 1997 Jul;47(3):627–634. doi: 10.1099/00207713-47-3-627. [DOI] [PubMed] [Google Scholar]
  29. Singer I. I., Kawka D. W., Scott S., Weidner J. R., Mumford R. A., Riehl T. E., Stenson W. F. Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology. 1996 Oct;111(4):871–885. doi: 10.1016/s0016-5085(96)70055-0. [DOI] [PubMed] [Google Scholar]
  30. Taylor N. S., Fox J. G., Yan L. In-vitro hepatotoxic factor in Helicobacter hepaticus, H. pylori and other Helicobacter species. J Med Microbiol. 1995 Jan;42(1):48–52. doi: 10.1099/00222615-42-1-48. [DOI] [PubMed] [Google Scholar]
  31. Tee W., Lambert J. R., Dwyer B. Cytotoxin production by Helicobacter pylori from patients with upper gastrointestinal tract diseases. J Clin Microbiol. 1995 May;33(5):1203–1205. doi: 10.1128/jcm.33.5.1203-1205.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Totten P. A., Fennell C. L., Tenover F. C., Wezenberg J. M., Perine P. L., Stamm W. E., Holmes K. K. Campylobacter cinaedi (sp. nov.) and Campylobacter fennelliae (sp. nov.): two new Campylobacter species associated with enteric disease in homosexual men. J Infect Dis. 1985 Jan;151(1):131–139. doi: 10.1093/infdis/151.1.131. [DOI] [PubMed] [Google Scholar]
  33. Ward J. M., Anver M. R., Haines D. C., Benveniste R. E. Chronic active hepatitis in mice caused by Helicobacter hepaticus. Am J Pathol. 1994 Oct;145(4):959–968. [PMC free article] [PubMed] [Google Scholar]
  34. Ward J. M., Anver M. R., Haines D. C., Melhorn J. M., Gorelick P., Yan L., Fox J. G. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Lab Anim Sci. 1996 Feb;46(1):15–20. [PubMed] [Google Scholar]
  35. Ward J. M., Fox J. G., Anver M. R., Haines D. C., George C. V., Collins M. J., Jr, Gorelick P. L., Nagashima K., Gonda M. A., Gilden R. V. Chronic active hepatitis and associated liver tumors in mice caused by a persistent bacterial infection with a novel Helicobacter species. J Natl Cancer Inst. 1994 Aug 17;86(16):1222–1227. doi: 10.1093/jnci/86.16.1222. [DOI] [PubMed] [Google Scholar]

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