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(American Journal of Pathology. 2002;160:739-751.)
© 2002 American Society for Investigative Pathology

Animal Models

Helicobacter bilis Infection Accelerates and H. hepaticus Infection Delays the Development of Colitis in Multiple Drug Resistance-Deficient (mdr1a-/-) Mice

Lillian Maggio-Price^*, Donna Shows, Kim Waggie, Andrew Burich^*, Weiping Zeng^*, Sabine Escobar, Phil Morrissey and Joanne L. Viney

From the Department of Comparative Medicine,^*
theUniversity of Washington, Seattle; the Department ofImmunobiology,
Immunex Corporation, Seattle;and ZymoGenetics Inc.,
Seattle, Washington

Abstract

mdr1a-deficient mice lack P-glycoprotein and spontaneously develop colitis with age. Helicobacter spp. are gram-negative organisms that have been associated with colitis in certain mouse strains, but Helicobacter spp. have been excluded as contributing to the spontaneous colitis that develops in mdr1a-/- mice. We wished to determine whether infection with either H. bilis or H. hepaticus would accelerate the development of inflammatory bowel disease (IBD) in mdr1a-/- mice. We found that H. bilis infection induced diarrhea, weight loss, and IBD in mdr1a-/- mice within 6 to 17 weeks post-inoculation and before the expected onset of spontaneous IBD. Histopathology of H. bilis-induced IBD included crypt hyperplasia, inflammatory cell infiltrates, crypt abscesses, and obliteration of normal gut architecture. Reverse transcription-polymerase chain reaction and Taqman analysis from colonic tissue showed increased transcripts for interferon- and interleukin-10 from H. bilis-infected colitic mdr1a-/- mice. Additionally, mesenteric lymph nodes had increased cellularity with expansion of CD4⁺ and CD8⁺ T cells and B cells and increased proliferation to soluble H. bilis antigens with elaboration of interferon-, tumor necrosis factor- and interleukin-10. In contrast, H. hepaticus infection of mdr1a-/- mice did not accelerate disease but rather delayed the onset of spontaneous colitis which was milder in severity. mdr1a-/- mice infected with Helicobacter spp. may provide a useful tool to explore the pathogenesis of microbial-induced IBD in a model with a presumed epithelial cell "barrier" defect.

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