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

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-gamma 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-gamma, tumor necrosis factor-alpha 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.

MDR1 C3435T Polymorphism Is Predictive of Later Onset of Ulcerative Colitis in Japanese

“…They also indicated that infection with Helicobacter bilis induced diarrhea, weight loss, and IBDs in mdr1a-/-knockout mice. [14][15][16] Macroscopic, microscopic and biochemical examinations have confirmed that the colitis which develops in this model is similar to that of human IBDs, [14][15][16][17] and very recently, it has been confirmed that MDR1 mRNA expression in colonic tissues is down-regulated in patients with UC, but not with CD. 18) Next, MDR1 is located on chromosome 7 at q21.1, 19) which was one of the loci of susceptibility to…”

“…14-16) Macroscopic, microscopic and biochemical examinations have confirmed that the colitis which develops in this model is similar to that of human IBDs, [14][15][16][17] and very recently, it has been confirmed that MDR1 mRNA expression in colonic tissues is down-regulated in patients with UC, but not with CD.…”

“…13) Since mdr1a-/-knock-out mice are immunologically normal, the development of spontaneous colitis is presumably due to a defect in the barrier function of the intestinal epithelium. They also indicated that infection with Helicobacter bilis induced diarrhea, weight loss, and IBDs in mdr1a-/-knockout mice.14-16) Macroscopic, microscopic and biochemical examinations have confirmed that the colitis which develops in this model is similar to that of human IBDs, [14][15][16][17] and very recently, it has been confirmed that MDR1 mRNA expression in colonic tissues is down-regulated in patients with UC, but not with CD.18) Next, MDR1 is located on chromosome 7 at q21.1, 19) which was one of the loci of susceptibility toIBDs identified by a genome-wide analysis in an UK cohort, 6) and the linkage in this region has recently been confirmed by genome scan meta-analysis. 20) Finally, in 2003Finally, in -2005, independent groups in Germany and Scotland indicated that a silent genetic polymorphism in exon 26, C3435T, is associated with susceptibility to UC, but not to CD, 21,22) though the results are disputed.…”

Of Mice and Microflora

“…Infection with 1 virus or bacterial species may alter the outcome of infection with another virus or bacterial species. 22,65,74 In this review, we provide a glossary of terms related to GEM, their microbes, and microbial status specifically (Table 1). Although most of these terms will be familiar to readers, certain concepts such as the different definitions of specific pathogen free between facilities, germ free, defined flora, and conventional mice are important to understand.…”

NovelHelicobacterspeciesH.japonicumisolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10−/−mice

“…Helicobacter hepaticus induces hepatitis and hepatocellular carcinoma in the liver in A/JCr mice; causes chronic intestinal inflammation in A/JCr, germfree Swiss Webster mice and immunodeficient mice; H.hepaticus also leads to IBD, associated colon cancer in immune-dysregulated mice (1). Helicobacter bilis is associated with hepatitis in aged inbred and outbred mice; caused IBD and colon cancer in severe combined immunodeficient mice multiple-drug resistance-deficient mice, and WASP-deficient mice and increases the susceptibility for gall stone formation in C57L/J mice (2)(3)(4)(5)(6). Several novel EHS have been reported in recent years.…”