Differential Susceptibility to Hepatic Inflammation and Proliferation in AXB Recombinant Inbred Mice Chronically Infected with Helicobacter hepaticus

Abstract

Helicobacter hepaticus is a naturally occurring pathogen of mice and has been used to develop models of chronic hepatitis , liver cancer , and , more recently , inflammatory bowel disease , in selected mouse strains. A/JCr mice are particularly susceptible to H. hepaticus-induced hepatitis and subsequent development of liver neoplasms , whereas C57BL/6 mice are resistant. In this study , we inoculated nine AXB recombinant inbred (RI) mouse strains , derived from A/J and C57BL/6 mice , with H. hepaticus to determine the genetic basis of resistance to Helicobacterinduced liver disease. Mice were surveyed 14 months after inoculation by culture and PCR for H. hepaticus colonization of the liver and cecum , and microscopic morphometric evaluations of the liver were performed to quantify and correlate the severity of inflammation , apoptosis , and proliferation. Analysis of variance of hepatic inflammation demonstrated significant variation among the RI strains (P < 0.0001), and the strain distribution pattern suggested a multigenic basis of disease resistance. Quantitative trait analysis using linear regression suggested possible linkage to loci on mouse chromosome 19. Hepatocellular and biliary epithelial apoptosis and proliferation indices , including proliferation of oval cells, were markedly increased and correlated with severity of inflammation. Prevalence of hepatic neoplasia was also increased in susceptible RI strains. These findings demonstrate a genetic basis for susceptibility to Helicobacter-induced disease and provide insight into its pathogenesis. (Am J Pathol 1999, 155:571-582)Helicobacter hepaticus is a well-described, naturally occurring pathogen of mice that causes chronic hepatitis and cancer and has been used as a model for the study of both hepatic carcinogenesis and the biology of Helicobacter-induced gastrointestinal disease. Like Helicobacter pylori, the organism is a gram-negative, ureasepositive, helical bacterium that is transmitted through fecal-oral contamination and results in chronic immune cell stimulation, inflammation, and neoplasia in susceptible animals.1-3 In A/J mice, infection causes severe hepatitis and the eventual development of preneoplastic altered foci, hyperplasia, adenoma, and carcinoma in the liver. In contrast, C57BL/6 mice infected with H. hepaticus are highly resistant to the development of disease and have minimal or no liver lesions.2 As with H. pylori-induced gastritis in people, the particular host factors in A/J and C57BL/6 mice that alter the pathogenesis and severity of disease expression after infection with H. hepaticus are poorly understood. Several studies have implicated an imbalance or dysregulation in immunity in response to the bacteria similar to that seen in H. pylori gastritis. [3][4][5][6]

Novel Helicobacter species isolated from rhesus monkeys with chronic idiopathic colitis

“…in IBD, H. hepaticus, which induces a strong Th1 immune response, can cause IBD and hepatitis in A/JCr and recombinant AXB mice as well as IBD in immune dysregulated rodents [10,22,30]. Although the causative role of a novel Helicobacter sp.…”

Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases

“…We observed similar pattern and severity of disease in Gpx1/2-DKO mice of the same genetic background regardless of whether the mice were carrying the kLIZ gene or not. All colonies harbor H. hepaticus, which can cause colitis but not hepatitis in B6 and B6.129 mice (20). 3 Animal care and treatment was approved by the City of Hope Research Animal Care Committee (Duarte, CA).…”

Prevalence of an Unidentified <i>Helicobacter</i> Species in Laboratory Mice and its Distribution in the Hepatobiliary System and Gastrointestinal Tract

“…One of the best-characterized gastric species, H. pylori, is a pathogen of the gastric mucosa, causing inflammation, ulcers, and neoplasia in humans [15,20]. enterohepatic Helicobacter species also known to cause diseases, such as H. hepaticus and H. bilis, have been associated with hepatitis and intestinal diseases in certain strains of mice and rats [1,5,10,17,18,22,28]. Furthermore, some other Helicobacter species including H. felis, classified in the gastric group, and H. pullorum, classified in the enterohepatic group, have been detected in both humans and animals and are recognized as zoo-notic pathogens [5,22].…”