PERSISTENT HEPATITIS AND ENTEROCOLITIS IN GERM-FREE MICE INFECTED WITH HELICOBACTER-HEPATICUS

Helicobacter hepaticas has been associated with naturally occurring he patitis in certain inbred strains of mice, and in A/JCr mice it has be en linked to the development of hepatic adenomas and adenocarcinomas. H. hepaticus was orally inoculated into 30 axenic, outbred female mice , and the mice were studied Longitudinally to fulfill Koch's postulate s and to ascertain the pathogenic potential of the organism under defi ned germfree conditions, Ten cage contact mice were also housed in the same germfree isolator to study transmission patterns, and 10 germfre e mice were maintained in separate isolators as controls. Mice seriall y euthanized from 3 weeks through 24 months postinoculation (p.i.) wer e surveyed by culture and PCR for H. hepaticus in liver and intestinal tissues. Tissues were analyzed for histopathological changes, and ser a were assayed for the presence of immunoglobulin G antibody to H. hep aticus and changes in the liver enzyme alanine aminotransferase. Inocu lated mice and cage contact mice were persistently infected with H. he paticas as identified by culture and PCR, in both the intestine and, l ess frequently, the liver, for the duration of the 2-year study, Anima ls developed persistent chronic hepatitis, and in some animals enteroc olitis was noted, Hepatocellular carcinoma was diagnosed in one H, hep aticus-infected mouse, The level of H. hepaticus serum antibody was hi ghest in experimentally infected mice at 12 to 18 months p.i.; this co rresponded in general to the time interval when the highest levels of alanine aminotransferase were recorded. Although cage contact mice bec ame persistently infected with H. hepaticus, lesions were less severe and the levels of serological biomarkers utilized in the study were lo wer. The H. hepaticus-infected mouse will provide an ideal model to st udy putative bacterial virulence determinants and how they interact wi th the host to induce chronic inflammation and tumorigenesis.