Ausschuss für Hygiene

Host and bacterial species:

Helicobacter spp. have been isolated from a wide range of laboratory animals (Fox & Lee 1997, Whary & Fox 2004). Various bacterial species have been found, and it is expected that additional species colonizing laboratory animals will be described in the near future. In laboratory rodents, the following Helicobacter spp. have been identified:

• mouse: H. muridarum (Lee et al. 1992), ‘H. rappini’ (Schauer et al. 1993), H. hepaticus (Fox et al. 1994), H. bilis (Fox et al. 1995), H. rodentium (Shen et al. 1997), H. typhlonius (Fox et al. 1999), H. ganmani (Robertson et al. 2001)
• rat: H. muridarum (Lee et al. 1992), H. hepaticus (Riley et al. 1996), H. bilis (Riley et al. 1996), H. trogontum (Mendes et al. 1996), H. rodentium (Goto et al. 2000), H. typhlonius (Livingston & Riley 2003)
• hamster: H. cinaedi (Gebhart et al. 1989), H. cholecystus (Franklin et al. 1996), H. aurati (Patterson et al. 2000), H. mesocricetorum (Simmons et al. 2000)
• Mongolian gerbil: H. bilis (Wang & Fox 1998), H. hepaticus (Goto et al. 2000).

This compilation will focus mainly on H. hepaticus because it is the most prominent of the rodent Helicobacter spp. and is responsible for the most lesions.

Strain susceptibility

Mouse strain differences in disease susceptibility and colonization sites have been reported:

• some mouse strains (including A/JCr, C3H/HeNCr, SJL/NCr, BALB/cAnNCr, and Prkdcscid/NCr) are highly susceptible to H. hepaticus-associated hepatitits, whereas others (C57BL/6NCr, B6C3F1) are resistant (Ward et al. 1994b)
• in aged male A/JCr mice, H. hepaticus infection is linked to the development of liver tumors (Ward et al. 1994b)
• hepatitis-prone A/JCr mice have lower cecal colonization levels of H. hepaticus than hepatitis-resistant C57BL/6 mice (Whary et al. 2001)
• several immunodeficient strains of mice (e.g., Foxn1nu, Prkdcscid, Il10tm1Cgn, Tcratm1Mom) are prone to develop inflammatory bowel disease in response to infections with H. hepaticus (Ward et al. 1996a, Burich et al. 2001), H. bilis (Shomer et al. 1997, Burich et al. 2001), or H. typhlonius (Fox et al. 1999, Franklin et al. 1999)

Organotropism:

• lower intestine (primary site)
• stomach (H. muridarum in mice, H. aurati in hamsters)
• liver (H. hepaticus, H. bilis, and H. ganmani in mice)
• gallbladder (H. cholecystus in hamsters)
  

Clinical disease:

• usually inapparent in immunocompetent rodents
• signs of inflammatory bowel disease in immunodeficient mice and rats include rectal prolapse, mild to severe hemorrhagic or watery diarrhea with resultant perianal dermatitis and weight loss (Ward et al. 1996a, Haines et al. 1998, Shomer et al. 1997, Burich et al. 2001)

Pathology:

• chronic active hepatitis with focal necrosis and mixed leukocytic infiltrates in mice infected with H. hepaticus (Ward et al. 1994a, Ward et al. 1994b, Fox et al. 1996a) or H. bilis (Fox et al. 1995, Franklin et al. 1998)
• hepatocellular adenoma and carcinoma in H. hepaticus-infected aged A/JCr male mice (Ward et al. 1994b, Fox et al. 1996a)
• proliferative typhlitis, colitis, and proctitis in immunodeficient mice infected with H. hepaticus (Ward et al. 1996a, Burich et al. 2001), H. bilis (Shomer et al. 1997, Burich et al. 2001), or H. typhlonius (Fox et al. 1999, Franklin et al. 1999) and in immunodeficient rats infected with H. bilis (Haines et al. 1998)
• gastritis in H. muridarum-infected mice (Queiroz et al. 1992)
• cholangiofibrosis and centrilobular pancreatitis in H. cholecystus-infected hamsters (Franklin et al. 1996)

Morbidity and mortality:

• the incidence and severity of Helicobacter-induced disease depend on strain, gender, and age of the host (Ward et al. 1994b, Fox et al. 1996a, Ward et al. 1996a, Haines et al. 1998, Ihrig et al. 1999, Burich et al. 2001, Livingston et al. 2004

Zoonotic potential:

• unclear; some Helicobacter spp. demonstrate zoonotic potential and may cause human disease (e.g., H. cinaedi and ‘H. rappini’ have been isolated from patients with enteritis and from patients with bacteremia) (De Groote et al. 2000, Andersen 2001)

Interference with research:

Physiology

• chronic H. hepaticus infection may lead to elevations in serum levels of alanine aminotransferase (Fox et al. 1996a, Fox et al. 1996b)

Pathology

• H. hepaticus, H. bilis, and H. typhlonius induce or trigger intestinal inflammation in various mouse models of inflammatory bowel disease (Cahill et al. 1997, Kullberg et al. 1998, Fox et al. 1999, Chin et al. 2000, Burich et al. 2001); in contrast, H. hepaticus delays the development of inflammatory bowel disease in multiple drug resistance-deficient mice (Maggio-Price et al. 2002)
• H. muridarum provokes inflammatory bowel disease in Prkdcscid mice reconstituted with CD4+ CD45RBhigh T cells (Jiang et al. 2002)
• H. hepaticus may alter gene expression profiles in the cecum (Myles et al. 2003)

Immunology

• H. hepaticus hepatitis is associated with expression of heat shock protein 70 in the liver and with production of serum antibodies against this protein (Ward et al. 1996b)
• H. hepaticus hepatitis is associated with a Th1 cell-mediated immune response (Whary et al. 1998)
• H. hepaticus and H. bilis increase MHC class II expression and proinflammatory cytokine mRNA expression (skewed towards a Th1 phenotype) in the colons of immunodeficient mice with inflammatory bowel disease (Burich et al. 2001, Kullberg et al. 2001, Tomczak et al. 2003)
• H. hepaticus induces IkB degradation and NF-kB activation in macrophages (Tomczak et al. 2003)

Interactions with other infectious agents

• H. hepaticus may modulate the pathogenesis of mouse hepatitis virus infection (Compton et al. 2003)

Toxicology

• H. hepaticus produces a toxin with granulating cytotoxic activity in mouse liver cells (Taylor et al. 1995) and a cytolethal distending toxin which causes cell distension, accumulation of filamentous actin, and G2/M cell cycle arrest in HeLa cells (Young et al. 2000)

Oncology

• H. hepaticus may alter hepatocellular amd biliary epithelial apoptosis and proliferation indices (Ward et al. 1994a, Fox et al. 1996a, Nyska et al. 1997, Ihrig et al. 1999)
• H. hepaticus hepatitis is associated with increased oxidative DNA damage and overexpression of specific cytochrome P450 isoforms (Sipowicz et al. 1997), epidermal growth factor, transforming growth factor-a, cyclin D1, cyclin-dependent kinase 4, and c-Myc in the liver (Ramljak et al. 1998)
• chronic H. hepaticus infection may increase the incidence of liver tumors (Ward et al. 1994b, Fox et al. 1996a, Hailey et al. 1998) and promote the development and malignancy of liver tumors initiated by chemical carcinogens (Diwan et al. 1997)
• H. hepaticus-driven inflammatory bowel disease may promote colon cancer (Erdmann et al. 2003)
• H. hepaticus can contaminate transplantable tumors (Goto et al. 2001)

References:

Andersen LP (2001) New Helicobacter species in humans. Digestive Diseases 19, 112-5

Burich A, Hershberg R, Waggie K, Zeng W, Brabb T, Westrich G, Viney JL, Maggio-Price L (2001) Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice.
American Journal of Physiology - Gastrointestinal and Liver Physiology 281, G764-78

Cahill RJ, Foltz CJ, Fox JG, Dangler CA, Powrie F, Schauer DB (1997) Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infection and Immunity 65, 3126-31

Chin EY, Dangler CA, Fox JG, Schauer DB (2000) Helicobacter hepaticus infection triggers inflammatory bowel disease in T cell receptor ab mutant mice. Comparative Medicine 50, 586-94

Compton SR, Ball-Goodrich LJ, Zeiss CJ, Johnson LK, Johnson EA, Macy JD (2003) Pathogenesis of mouse hepatitis virus infection in gamma interferon-deficient mice is modulated by co-infection with Helicobacter hepaticus. Comparative Medicine 53, 197-206

De Groote D, Ducatelle R, Haesebrouck F (2000) Helicobacters of possible zoonotic origin: a review. Acta Gastro-Enterologica Belgica 63, 380-7

Diwan BA, Ward JM, Ramljak D, Anderson LM (1997) Promotion by Helicobacter hepaticus-induced hepatitis of hepatic tumors initiated by N-nitrosodimethylamine in male A/JCr mice. Toxicologic Pathology 25, 597-605

Erdmann SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH, Fox JG (2003) CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. American Journal of Pathology 162, 691-702

Fox JG, Dewhirst FE, Tully JG, Paster BJ, Yan L, Taylor NS, Collins MJ, Gorelick PL, Ward JM (1994) Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. Journal of Clinical Microbiology 32, 1238-45

Fox JG, Gorelick PL, Kullberg MC, Ge Z, Dewhirst FE, Ward, JM (1999) A novel urease-negative Helicobacter species associated with colitis and typhlitis in IL-10-deficient mice. Infection and Immunity 67, 1757-62

Fox JG, Lee A (1997) The role of Helicobacter species in newly recognized gastrointestinal tract diseases of animals. Laboratory Animal Science 47, 222-55

Fox JG, Li X, Yan L, Cahill RJ, Hurley R, Lewis R, Murphy JC (1996a) Chronic proliferative hepatitis in A/JCr mice associated with persistent Helicobacter hepaticus infection: a model of Helicobacter-induced carcinogenesis. Infection and Immunity 64, 1548-58

Fox JG, Yan LL, Dewhirst FE, Paster BJ, Shames B, Murphy JC, Hayward A, Belcher JC, Mendes EN (1995) Helicobacter bilis sp. nov., a novel Helicobacter species isolated from bile, livers, and intestines of aged, inbred mice. Journal of Clinical Microbiology 33, 445-54

Fox JG, Yan L, Shames B, Campbell J, Murphy JC, Li X (1996b) Persistent hepatitis and enterocolitis in germfree mice infected with Helicobacter hepaticus. Infection and Immunity 64, 3673-81

Franklin CL, Beckwith CS, Livingston RS, Riley LK, Gibson SV, Besch-Williford CL, Hook RR (1996) Isolation of a novel Helicobacter species, Helicobacter cholecystus sp. nov., from the gallbladders of Syrian hamsters with cholangiofibrosis and centrilobular pancreatitis. Journal of Clinical Microbiology 34, 2952-8

Franklin CL, Riley LK, Livingston RS, Beckwith CS, Besch-Williford CL, Hook RR (1998) Enterohepatic lesions in SCID mice infected with Helicobacter bilis. Laboratory Animal Science 48, 334-9

Franklin CL, Riley LK, Livingston RS, Beckwith CS, Hook RR, Besch-Williford CL, Hunziker R, Gorelick PL (1999) Enteric lesions in SCID mice infected with “Helicobacter typhlonicus”, a novel urease-negative Helicobacter species. Laboratory Animal Science 49, 496-505

Gebhart CJ, Fennell CL, Murtaugh MP, Stamm WE (1989) Campylobacter cinaedi is normal intestinal flora in hamsters. Journal of Clinical Microbiology 27, 1692-4

Goto K, Ishihara K-I, Kuzuoka A, Ohnishi Y, Itoh T (2001) Contamination of transplantable human tumor-bearing lines by Helicobacter hepaticus and its elimination. Journal of Clinical Microbiology 39, 3703-4

Goto K, Ohashi H, Takakura A, Itoh T (2000) Current status of Helicobacter contamination of laboratory mice, rats, gerbils, and house musk shrews in Japan. Current Microbiology 41, 161-6

Hailey JR, Haseman JK, Bucher JR, Radovsky AE, Malarkey DE, Miller RT, Nyska A, Maronpot RR (1998) Impact of Helicobacter hepaticus infection in B6C3F1 mice from twelve National Toxicology Program two-year carcinogenesis studies. Toxicologic Pathology 26, 602-11

Haines DC, Gorelick PL, Battles JK, Pike KM, Anderson RJ, Fox JG, Taylor NS, Shen Z, Dewhirst FE, Anver MR, Ward JM (1998) Inflammatory large bowel disease in immunodeficient rats naturally and experimentally infected with Helicobacter bilis. Veterinary Pathology 35, 202-8

Ihrig M, Schrenzel MD, Fox JG (1999) Differential susceptibility to hepatic inflammation and proliferation in AXB recombinant inbred mice chronically infected with Helicobacter hepaticus. American Journal of Pathology 155, 571-82

Jiang H-Q, Kushnir N, Thurnheer MC, Bos NA, Cebra JJ (2002) Monoassociation of SCID mice with Helicobacter muridarum, but not four other enterics, provokes IBD upon receipt of T cells. Gastroenterology 122, 1346-54

Kullberg MC, Rothfuchs AG, Jankovic D, Caspar P, Wynn TA, Gorelick PL, Cheever A, Sher A (2001) Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infection and Immunity 69, 4232-41

Kullberg MC, Ward JM, Gorelick PL, Caspar P, Hieny S, Cheever A, Jankovic D, Sher A (1998) Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infection and Immunity 66, 5157-66

Lee A, Phillips MW, O'Rourke JL, Paster BJ, Dewhirst FE, Fraser GJ, Fox JG, Sly LI, Romaniuk PJ, Trust TJ, Kouprach S (1992) Helicobacter muridarum sp. nov., a microaerophilic helical bacterium with a novel ultrastructure isolated from the intestinal mucosa of rodents. International Journal of Systematic Bacteriology 42, 27-36

Livingston RB, Myles MH, Livingston BA, Criley JM, Franklin CL (2004) Sex influence on chronic intestinal inflammation in Helicobacter hepaticus-infected A/JCr mice. Comparative Medicine 54, 301-8

Livingston RB, Riley LK (2003) Diagnostic testing of mouse and rat colonies for infectious agents. Lab Animal 32(5), 44-51

Maggio-Price L, Shows D, Waggie K, Burich A, Zeng W, Escobar S, Morrissey P, Viney JL (2002) Helicobacter bilis infection accelerates and H. hepaticus infection delays the development of colitis in multiple drug resistance-deficient (mdr1a-/-) mice. American Journal of Patholology 160, 739-51

Mendes EN, Queiroz DMM, Dewhirst FE, Paster BJ, Moura SB, Fox JG (1996) Helicobacter trogontum sp. nov., isolated from the rat intestine. International Journal of Systematic Bacteriology 46, 916-21

Myles MH, Livingston RS, Livingston BA, Criley JM, Franklin CL (2003) Analysis of gene expression in ceca of Helicobacter hepaticus-infected A/JCr mice before and after development of typhlitis. Infection and Immunity 71, 3885-93

Nyska A, Maronpot RR, Eldridge SR, Haseman JK, Hailey JR (1997) Alteration in cell kinetics in control B6C3F1 mice infected with Helicobacter hepaticus. Toxicologic Pathology 25, 591-6

Patterson MM, Schrenzel MD, Feng Y, Xu S, Dewhirst FE, Paster BJ, Thibodeau SA, Versalovic J, Fox JG (2000) Helicobacter aurati sp. nov., a urease-positive Helicobacter species cultured from gastrointestinal tissues of Syrian hamsters. Journal of Clinical Microbiology 38, 3722-28

Queiroz DMM, Contigli C, Coimbra RS, Nogueira AMMF, Mendes EN, Rocha GA, Moura SB (1992) Spiral bacterium associated with gastric, ileal and caecal mucosa of mice. Laboratory Animals 26, 288-94

Ramljak D, Jones AB, Diwan BA, Perantoni AO, Hochadel JF, Anderson LM (1998) Epidermal growth factor and transforming growth factor-a-associated overexpression of cyclin D1, Cdk4, and c-Myc during hepatocarcinogenesis in Helicobacter hepaticus-infected A/JCr mice. Cancer Research 58, 3590-7

Riley LK, Franklin CL, Hook RR, Besch-Williford C (1996) Identification of murine helicobacters by PCR and restriction enzyme analyses. Journal of Clinical Microbiology 34, 942-6

Robertson BR, O’Rourke JL, Vandamme P, On SLW, Lee A (2001) Helicobacter ganmani sp. nov., a urease-negative anaerobe isolated from the intestines of laboratory mice. International Journal of Systematic and Evolutionary Microbiology 51, 1881-9

Schauer DB, Ghori N, Falkow S (1993) Isolation and characterization of “Flexispira rappini” from laboratory mice. Journal of Clinical Microbiology 31, 2709-14

Shen Z, Fox JG, Dewhirst FE, Foltz CJ, Yan L, Shames B, Perry L (1997) Helicobacter rodentium sp. nov., a urease-negative Helicobacter species isolated from laboratory mice. International Journal of Systematic Bacteriology 47, 627-34

Shomer NH, Dangler CA, Schrenzel MD, Fox JG (1997) Helicobacter bilis-induced inflammatory bowel disease in scid mice with defined flora. Infection and Immunity 65, 4858-64

Simmons JH, Riley LK, Besch-Williford CL, Franklin CL (2000) Helicobacter mesocricetorum sp. nov., a novel Helicobacter isolated from the feces of Syrian hamsters. Journal of Clinical Microbiology 38, 1811-7

Sipowicz MA, Chomarat P, Diwan BA, Anver MA, Awasthi YC, Ward JM, Rice JM, Kasprzak KS, Wild CP, Anderson LM (1997) Increased oxidative DNA damage and hepatocyte overexpression of specific cytochrome P450 isoforms in hepatitis of mice infected with Helicobacter hepaticus. American Journal of Pathology 151, 933-41

Taylor NS, Fox JG, Yan L (1995) In-vitro hepatotoxic factor in Helicobacter hepaticus, H. pylori, and other Helicobacter species. Journal of Medical Microbiology 42, 48-52

Tomczak MF, Erdman SE, Poutahidis T, Rogers AB, Holcombe H, Plank B, Fox JG, Horwitz BH (2003) NF-kB is required within the innate immune system to inhibit microflora-induced colitis and expression of IL-12 p40. Journal of Immunology 171, 1484-92

Wang TC, Fox JG (1998) Helicobacter pylori and gastric cancer: Koch’s postulates fulfilled? Gastroenterology 115, 780-3

Ward JM, Anver MR, Haines DC, Benveniste RE (1994a) Chronic active hepatitis in mice caused by Helicobacter hepaticus. American Journal of Pathology 145, 959-68

Ward JM, Anver MR, Haines DC, Melhorn JM, Gorelick P, Yan L, Fox JG (1996a) Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Laboratory Animal Science 46, 15-20

Ward JM, Benveniste RE, Fox CH, Battles JK, Gonda MA, Tully JG (1996b) Autoimmunity in chronic active Helicobacter hepatitis of mice. Serum antibodies and expression of heat shock protein 70 in liver. American Journal of Patholology 148, 509-17

Ward JM, Fox JG, Anver MR, Haines DC, George CV, Collins MJ, Gorelick PL, Nagashima K, Gonda MA, Gilden RV, Tully JG, Russell RJ, Benveniste RE, Paster BJ, Dewhirst FE, Donovan JC, Anderson LM, Rice JM (1994b) Chronic active hepatitis and associated liver tumors in mice caused by a persistent bacterial infection with a novel Helicobacter species. Journal of the National Cancer Institute 86, 1222-7

Whary MT, Cline J, King A, Ge Z, Shen Z, Sheppard B, Fox JG (2001) Long-term colonization levels of Helicobacter hepaticus in the cecum of hepatitis-prone A/JCr mice are significantly lower than those in hepatitis-resistant C57BL/6 mice. Comparative Medicine 51, 413-7

Whary MT, Fox JG (2004) Natural and experimental Helicobacter infections. Comparative Medicine 54, 128-58

Whary MT, Morgan TJ, Dangler CA, Gaudes KJ, Taylor NS, Fox JG (1998) Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response. Infection and Immunity 66, 3142-8

Young VB, Knox KA, Schauer DB (2000) Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus. Infection and Immunity 68, 184-91