Helicobacter spp.

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), H. mastomyrinus (Shen et al. 2005), H. pullorum (Boutin et al. 2010) • 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), H. ganmani (Johansson et al. 2006), H. pullorum (Cacioppo et al. 2012) • 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), H. rodentium (Bergin et al. 2005). Additional Helicobacter spp. have been detected in laboratory rodents but they have not yet been formally named as Helicobacter species (Shomer et al. 2001, Bohr et al. 2006, Nambiar et al. 2006, Fox et al. 2009, Yamanaka et al. 2013). This compilation will focus mainly on H. hepaticus because it is the most prominent of the rodent Helicobacter spp. (Taylor et al. 2007) and is responsible for the most lesions. For further information about the impact of H. hepaticus on animal experiments, the reader is referred to a review article by Fox et al. (2011).

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 hepatitis, 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, Rag2tm1Fwa) and selected immunocompetent strains of mice (e.g., A/JCr, C3H/HeN) are prone to develop inflammatory bowel disease in response to infections with H. hepaticus (Ward et al. 1996a, Burich et al. 2001, Erdmann et al. 2003, Livingston et al. 2004), H. bilis (Shomer et al. 1997, Burich et al. 2001, Jergens et al. 2007, Nguyen et al. 2013), H. typhlonius (Fox et al. 1999, Franklin et al. 1999), H. ganmani (Zhang et al. 2005), H. rodentium (Chichlowski et al. 2008), or H. mastomyrinus (Eaton et al. 2011)

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, Rogers et al. 2004) or H. bilis (Fox et al. 1995, Franklin et al. 1998, Fox et al. 2004) • 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) • ulcerative typhlocolitis in telomerase-deficient mice infected with H. mastomyrinus (Eaton et al. 2011) • 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, age, and intestinal microbiota composition 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, Rogers et al. 2004, Yang et al. 2013), bacterial exposure timing (Rogers et al. 2004), and bacterial virulence factors (Boutin et al. 2005, Mehta et al. 2005, Ge et al. 2008a, Ge et al. 2008b, Ge et al. 2008c, Bartonickova et al. 2013)

Zoonotic potential • unclear; some Helicobacter spp. demonstrate zoonotic potential and may cause human disease (e.g., H. cinaedi, H. pullorum, 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) • H. hepaticus changes numerous metabolite pathways, including tryptophan metabolism, glycerophospholipids, methionine-homocysteine cycle, citrate cycle, fatty acid metabolism and purine metabolism, with the majority of metabolites being down-regulated (Lu et al. 2012) • infections with H. typhlonius, H. rodentium, or both reduce reproductive performance in IL10-deficient mice (Sharp et al. 2008)

Pathology • H. hepaticus, H. bilis, H. typhlonius, H. muridarum, H. ganmani, H. rodentium, and H. mastomyrinus 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, Jiang et al. 2002, Zhang et al. 2005, Chichlowski et al. 2008, Eaton et al. 2011, Liu et al. 2011, Nguyen et al. 2013); in contrast, H. hepaticus delays the development of inflammatory bowel disease in multiple drug resistance- deficient mice (Maggio-Price et al. 2002) • H. hepaticus increases intestinal injury in a rat model of necrotizing enterocolitis (Dvorak et al. 2013) • H. hepaticus may alter gene expression profiles in the cecum (Myles et al. 2003, Myles et al. 2007) and liver (Boutin et al. 2004) • infection with H. bilis or co-infection with H. hepaticus and H. rodentium accelerates the formation of cholesterol gallstones in C57L/J mice fed a lithogenic diet (Maurer et al. 2005)

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-induced hepatitis and typhlitis are associated with a Th1 cell-mediated immune response (Whary et al. 1998, Myles et al. 2007) • 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 IκB degradation and activation of NF-κB and ERK in bone-marrow- derived macrophages (Tomczak et al. 2003, Tomczak et al. 2006) • H. hepaticus modulates intestinal muscularis macrophage responses to become more anti- inflammatory and resistant to secondary stimulation (Hoffman & Fleming 2010) • H. hepaticus inhibits innate immune responses of intestinal epithelial cells (Sterzenbach et al. 2007) • H. hepaticus increases expression of immune-related genes in the cecum (Myles et al. 2003, Myles et al. 2004, Myles et al. 2007) and liver (Boutin et al. 2004, Garcia et al. 2008) • H. hepaticus-driven typhlocolitis is associated with an increased production of IL-17, IL- 22, IL-23, and IFN-γ in the large intestine (Hue et al. 2006, Kullberg et al. 2006, Buonocore et al. 2010) • H. hepaticus modulates the mechanism of hemorrhage-induced intestinal damage and inflammation from a complement-mediated response to a macrophage response with elevated TNF-α and nitric oxide (Hylton et al. 2010) • H. hepaticus alters MyD88 and Trif signalling in response to intestinal ischaemia/ reperfusion (Hoffman et al. 2011) • H. hepaticus increases levels of TLR4 receptor, expression of proinflammatory cytokines CXCL1, IL-1β, IL-12, and IL-23, and alters activation of autophagy in a rat model of necrotizing enterocolitis (Dvorak et al. 2013) • H. bilis triggers IgG antibody and T cell responses (increased production of IFN-γ, TNF-α, IL-6, and IL-12) to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice (Jergens et al. 2007)

Interactions with other infectious agents • H. hepaticus may modulate the pathogenesis of mouse hepatitis virus infection (Compton et al. 2003) • H. hepaticus delays recovery from acute diarrheal disease induced by Citrobacter rodentium (McBee et al. 2008) • Coinfection with enterohepatic Helicobacter spp. can ameliorate or promote H. pylori- induced gastric pathology in C57BL/6 mice (Lemke et al. 2009, Ge et al. 2011)

Toxicology • H. hepaticus produces a toxin with granulating cytotoxic activity in mouse liver cells (Taylor et al. 1995) • H. hepaticus produces cytolethal distending toxin (CDT) which causes cell distension,

accumulation of filamentous actin, and G2/M cell cycle arrest in HeLa cells (Young et al. 2000) and apoptosis in intestinal epithelial cells (Liyanage et al. 2010, Liyanage et al. 2013); in addition, CDT activity has been found in several other helicobacters, including H. bilis, H. cinaedi, H. mastomyrinus, and H. pullorum (Shen et al. 2005, Ge et al. 2008b)

Oncology • H. hepaticus may alter hepatocellular and 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-α, 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, Nagamine et al. 2008a) • H. hepaticus may increase expression of genes associated with neoplasia and proliferation in the liver (Boutin et al. 2004) • H. hepaticus, H. bilis, H. typhlonius, H. rodentium, or co-infection with Helicobacter spp. promotes the development of colonic cancer associated with inflammatory bowel disease in immunodeficient mice (Engle et al. 2002, Erdman et al. 2003, Maggio-Price et al. 2006, Hale et al. 2007, Chichlowski et al. 2008, Mangerich et al. 2012, Nguyen et al. 2013) • H. hepaticus promotes intestinal, mammary, and prostate tumor development in ApcMin/+ mice (Rao et al. 2006, Nagamine et al. 2008b, Poutahidis et al. 2013) • H. hepaticus can contaminate transplantable tumors (Goto et al. 2001)

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Authors: M. Mähler / H. Meyer

Date: 15/10/2013