Helicobacter hepaticus

H. hepaticus is currently the most well-studied enterohepatic Helicobacter species. The discovery of H. hepaticus in 1992 is a cautionary tale that illustrates the insidious nature of this emerging group of pathogens. At that time, investigators at the National Cancer Institute–Frederick Cancer Research and Development Center recognized that male A/JCr mice serving as saline-injected controls in a long-term chemical carcinogenesis assay had a higher incidence of liver tumors than expected (129). Historically, approximately 1% of male mice of this inbred strain developed hepatocellular tumors by 15 months of age. However, evaluation of tissue from animals euthanized in the autumn of 1992 revealed liver tumors in 3 of 6 mice, and in December of that year liver tumors were found in 11 of 12 mice (129). All of the animals with liver tumors also had chronic active hepatitis. Contamination with an environmental chemical was initially suspected as the cause of the hepatocellular tumors and the hepatitis, but extensive analyses of food, bedding, and water proved negative (129). An environmental toxin seemed even less likely when it was discovered that mice in the breeding colony, housed in a separate facility, also had hepatic lesions. Hepatitis was worse in males than in females and was documented in A/JCr, C3H/HeNCr, SJL/NCr, BALB/cAnNCr, and SCID/NCr mice, but not in C57BL/6NCr mice (129). A/J mice without hepatitis were obtained from a commercial vendor, and when the disease was shown to be transmissible by inoculating these animals with homogenates of liver from affected A/JCr mice, the search for an infectious agent was intensified. Using Steiner's silver impregnation as a special stain, spiral-shaped bacteria were found in bile canaliculi and gallbladders of affected mice (129). It was then that microaerobic culture and isolation were performed on liver tissue and on cecal and colonic mucosal scrapings (38).

Fox et al. isolated H. hepaticus by incubating liver and cecal and colonic mucosal samples from mice with chronic active hepatitis for 3 to 7 days under anaerobic or microaerobic, but not aerobic, conditions (38). H. hepaticus grows as a spreading film on solid media supplemented with serum or blood at 37°C, but not at 42 or 25°C. The organism is spiral shaped, 1.5 to 5 μm long, and 0.2 to 0.3 μm in diameter and has bipolar sheathed flagella but no periplasmic fibers. H. hepaticus exhibits catalase, urease, and oxidase activity, and by 16S rRNA gene sequence, it represents a distinct species of Helicobacter most closely related to H. muridarum (38). H. hepaticus is now known to cause chronic active hepatitis and typhlitis in many susceptible strains and stocks of mice (42, 126, 129), and hepatic neoplasia in male A/J (42, 129) and B6C3F1 mice (43, 51). H. hepaticus has also been associated with inflammatory bowel disease (IBD)-like lesions in a variety of mouse lines with altered immune function (10, 13, 64, 68, 125, 127). Infection with H. hepaticus is highly prevalent in laboratory mouse colonies (99), but the organism has not been isolated from other host species. In immunocompetent mice, there are no clinical signs of disease and no obvious reduction in breeding efficiency. Thus, many investigators may not be aware that their mice are infected with H. hepaticus.

Helicobacter cinaedi and Helicobacter fennelliae

First identified as Campylobacter species, H. cinaedi and H. fennelliae are spiral-shaped organisms that resemble H. hepaticus morphologically but do not produce urease. Totten et al. isolated these organisms from rectal swabs taken from homosexual men (119). Over 30 isolates of H. cinaedi (from the Latin for "of a homosexual") were recovered from asymptomatic individuals and individuals with proctitis, proctocolitis, and enteritis. Another six isolates, all recovered from patients with clinical signs, were shown to comprise a distinct species and were named H. fennelliae after Cynthia Fennell, the technologist who first isolated the organism. A lone isolate from a symptomatic individual was designated Campylobacter-like organism 3 (CLO-3) and has still not been named (119). Additional isolates of H. cinaedi from dogs, cats, and Syrian hamsters were shown by DNA-DNA hybridization to belong to a single species (61). Although the hamsters from which H. cinaedi was isolated appeared healthy (49), experimental inoculation of infant pig-tailed macaques with H. cinaedi or H. fennelliae caused diarrhea and bacteremia (28).

H. cinaedi has been documented as a cause of acute diarrhea in otherwise healthy individuals (116); however, bacteremia without gastroenteritis is more frequently associated with H. cinaedi and H. fennelliae infection in immunocompromised patients with AIDS (15, 56, 72, 77, 94, 124) or other underlying conditions (55, 118). These infections can manifest as cellulitis or septic arthritis (7, 114, 118). H. cinaedi is also a rare cause of bacteremia and/or septic arthritis in immunocompetent individuals (65, 122), and a case of meningitis in a neonate has been reported (82). Thus, H. cinaedi and H. fennelliae have zoonotic potential and cause invasive disease as well as gastroenteritis in humans, particularly in immunocompromised individuals.

There are also reports of other enterohepatic Helicobacter species being isolated from immunocompromised patients with bacteremia. "H. mainz" was isolated from an AIDS patient with septic arthritis (57) and from two other AIDS patients with bacteremia (27). Provisionally named after Mainz, Germany, the city where it was first isolated, these isolates have a 16S rRNA gene sequence that is 97.7% similar to H. fennelliae. Likewise, "H. westmeadii" was isolated from two AIDS patients with bacteremia and provisionally named after Westmead, New South Wales, Australia (120). A similar organism was isolated by Weir et al. from a third AIDS patient (131). Because the 16S rRNA gene sequence of these isolates is very similar to that of H. cinaedi, they may not represent a distinct species. Indeed, Vandamme et al. recently concluded on the basis of protein profiling and qualitative dot blot DNA-DNA hybridization that both "H. mainz" and "H. westmeadii" are in fact H. cinaedi strains (123).

Helicobacter canis

A separate group of isolates was recovered from the feces of dogs with or without diarrhea. These isolates morphologically resemble H. hepaticus but grow at 42°C as well as at 37°C and do not exhibit urease activity. By DNA-DNA hybridization and 16S rRNA gene sequencing, these strains were shown to comprise a distinct species that was named H. canis (111). H. canis has also been isolated from a 5½-year-old boy with gastroenteritis (9) and the liver of a 2-month-old puppy with multifocal necrotizing hepatitis (39). More recently, H. canis has been isolated from Asian leopard cat–domestic cat hybrids (Bengal cats) with a 6-month history of episodic diarrhea that were coinfected with Campylobacter helveticus (29). Further studies are needed, but it appears that H. canis can cause hepatic disease as well as gastroenteritis in carnivores such as dogs and cats, as well as in humans. Like H. hepaticus, H. canis has cdt gene homology and expresses CDT activity (12).

Foley et al. have described an organism that was identified in the intestine of a kitten with diarrhea (30). This organism was provisionally named "H. colifelis" and was found to have a 16S rRNA gene sequence 98.3% similar to that of H. canis. Because the organism was not successfully cultured, it is difficult to determine whether this in fact represents a novel enterohepatic Helicobacter species.

Helicobacter pametensis and Helicobacter pullorum

H. pametensis and H. pullorum have been shown to infect birds and mammals. H. pametensis was first isolated from the feces of wild birds and a domestic pig near the Pamet River on Cape Cod, Mass. (98). Six isolates were characterized by 16S rRNA gene sequencing and were found to represent a single, distinct species (22). In addition, other Helicobacter species were isolated from terns and a house sparrow. These Helicobacter species were designated Helicobacter sp. Bird-B and Helicobacter sp. Bird-C, respectively, and have not yet been named (22). H. pametensis has also been isolated from the stomach of a cat coinfected with "H. heilmannii" (76); however, there is no evidence that H. pametensis persistently infects the stomach or causes gastritis.

H. pullorum was designated as a separate species on the basis of 16S rRNA gene sequencing (110). Isolates were recovered from the ceca of subclinically infected broiler chickens, the liver and intestinal contents of laying hens with vibrionic hepatitis, and humans with gastroenteritis (2, 110, 113). One individual, in addition to having diarrhea, also developed elevated liver enzymes and hepatomegaly (8). There is clearly a potential for zoonotic food-borne transmission of H. pullorum to humans, as is known to occur with Campylobacter species. While both H. pametensis and H. pullorum are urease negative and grow readily at 42 as well as 37°C, they can be distinguished by the fact that the flagella of H. pametensis are sheathed, but the flagella of H. pullorum are not (110). Several studies have shown that a polyphasic approach should be used to distinguish H. pullorum from other enterohepatic Helicobacter species and from Campylobacter species because identification based on a single test is unreliable (2, 73, 110, 112). Recently, isolates that had been identified as H. pullorum on the basis of a species-specific PCR assay were shown to in fact represent a separate species designated H. canadensis (36). H. pullorum produces CDT, hydrolyzes indole acetate, and is sensitive to nalidixic acid, while H. canadensis does not produce CDT, does not hydrolyze indole acetate, and is resistant to nalidixic acid (36, 73, 134). The species can also be distinguished by molecular genotyping methods such as amplified fragment length polymorphism or pulsed-field gel electrophoresis (50).

Other Urease-negative Helicobacter Species from Mice and Hamsters

H. rodentium is a urease negative, spiral-shaped organism that grows at 42 as well as 37°C (101). Like H. pullorum, H. rodentium has unsheathed flagella. This organism was first isolated from subclinically infected laboratory mice. Subsequently, Shomer et al. reported an outbreak of diarrhea in a colony of SCID mice carrying mutations in the p53 tumor suppressor gene that were coinfected with H. rodentium and H. bilis (103). The true pathogenic potential of H. rodentium in immunodeficient and immunocompetent mice remains to be determined.

A distinct enterohepatic Helicobacter species was isolated from H. hepaticus-free IL-10-deficient mice with IBD (40). Experimentally infected IL-10-deficient mice developed typhlocolitis and proctitis by 4 months postinoculation. Although the infected IL-10-deficient mice had focal hepatic granulomatous inflammation and mild cholangitis, no bacteria were seen in the liver. In SCID mice experimentally infected with this organism, there was mild to moderate proliferative typhlitis at 4 months postinoculation, while experimentally infected A/JCr mice had minimal to mild typhlitis 6 months postinoculation (40). The 16S rRNA gene sequence of this organism is essentially identical to the provisionally named "H. typhlonicus," which has also been shown to cause IBD, but not hepatitis, in experimentally infected SCID mice (48).

H. cholecystus has been isolated from the gall-bladder of Syrian hamsters with cholangiofibrosis and centrilobular pancreatitis (46). This organism is somewhat morphologically distinct from the other enterohepatic Helicobacter species without periplasmic fibers in that it has a rod-shaped protoplasmic cylinder and a single polar, sheathed flagellum. H. cholecystus is urease negative and grows at 42 as well as 37°C.

More recently, H. mesocricetorum has been isolated from apparently healthy Syrian hamsters (105). By 16S rRNA gene sequencing, H. mesocricetorum was found to be most closely related to H. rodentium. Both organisms grow at 42 as well as 37°C and have unsheathed flagella. Like H. rodentium, the true pathogenic potential of H. mesocricetorum remains to be determined.

H. muridarum

Phillips and Lee isolated H. muridarum from the intestine of Wistar rats and BALB/c mice in 1983, almost 10 years before it would be formally named as a Helicobacter species (85). The isolates grew slowly in microaerobic conditions, spreading as a thin film after a few days of incubation at 37°C, even on media containing 3% agar. H. muridarum is indistinguishable from the organisms observed by Davis et al. (19) and Erlandsen and Chase (26). It is 3.5 to 5 μm long and 0.5 to 0.6 μm in diameter, with two to three spiral turns, periplasmic fibers, and bipolar tufts of sheathed flagella. By 16S rRNA gene sequencing, H. muridarum was shown to be a distinct enterohepatic Helicobacter species (67).

By microscopic visualization, H. muridarum was found to have a higher density of colonization in the ileum than the cecum or colon in conventional mice and rats (85). However, when gnotobiotic animals were experimentally inoculated with pure cultures of H. muridarum, no ileal crypts in mice and few ileal crypts in rats contained spirals. Instead, the cecum, and to a lesser extent the colon, was found to contain the greatest density of organisms. This suggests that in the absence of competing microbiota, the large intestine, and the cecum in particular, is the primary site of colonization by H. muridarum. Phillips and Lee also observed H. muridarum free in the cytoplasm of epithelial cells lining the crypts in gnotobiotic mice and rats, but not in conventional animals. Intracellular H. muridarum was associated with pathologic changes, including vacuole formation and mitochondrial swelling (85). Thus, H. muridarum can invade the intestinal mucosa of rodents, and its presence is associated with cellular degeneration. The circumstances under which tissue invasion occurs and the ultimate fate of the invading bacteria remain to be determined.

"Helicobacter rappini"

"Flexispira rappini" is the provisional name given to a diverse group of organisms that all have a fusiform shape, helically wound periplasmic fibers, and bipolar tufts of sheathed flagella (5). The species is named for Rappin, who in 1881 described spiral organisms in the gastric mucosa of dogs. The provisional name "F. rappini" should be abandoned in favor of the combined name "Helicobacter rappini," since several studies have shown that these organisms are members of this taxon (35, 37, 45, 67, 96). By 16S rRNA gene sequencing, there are at least 10 separate species that comprise this group of bacteria (21), including the named species H. bilis (45) and H. trogontum (74). Members of the remaining eight species have been isolated from aborted sheep fetuses (16, 63), humans with or without diarrhea (17, 54, 91, 109, 117, 130), dogs (25, 59, 91), and apparently healthy laboratory mice (96). One of the eight species, which has not yet been named, is represented exclusively by strains isolated from cotton-top tamarins with colitis (95).

Organisms fitting the description of "H. rappini" were first isolated from late-term aborted sheep fetuses by Kirkbride et al. (63). The fetal lambs had focal hepatic necrosis that was suggestive of infection with Campylobacter species. However, culture of fetal liver, lung, and abomasal contents yielded "H. rappini" after a week of microaerobic incubation (63). Koch's postulates were fulfilled by producing abortion in a small percentage of pregnant ewes inoculated intravenously with "H. rappini" (62). Bryner et al. went on to show that intraperitoneal inoculation of pregnant guinea pigs caused abortion featuring suppurative placentitis and splenitis (6). The organism was cultured from heart blood at necropsy of the guinea pigs 11 days after inoculation, suggesting persistent bacteremia. Characterization of this "H. rappini" isolate demonstrated that it was positive for catalase, oxidase, and urease activity (1). "H. rappini" isolates that were catalase, oxidase, and urease negative were recovered from the placenta, liver, and abomasal contents of aborted lambs in Britain (16), but these isolates have not been extensively characterized and may represent a separate taxon.

H. bilis

First identified in aged, inbred mice with chronic hepatitis, H. bilis is a distinct species that also has an "H. rappini"-like ultrastructure (45). Fox et al. recovered H. bilis from the liver and the intestine of subclinically infected C57BL/6, CBA/CA, DBA/2, and BALB/c mice between 19 and 27 months of age. The isolates grew at 42 as well as 37°C and exhibited catalase, oxidase, and urease activities. Growth was observed in the presence of bile, at concentrations of up to 20%. Infection with H. bilis has also been associated with typhlocolitis and diarrhea in immunodeficient rodents. The first case report described dual infection with both H. bilis and H. rodentium (103). The affected animals were SCID mice and had germ line mutations in the p53 tumor suppressor gene. These animals were a combination of C57BL/6 and 129/Sv crossed with a C.B-17 genetic background, and they developed epizootic diarrhea associated with proliferative typhlocolitis. Younger animals in particular had marked thickening of the colon, with dramatic crypt elongation and bloody mucoid diarrhea (103). The only liver lesions seen in these young animals were consistent with septicemia. One adult female SCID mouse also developed diarrhea and rectal prolapse.

Two groups have fulfilled Koch's postulates with H. bilis in SCID mice. Shomer et al. experimentally inoculated defined flora outbred ICR SCID mice with the H. bilis type strain (104). Franklin et al. inoculated inbred C.B-17 SCID mice with a different strain of H. bilis (47). Defined flora SCID mice, which have a microbiota composed entirely of eight species of anaerobic bacteria (the altered Schaedler's flora) (20), developed a proliferative typhlocolitis. Some of the experimentally inoculated mice developed diarrhea, but at 7 weeks postinoculation, which was the conclusion of the study, there was no evidence of hepatitis (104). Conversely, the C.B-17 SCID mice with conventional microbiota did not exhibit clinical signs of disease. By 3 months postinoculation, the animals had proliferative typhlitis and more mild lesions in the proximal colon (47). Male mice also developed chronic active hepatitis by 3 months postinoculation. Liver lesions were seen in the female mice at 6 and 9 months postinoculation.

H. bilis has also been isolated from outbred athymic nude rats with typhlitis (52). These animals, some of which exhibited mild diarrhea, had proliferative typhlitis with or without colonic inflammation. The 5- to 8-month-old male rats did not have any significant lesions in the stomach or in the liver. The H. bilis isolate was inoculated by intraperitoneal injection into Helicobacter-free 2-month-old male outbred nude rats (52). These animals lost weight and some developed watery diarrhea 2 to 3 months postinoculation. All of the experimentally inoculated rats developed proliferative typhlocolitis that was seen as early as 1 month postinoculation. None of these animals developed any significant lesions in the stomach or in the liver.

Like "H. rappini," H. bilis may be transmitted between host species and cause zoonotic infections. As mentioned above, a Helicobacter isolate from the stomach of a random-source laboratory dog was identified as H. bilis by 16S rRNA gene sequencing (25). Sequencing of PCR-amplified 16S rRNA gene fragments has also been used to show that H. bilis can infect the gallbladder of humans with chronic cholecystitis (37). Thus, it seems likely that H. bilis-associated diseases are not limited to laboratory rats and mice. In unpublished studies, H. bilis has also been isolated from the stomach and the cecum of gerbils and from the feces of cats (37).

H. trogontum

A Helicobacter species that seemed essentially identical to H. bilis was isolated from the colonic mucosa of Holtzman and Wistar rats by Mendes et al. (74). Like H. bilis, H. trogontum grows at 42 as well as 37°C, but not at 25°C. H. trogontum is positive for urease, catalase, and oxidase activities. Despite the phenotypic similarities, nucleotide sequence determination of 16S rRNA gene fragments from H. trogontum showed it to differ from that of H. bilis by 3.9% and from that of Kirkbride's ovine "H. rappini" isolate by 4.3% (74). Thus, H. trogontum is a distinct species. Experimental inoculation of gnotobiotic outbred mice resulted in primarily cecal colonization, with fewer organisms in the colon, at 3 weeks postinoculation (75). Transmission electron microscopy revealed that, like H. muridarum, H. trogontum invades enterocytes in the cecum of gnotobiotic mice, where it is found free in the cytoplasm. An organism with an ultrastructure indistinguishable from H. trogontum was seen in the common bile duct of rats experimentally inoculated with the liver fluke Fasciola hepatica (34). Since the organism was not cultured, it is not clear if these rats were infected with H. trogontum, H. bilis, or another member of the "H. rappini" group of species. It remains to be determined whether H. trogontum can colonize the liver of rats and whether rats are susceptible to Helicobacter-associated hepatitis.

Helicobacter aurati

H. aurati (from the Latin for "of the golden one" referring to the Syrian golden hamster, Mesocricetus auratus) has been isolated from hamsters with chronic gastritis, intestinal metaplasia, and typhlitis (84). H. aurati has a typical "H. rappini"-like ultrastructure with a fusiform shape, periplasmic fibers, and bipolar tufts of sheathed flagella. The organism grows at 42 as well as 37°C and is positive for catalase, oxidase, and urease. By 16S rRNA gene sequence, H. aurati is a distinct species, more closely related to H. muridarum and H. hepaticus than to any of the "H. rappini" species. Because H. aurati was isolated from hamsters coinfected with a second novel Helicobacter species and a Campylobacter species (83), the contribution of each organism to gastritis, intestinal metaplasia, and typhlitis remains to be determined. Still, it seems likely that the primary site of infection by H. aurati is the intestine, and like H. muridarum, it can reach the stomach and cause gastritis under certain conditions.

Enterohepatic Helicobacter Species in Human Liver Disease

Sequencing of PCR-amplified 16S rRNA gene fragments has been used to show that enterohepatic Helicobacter species can infect the gallbladder of humans with chronic cholecystitis (37). Nine of 23 gall-bladders and 13 of 23 bile samples taken from Chilean patients undergoing cholecystectomy were PCR positive for Helicobacter species (37). Although culture and isolation were also attempted, no Helicobacter organisms were recovered from the samples. The complete nucleotide sequence of eight of the amplicons was determined. Five of these were found to be H. bilis (37). Two of amplicons were "H. rappini" with a high degree of similarity to the 16S rRNA gene sequence of the isolates described by Romero et al. (91). One additional amplicon was found to be H. pullorum. Establishing a causal relationship between H. bilis infection and human diseases, including chronic cholecystitis and biliary cancer, for which the Chilean population is at high risk, will require further studies.

Other studies have failed to detect Helicobacter species in bile from patients with hepatobiliary disease (92) or have found evidence of H. pylori in association with cholangitis (60, 69, 90), primary sclerosing cholangitis, and/or primary biliary cirrhosis (78–80), or hepatocellular carcinoma (3). Nonetheless, additional studies on enterohepatic Helicobacter species as a cause of human hepatobiliary disease are warranted. Given the extraordinary impact that the discovery and characterization of H. pylori have had on our understanding of gastroduodenal disease, it is perhaps not surprising that other species in this remarkable genus are emerging as important causes of enterohepatic disease in humans and in animals.

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