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Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

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Helicobacter pylori: Physiology and Genetics.

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Chapter 43Enterohepatic Helicobacter Species

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Most of the members of the genus Helicobacter do not normally colonize the gastric mucosa, but instead thrive in the mucosal surfaces of the intestinal tract and/or the liver of humans, other mammals, and birds. These enterohepatic Helicobacter species have features of ultrastructure and physiology in common with Helicobacter pylori and the other gastric Helicobacter species, and have been the subject of several recent reviews (35, 41, 108). Because the enterohepatic Helicobacter species were first recognized in laboratory rodents, in which they are highly prevalent in most inbred strains and outbred stocks, they have been considered a component of the resident microbiota, or "normal flora." It is now clear that some of the enterohepatic Helicobacter species, and perhaps all, have the ability to cause disease in normal, immunocompetent rodents. A growing number of enterohepatic Helicobacter species have also been reported to be associated with gastroenteritis, hepatitis, and other disease states in humans and in other animal species. The significance of the enterohepatic Helicobacter species in human disease and the true prevalence of these organisms in human populations remain to be determined. What follows is a survey of this emerging group of organisms.

Early studies characterizing the resident microbiota in the gut of laboratory rodents led to the discovery of a diverse population of spiral-shaped bacteria uniquely adapted to thrive in the mucosal surfaces of the intestine. These early studies, which used transmission electron microscopy rather than culture and isolation, described two morphologic types of organisms, both of which are now known to be enterohepatic Helicobacter species. Members of the first group superficially resemble Campylobacter species but are longer and have a single polar flagellum at each end. Representative organisms are shown in Fig. 1 and are listed in Table 1 as having no periplasmic fibers. Members of the second group have periplasmic fibers that wrap helically around the body of the bacterium as well as bipolar tufts of sheathed flagella. Representative organisms are shown in Fig. 2 and are listed in Table 1 as having periplasmic fibers. In studies that characterized the patterns of bacterial colonization of the large intestine of laboratory rodents, Davis et al. identified both morphologic types of organisms in the mucus of the cecum and colon (18, 19). The bacteria could be found during the first week of life, and they remained on the surface of the intestinal epithelium and packed deep in the crypts throughout the life of the animals.

Figure 1. Transmission electron micrograph of H.

Figure 1

Transmission electron micrograph of H. hepaticus grown in pure culture (A), scanning electron micrograph of an organism with typical H. hepaticus ultrastructure in the intestine of a mouse (more...)

Table 1. Selected characteristics of enterohepatic Helicobacter speciesa.

Table 1

Selected characteristics of enterohepatic Helicobacter speciesa.

Figure 2. Transmission electron micrographs of "H.

Figure 2

Transmission electron micrographs of "H. rappini" grown in pure culture (A), and in an intestinal crypt in a mouse (B), and scanning electron micrograph of "H. rappini" on the mucosal surface (more...)

Perhaps because their ultrastructure is less remarkable, the early literature contains fewer reports of the simple spiral-shaped organisms than of the organisms with periplasmic fibers. Nonetheless, the simple spiral-shaped organisms have been isolated from a variety of mammals, including humans, pigs, dogs, cats, mice, rats, hamsters, gerbils, and several wild and domestic species of birds. The distinction between these organisms and the organisms with periplasmic fibers has a morphologic basis only. No comparable phylogenetic dichotomy has been recognized. On the other hand, the presence of periplasmic fibers has facilitated the recognition of members of the second group of enterohepatic Helicobacter species in a variety of locations. Spiral-shaped bacteria with periplasmic fibers were observed free in the cytoplasm of enterocytes as well as deeper in the lamina propria of mice following treatment with nitrogen mustard (53). Such treatment results in a generalized loss of epithelial integrity, but it is interesting to note that the enterohepatic Helicobacter species were the only organisms found to invade under these conditions. The abundance of these organisms in the mucus deep in the crypts of the ileum and their proximity to the apical surface of the epithelial cells lining the crypts may account, at least in part, for these observations. Erlandsen and Chase exploited the ultrastructural characteristics of these organisms to ascertain the fate of bacteria following phagocytosis from the crypts by differentiated enterocytes in the ileum of untreated rats (26). Davis et al. also noted the occasional penetration of enterohepatic Helicobacter species into the epithelium of the rat cecum (19). More recently, invasion into the lamina propria of the cecum by enterohepatic Helicobacter species in mice following challenge with the spirochete Serpulina hyodysenteriae has been reported (58). The significance of cell entry and/or tissue invasion by enterohepatic Helicobacter species and the conditions under which these events take place have not been fully elucidated. Tissue invasion may be a prerequisite for or a consequence of Helicobacter-associated disease in the gastrointestinal tract. It may also play a role in bacterial translocation to the liver and/or into systemic circulation, either as a primary event or secondary to other disease states.

The fact that many investigators have encountered enterohepatic Helicobacter species with periplasmic fibers in the gastrointestinal tract of laboratory rodents no doubt reflects the frequency with which these animals are used in biomedical research. Bacteria with the same morphology have also been isolated from the gastrointestinal tract of many mammal species, including humans, monkeys, sheep, pigs, dogs, cats, mice, rats, hamsters, and gerbils. The complete range of host species from which these organisms can be isolated is not known. It may be that such bacteria can flourish wherever a mucus-rich interface between epithelial cells and the lumen of an alimentary tract is found. Certainly the observation of bacteria that appear morphologically indistinguishable from enterohepatic Helicobacter species in the hind-gut of Periplaneta americana, the American cockroach (4), suggests that the distribution of these microbes is wide indeed.

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.

Liver Disease

In naturally infected A/JCr mice, H. hepaticus causes focal nonsuppurative necrotizing hepatitis that progresses to chronic active hepatitis characterized by oval cell hyperplasia, cholangitis, and minimal necrosis (42, 126). Males have liver lesions that develop earlier and are more severe than do females; however, the basis for increased susceptibility in males is not understood. Most animals have no gross liver lesions, but severely affected mice may have yellow to white foci and/or a prominent reticular pattern in one or more liver lobes (42, 126). Microscopically, focal lesions can be seen in naturally infected mice as early as one month of age (126). These areas of hepatic necrosis and inflammation become multifocal and may coalesce by 3 to 6 months of age (42). With time, oval cell hyperplasia and lymphoplasmacytic infiltration of surrounding bile ducts and portal veins become prominent (42, 126). The most chronic lesions, seen after 8 months of age, include bile duct hyperplasia in many portal areas, cytomegaly and karyomegaly of hepatocytes, as well as intranuclear pseudoinclusions (42, 126). Hepatocellular necrosis becomes less prominent at this stage. Between 12 and 18 months of age, most male mice go on to develop preneoplastic nodular hyperplasia and hepatocellular tumors (42, 126). Chronic active hepatitis leading to hepatocellular neoplasia was also observed in germ-free female Swiss Webster mice following experimental infection with H. hepaticus, clearly establishing the organism as a murine pathogen (44).

More recently, H. hepaticus infection has also been shown to be associated with hepatic neoplasia in B6C3F1 mice used for carcinogenesis testing by the National Toxicology Program (43, 51). Unfortunately, several 2-year carcinogenesis studies were confounded by the presence of hepatocellular tumors and hepatic hemangiosarcoma in control male mice. Genetic susceptibility to Helicobacter hepatitis and hepatic neoplasia appears to have a dominant pattern of inheritance, since B6C3F1 mice are produced by interbreeding susceptible C3H and resistant C57BL/6 strains of mice. The mechanism by which H. hepaticus infection leads to hepatic neoplasia remains poorly understood. No mutations in ras or in the p53 tumor suppressor gene were found in liver tumors taken from A/JCr mice infected with H. hepaticus (107). The absence of p53 mutations is consistent with earlier findings, but activating mutations in the H-ras oncogene are characteristic of chemically initiated murine liver tumors. The absence of mutations in H. hepaticus-associated liver tumors suggests that the mechanism of H. hepaticus carcinogenesis may be independent of genotoxic damage (11). The enhanced rate of hepatocyte proliferation and apoptosis seen in infected mice may influence hepatocarcinogenesis by acting as a tumor promoter (24, 42, 81). The increased expression of growth factors, alterations in cytochrome P450 activity, and increased oxidative stress associated with H. hepaticus infection in male A/JCr mice are all consistent with a tumor promotion mechanism (14, 88, 106).

Inflammatory Bowel Disease

Although initially recognized in the liver in association with hepatic lesions, the primary site of H. hepaticus infection is the cecum and the colon. C57BL/6 mice that are resistant to liver disease are susceptible to H. hepaticus infection in the intestine, and in strains of mice that are susceptible to liver disease, infection is found earlier and more consistently in the intestine than in the liver (42). In immunocompetent mice, H. hepaticus infection causes mild intestinal inflammation and epithelial hyperplasia that are typically seen as a relatively late change (44, 133). In contrast, H. hepaticus infection in immunodeficient nude and SCID mice is associated with marked typhlitis, colitis, and proctitis, often with a high incidence of rectal prolapse (68, 93, 127). Similar lesions have been associated with H. hepaticus infection in lines of targeted gene mutant (knockout) mice that have been used as models of IBD (31). Furthermore, experimental infection with H. hepaticus has been shown to cause IBD in SCID mice reconstituted with CD4+ CD45RBhigh T cells (10), IL-10 deficient mice (64), Rag-2 deficient mice (125), and T-cell receptor αβ-deficient mice (13). Some controversy remains about the exact role of H. hepaticus infection in the etiopathogenesis of IBD in various knockout mouse models (23, 97). Nonetheless, H. hepaticus infection can clearly cause severe intestinal inflammation resembling Crohn's disease and ulcerative colitis in knockout mice with altered immune function.

Bacterial Pathogenesis

The mechanism by which H. hepaticus causes hepatic and intestinal disease remains poorly understood. Infected mice develop persistent humoral and mucosal immune responses that are not protective (42, 70, 126, 133). Both chronic active hepatitis in A/JCr mice and IBD in interleukin-10 (IL-10) knockout and Rag-2 knockout mice are associated with a Th1 immune response, characterized by high levels of interferon gamma and the presence of activated macrophages (64, 125, 133). H. hepaticus and HSP 70 share cross-reactive epitopes, and it has been suggested that autoimmunity could play a role in disease pathogenesis (128). A novel toxin activity has been identified in H. hepaticus that causes vacuole formation in a murine liver cell line, resulting in a granular appearance of the affected cells (115). This granulating cytotoxin is a heat-labile secreted protein with a native molecular mass of >100 kDa that is distinct from the vacuolating cytotoxin of H. pylori. More recently, Young et al. have identified three genes encoding cytolethal distending toxin (CDT) and CDT activity in H. hepaticus (135). H. hepaticus CDT causes cell cycle arrest in HeLa cells and is closely related to the CDT of Campylobacter species (86). The role of these toxins in H. hepaticus pathogenesis remains to be determined.

Diagnosis and Treatment

H. hepaticus can be isolated from the liver of animals with hepatitis (38). However, the organism can be more consistently recovered from the intestinal tract (42). This is particularly true in C57BL/6 mice that are resistant to hepatic disease. Sensitive isolation procedures typically include incubation on selective media and/or passage through a 0.45-μm pore size filter to enrich for H. hepaticus (99). Although reliable in the hands of an experienced microbiologist, these procedures are tedious and require days to weeks for successful culture and isolation. PCR provides more rapid results and greater sensitivity. Several methods have been described, including H. hepaticus-specific amplification with primers complementary to a fragment of the 16S rRNA gene (99) and PCR restriction fragment length polymorphism (RFLP) methods that combine genus-level 16S rRNA amplification with species identification (71, 89, 100). A PCR-RFLP assay that specifically amplifies a portion of the H. hepaticus urease structural genes ureAB and allows for genotyping to be performed has also been described (102). In immunocompetent mice, sensitive and specific serodiagnosis of H. hepaticus infection can be accomplished by enzyme-linked immunosorbent assay against a bacterial membrane preparation (70, 132). Several antibiotic regimens have been described for eradication of H. hepaticus (32, 33, 93), but treatment failures do occur. Fostering of neonatal mice to Helicobacter-free dams has also been reported (121), but rederivation using Helicobacter-free recipient mice and embryo transfer may be the most reliable method to eliminate this pervasive pathogen from mouse colonies.

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.

Gastritis

H. muridarum can infect the stomach of mice and cause gastritis. Queiroz et al. described gastritis characterized by a mixed-cell infiltrate that varied from mild to severe in 6- to 8-week-old BALB/c mice (87). All of these mice also had H. muridarum in the cecum, although no typhlitis was observed, suggesting that under certain conditions intestinal colonization can lead to gastric infection. In some mouse colonies, occasional gastric infection with H. muridarum occurs spontaneously in older animals, which is associated with gastritis, presumably as a consequence of reduced parietal cell mass (35). It has also been reported that when mice enzootically colonized with H. muridarum in the intestine are experimentally challenged with gastric Helicobacter species, H. muridarum can take advantage of the altered gastric milieu, displace the gastric spirals, persistently infect the stomach, and cause gastritis (66). In the report by Queiroz et al., however, the mice were young and had not been experimentally inoculated with another Helicobacter species. Details of the process by which hypochlorhydria and/or perturbations of the indigenous gastric microbiota leads to infection of the stomach with enterohepatic Helicobacter species remain to be determined. However, the potential confounding influence of enterohepatic Helicobacter species on in vivo studies of helicobacter gastritis should not be ignored.

"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.

Human Infection and Disease

Two cases of adults with chronic diarrhea apparently caused by "H. rappini" have been described by Romero et al. (91). The first was a 47-year-old male with a 1-month history of nonbloody diarrhea, fever, headache, and lower abdominal pain. The organism was also recovered from his asymptomatic 16-year-old daughter and from a subclinically infected 5-month-old female puppy in the household. The second case was a 40-year-old male with a 2-month history of nonbloody diarrhea without fever. This individual had no known contact with animals. Both patients were successfully treated with erythromycin. These strains were shown to differ from Kirkbride's ovine isolate by the lack of catalase activity (1). An essentially identical strain was isolated from the ileum and cecum of healthy outbred mice (96). The nucleotide sequence of a partial 16S rRNA gene fragment from the murine isolate was shown to be >99% similar to that of the human isolates (96), indicating that these organisms are closely related.

"H. rappini" has also been reported as a cause of bacteremia. Strains isolated from blood cultures of a 9-year-old girl with pneumonia (117) and a 65-year-old male undergoing hemodialysis for end-stage renal failure (109) have 16S rRNA gene sequences that are 99.6% similar. The adult patient also had a history of pancreatitis due to alcoholism with secondary diabetes mellitus and severe peripheral vascular disease. More recently, "H. rappini" has been isolated from two patients with X-linked agammaglobulinemia with recurrent bacteremia (130), and bacteremia and osteomyelitis (17), and have been detected by PCR in a third X-linked agammaglobulinemia patient with recurrent abdominal abscesses (54). By 16S rRNA sequencing, all of these strains, as well as the isolates from humans with gastroenteritis and the murine isolate, are reported to comprise a single species (21). However, these strains exhibit some biochemical variability. For example, most of the strains are urease positive, but the isolate from the child with pneumonia is urease negative (117), and most of the strains are catalase negative, but the strains from the X-linked agammaglobulinemia patients are catalase positive. Furthermore, some of the strains have a 187-bp intervening sequence in the 16S rRNA gene, but others do not (21). Consequently, Dewhirst et al. felt that it was inappropriate to name the species at this time but suggested that "H. rappini" be reserved for either this species (taxon 8) or the original ovine isolate of Kirkbride et al. (taxon 5) (21).

Other Host Species

Other "H. rappini"-like organisms have been isolated from the stomachs of healthy dogs from a commercial supplier of random-source animals (25) and pet dogs that presented for gastrointestinal signs or for euthanasia (59). In the study by Eaton et al., pure cultures of gastric Helicobacter species were isolated from 6 of 54 dogs. Two of the isolates had a "H. rappini"-like morphology and were urease positive and catalase negative. The nucleotide sequence of the 16S rRNA gene from one of these isolates indicated that it was a distinct species, while the other isolate was an H. bilis strain (see below). In the study by Jalava et al., gastric Helicobacter species were isolated from 48 of 95 dogs. Two of the isolates were reported to be "H. rappini" on the basis of their morphology. The strains were both catalase positive, and one had urease activity while the other was urease negative. Total bacterial protein profiles indicated that the two strains were similar to one another but sufficiently different from the isolate described by Romero et al. to be a distinct species (59). More recently, Saunders et al. reported that a novel Helicobacter species could be isolated from cotton-top tamarins, a species of New World monkey that develops ulcerative colitis and colon cancer (95). This Helicobacter species is morphologically "H. rappini"-like and exhibits oxidase and catalase activity, but is urease negative. Nucleotide sequence determination of the 16S rRNA gene from this organism indicated that it is a separate species, which has been designated taxon 10 but not yet formally named due to the limited number of isolates obtained from animals in a single colony (21).

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 (7880), 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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