Gastric Helicobacters in Cats

Abstract

The types of helicobacter which are found in the stomachs of carnivorous pets, especially cats, have been traditionally referred to as ‘gastric helicobacter-like organisms’ (GHLOs). These are microaerophilic, Gram-negative, spiral bacteria with multiple terminal flagellae and are endowed with high-level urease activity which allows them to survive in an acidic environment. Certain species have one or more periplasmic fibrils. The two GHLOs most commonly found in cats are Helicobacter felis and a species related to H heilmannii which was recently cultured from dogs. All phenotypic and genotypic (16S RNA gene sequences) evidence suggests that both of these bacteria belong in the genus Helicobacter. Whether or not helicobacters can be transmitted to humans from carnivorous pets is controversial but the recent discovery of H pylori-infected cats may be evidence of an animal reservoir for this pathogen. Although the role of H pylori in inducing antral gastritis and perpetuating pyloric ulcers in humans is well established, whether or not Helicobacter spp are causally involved in any feline gastric inflammatory conditions is unknown.

Spiral bacteria in carnivorous pets were first reported by Rappin in 1881 and Bizzozero in 1893. That ‘spirella’ could be found in the gastric mucosae of dogs and cats was confirmed in a few subsequent studies (Salomon, 1898) but it is only recently, since the discovery by Warren and Marshall in 1983 that Helicobacter pylori causes disease in humans, that any kind of detailed investigation of helicobacters in carnivorous pets has been undertaken. These bacteria, which have been traditionally referred to as a ‘gastric helicobacter-like organisms’ (GHLOs) are mostly microaerophilic, Gram-negative, spiral species with multiple terminal flagellae and high-level urease activity which allows them to survive in an acidic environment. Helicobacter felis was the first species cultured from the gastric tissue of cats (Lee et al 1988, Paster et al 1991) and subsequently another common feline GHLO was identified which has not yet been cultured but which is morphologically similar to both H heilmannii (formerly called Gastrospirillum hominis) observed in some cases of human gastritis (Heilmann & Borchard 1991, Geyer et al 1993, Solnick et al 1993) and H bizzozeronii which was recently isolated and cultured from dogs by Hanninen et al (1996). However, it has not been proved that H heilmannii and H bizzozeronii are the same bacterium. Finally, Handt et al (1994) have detected H pylori in cats and proposed that the cat might represent a significant reservoir for this bacterium, whose natural host is man.

The detection of cat GHLOs in the human stomach has indicated that they may be relatively widespread and this has led certain investigators to propose that feline helicobacters may be transmitted to humans (Wegmann et al 1991, Heilmann et al 1991, Otto et al 1994, Handt et al 1994, Fox et al 1995).

Several reports have been published on low-grade to moderate gastritis associated with GHLO infection but it has not been possible to ascribe the inflammatory lesions definitively to microbial activity (Geyer et al 1993, Otto et al 1994, Herrmanns et al 1995, Happonen et al 1996, Kanji et al 1998). Some investigations have failed to detect any correlation between gastritis and GHLO infection as both infected and uninfected cats show the same type and quantity of lesions (Geyer et al 1993, Papasouliotis et al 1997, Neiger et al 1998).

In this article, we will review the current state of knowledge concerning feline helicobacter infections.

Morphology

Until recently, most reports describing the GHLOs of carnivorous pets have relied on purely morphological criteria (Weber et al 1958, Lockard & Boler 1970, Lee et al 1988, Geyer et al 1993) (Table 1).

Table 1.

Helicobacter spp isolates in stomach of dogs, cats and humans

	H pylori	H felis	H heilmannii	H bizzozeronii	‘Flexispira rapini’	H salomonis	H pametensis
Cat	+	+	+***				+
	(Handt et al 1994)	(Lee et al 1988)	(Jalava et al 1998)				(Neiger et al 1998)
Dog	(+)*	+	+	+	+	+	+
	(Lee et al 1990)	(Lee et al 1992)	(Jalava et al 1998)	(Hanninen et al 1996)	(Jalava et al 1998)	(Jalava et al 1997)	(Eaton et al 1996)
Human	+	(+)**	+
	(Warren & Marshal 1983)	(Wegmann et al 1991)	(Heilmann & Borchard 1991)

*Experimentally established infection.

Only discovered in two cases.

***

H heilmannii-like.

Two different GHLOs have been reported in cats: ‘H heilmanii-like’ and H felis. Helicobacter pylori was detected by Handt et al (1994) in cats but as this infection is apparently anecdotal, we will not describe here the morphological characters of this human bacterium.

The ‘H heilmannii-like’ species is a large bacterium with a diameter of between 0.5 and 1.0 μm and an average length of 4–8 μm. It consists of a tightly spiralled cell with an overall rectangular shape. Its body makes a total of between four and eight turns with a gap of 0.8–1.0 μm between each parallel strand. The bacterium's coat is smooth but at each pole there are insertion complexes from each of which project 10–20 sheathed flagellae.

Helicobacter felis is a medium-sized bacterium which is about 0.4 μm thick and on average 5 μm long (up to 7.5 μm). This species is also tightly spiralled with the body making between five and seven turns. Between 10 and 17 terminal sheathed flagellae are again seen at either pole but, unlike the smooth surface of the H heilmannii-like species, H felis has either one, two or four periplasmic fibrils spread out along the bacterial cell (Lee et al 1988). However two strains of H felis with no periplasmatic fibres have been isolated (Eaton et al 1996), suggesting that this anatomical feature is not necessarily characteristic of H felis.

Ecology and epidemiology

The prevalence of GHLO infection in cats

The relationship between helicobacter and its environment (habitat, conditions for survival and development, how the infection is transmitted, etc) has been extensively studied and, in both humans and carnivorous pets, it has been shown that promiscuity, confined living conditions and poor hygiene are the most important predisposing factors for infection (Lee et al 1991, Vincent 1996, Lecoindre et al 1997a, Lecoindre et al 1998b).

The frequency of helicobacter infection in cats is high, ranging from 45 to 100% in different reports (Table 2) with the differences probably being due to differences in the detection methods used, how the animal populations were selected and also, possibly, geographical considerations. The infection rate is as high in healthy cats as in those with gastrointestinal problems (Table 2) and neither sex- nor race-dependence was observed. Some studies show a correlation between the age of an animal and the chance of its being infected (Weber et al 1958, Otto et al 1994) but more recent investigations have failed to reproduce this result (Papasouliotis et al 1997, Neiger et al 1998). Even very young infected individuals can be found—this is probably due to direct mouth-to-mouth or fecal transmission from the mother (Lee et al 1991).

Table 2.

Prevalence in cats in different studies

Number of cases clinically abnormal/normal	Global prevalence (%)	Prevalence in normal cat (%)	Prevalence in abnormal cat (%)	Reference
29/60	—	41	57	Geyer et al (1993)
30/24	100	100	100	Papasouliotis et al (1997)
58	91	—	—	Neiger et al (1998)
10/33	—	90	64	Kanji et al (1998)
127	76	—	—	Herrmanns et al (1995)
55	86	—	—	Otto et al (1994)
10	60	—	—	Happonen et al (1996)

Only a few studies have been conducted using methods capable of differentiating different Helicobacter species (eg, the polymerase chain reaction [PCR] or electron microscopy) and these suggested that the H heilmannii-like species was the most commonly found GHLO in the stomach, that H felis could be isolated less often and that the presence of H pylori in cats remains anecdotal (Neiger et al 1998). Infection with more than one species may occur (Lee et al 1988, Lecoindre et al 1997b).

Location of organisms

In cats, most publications report finding bacteria in both in the gastric antrum and fundus (Geyer et al 1993, Happonen et al 1996) whereas in dogs, it was the fundus and the body of the stomach which were usually infected and bacteria were only found in other parts of the organ in the most severe cases (Lee et al 1992, Lecoindre et al 1995, Happonen et al 1996).

In cats, helicobacter organisms were found most commonly within the mucus layer but were also often observed in the crypts of fundic glands and in intracellular parietal cell canaliculi (Weber et al 1958, Herrmanns et al 1995; Happonen et al 1996). The latter focus of infection is common in carnivorous pets showing that GHLOs have an affinity for parietal cells. No such tropism is observed in human H pylori infection (Geyer et al 1993, Herrmanns et al 1995, Lecoindre et al 1997c, Peyrol et al 1998).

Pathogenicity . The pathogenicity of helicobacter has been extensively studied in recent years, mainly in animal models (Lee et al 1988, 1990, Radin et al 1990). A strain's pathogenicity depends on its ability to colonise the gastric mucosa and there create an ecological niche in which it can survive avoiding the host's defence mechanisms. Different strains may also induce different levels of damage at the gastric epithelium. Motility, level of characteristic urease activity and capacity to adhere to epithelial cells are the most important factors determining the likelihood of any strain being able to establish an infection in the stomach. The organisms (which are probably taken in orally) possess an endogenous urease which allows them to catabolise urea diffusing from the mucosal surface towards the lumen of the stomach. In this way, they create a neutral micro-environment in which they can survive. As suggested by their morphological structure, these bacteria are highly motile and can migrate through the mucus to colonise the gastric epithelium. Helicobacter pylori which have been genetically modified to fail to produce either the urease or the flagellin monomers essential for flagella formation cannot establish infection when experimentally inoculated into animals which would normally be susceptible (Monteiro 1995). Although the great majority of the GHLOs of carnivorous pets never leave the mucus layer, where there is a pH gradient of between 2 (lumen interface) and 7 (mucosal interface), electron micrographs show that these bacteria, just like H pylori, can adhere to the epithelial surface and even invade epithelial cells (Lecoindre et al 1997c, Peyrol et al 1998). This implies that adhesins are expressed on the surface of the bacterium with corresponding receptors on the mammalian cell. The unique tropism of these bacteria for the gastric epithelium is almost certainly involved in the phenomenon that infection with these bacteria persists throughout the lifetime of the infected host (Monteiro 1995). The same colonisation factor is probably also responsible for mediating damage to the gastric mucosa.

When allowed to adhere to epithelial cells, H pylori stimulated them in vitro to release interleukin-8 (IL-8) and induced structural modifications including microvillus resorption and cytoskeletal rearrangements. Similar morphological changes have been observed in vivo in both cats and dogs which supports the idea that the GHLOs of carnivorous pets may have cytotoxic activity (Lecoindre et al 1997c, Peyrol et al 1998). Bacterial phospholipase and haemolysin secretion also play a role in the pathogenesis of gastric lesions, as may the urease activity although this is not established. Certain H pylori phenotypes (VacA and CagA) are more likely to cause ulcers or other more serious gastrointestinal pathologies. Helicobacter pylori could also play a role in the pathogenesis of autoimmune gastritis by inducing the production of antibodies specific for the Lewis antigen which is a normal component of the parietal cell H⁺/K⁺ ATPase (a ‘proton pump’) (Monteiro 1995). The recent sequencing of the genomes of certain strains of H pylori will almost certainly reveal other virulence genes (Labigne 1998). The idea of strain-dependent virulence is compelling in the light of the fact that, while certain helicobacter-infected carnivorous pets develop gastritis, the presence of such organisms in the stomach does not necessarily seem to cause any problem.

GHLO infection and gastritis in cats

Several reports have been published concerning low-grade to moderate gastritis associated with GHLO infection but it has not been possible to ascribe the inflammatory lesions definitively to microbial activity (Geyer et al 1993, Otto et al 1994, Herrmanns et al 1995, Happonen et al 1996, Kanji et al 1998). Some investigations failed to detect any correlation between gastritis and GHLO infection both clinically abnormal and normal cats showing the same type and quantity of lesions (Geyer et al 1993, Papasouliotis et al 1997, Neiger et al 1998).

The crucial issue is whether these organisms can cause disease in cats and whether any lesion can be associated with their presence. This association is not yet proven and remains unclear.

Endoscopy

It is difficult to define a specific endoscopic pattern which is typical of GHLO infection but, if infection is severe, some or all of the following may be observed: the fundic mucosa may appear congested, oedematous and somewhat squamous; the folds of the antrum may be hypertrophic; the antral mucosa may be congested; and sometimes in adults, but especially in young subjects, elevations resembling pathological nodules may be observed (Lecoindre et al 1997b).

However, these symptoms are only ever observed in a small minority of infected animals and little importance is attached to them compared with the results from histological analysis of biopsies (Lecoindre et al 1997b, Kanji et al 1998, Neiger et al 1998).

Pathology

Pathological analysis of gastric biopsies taken from GHLO-infected cats shows a similar picture to that seen in humans (Flejou et al 1990, Heilmann et al 1991): low grade to moderate inflammation which is usually focused around the antrum (Geyer et al 1993, Herrmanns et al 1995, Happonen et al 1996). The main inflammatory cells are lymphocytes and plasma cells, with occasional neutrophils. Multiple lymphoid follicles have been described in follicular gastritis in H pylori-infected human subjects (Pariente 1993, Zerbib 1994) and similar lesions have been observed in infected cats, first by Otto et al (1994) and later by Herrmanns et al (1995), Happonen et al (1996), and Lecoindre et al (1997c). For a long time, these nodules were considered part of the normal architecture of the gastric mucosa of carnivorous pets but this is now under review in the light of results in humans which tend to indicate that this histological feature is associated with a local immune response to antigens and inflammatory mediators which are being generated in the lumen of the stomach (probably derived from the bacteria if there is infection with helicobacter).

However, evidence of the activity of the neutrophil component of the inflammatory influx which is always present in the human disease is not a consistently observed feature in cats (Herrmanns et al 1995, Happonen et al 1996). Inflammatory lesions are often associated with early fibrosis but no correlation could be established with GHLO infection (Kanji et al 1998).

Recent electron microscopy results have confirmed not only that feline helicobacter organisms bind efficiently to host cells but also that they can gain intracellular access. Intracellular GHLOs are associated with signs of cellular degeneration including mitochondrial swelling, the formation of cytoplasmic vacuoles around the bacteria and the blebbing of organelles (Herrmanns et al 1995, Lecoindre et al 1997c). Peyrol et al (1998) showed that, in dogs, only H felis induced this kind of lesion and that heavy H heilmannii infection was not associated with damage at the gastric epithelium. This observation has not been confirmed in cats in which it seems that the combination of different GHLOs proves the most pathogenic (Lecoindre et al 1997c).

The clinical picture

The main symptoms of GHLO-associated gastritis in cats are chronic vomiting and diarrhoea (Geyer et al 1993, Herrmanns et al 1995), while weight loss, dysorexia and fever occur less often. In some cases haematemesis or melena and anaemia may be observed if there is concurrent erosive or ulcer disease (Fox 1995). Regression after treatment with antacids or antisecretories appears complete and rapid. In addition, many GHLO infections are completely asymptomatic (Happonen et al 1996, Papasouliotis et al 1997, Neiger et al 1998).

The relationships between GHLOs and clinical manifestations are unclear because GHLOs have been found in clinically normal and abnormal cats and the prevalence of GHLO infection in cats is not higher than that in those which were clinically normal (Kanji et al 1998).

Diagnosis of helicobacter infection

There are many different methods of diagnosing helicobacter infection in humans and most of these can be adapted for animals. A distinction is made between direct, or invasive, tests (which require endoscopically obtained gastric tissue samples) and indirect, non-invasive, tests which are of particular value for high volume epidemiological investigations and in post-treatment follow-up.

Direct methods

All direct methods initially entail peroral endoscopy in order to obtain biopsy material. GHLOs seem to be localised in all regions of the stomach in cats (Happonen et al 1996). This may mean that only samples from the fundus and corpus are sufficient to demonstrate the presence of GHLOs.

Rapid urease test . This procedure involves incubation of tissue samples in a urea broth containing a pH indicator (phenol red). GHLOs have high-level urease activity that breaks down urea into ammonia. This raises the pH, thereby causing an indicator to change colour. This test can be used for rapid detection of helicobacter infection and can even be performed before the endoscope has been withdrawn. The speed at which the indicator changes colour can be used to estimate the bacterial load (Otto et al 1994, Kanji et al 1998). Because at least 104 organisms are required for the rapid urease test to produce a positive result, the sensitivity of the test is only 70–90% (Jenkins 1997, Neiger et al 1998).

Histopathological examination . GHLOs can be visualised in sections stained with haematoxylin and eosin, haematoxylin–phloxine/safranin, Gram or Warthin-Starry silver. This test has high sensitivity and specificity, but false-negative results are possible because the distribution of bacteria in gastric tissue is often patchy. Analysis of multiple biopsies from the corpus, fundus and antrum is recommended.

This test is usually used as the reference method for studies in animals.

Brush cytology . This direct technique can easily be performed with a cytology brush introduced into the operating canal of the endoscope and is currently in use.

Culture . All Helicobacter species are microaerophilic and require special incubation conditions (5% oxygen, 10% carbon dioxide and 85% nitrogen) because the bacteria die at an oxygen tension of 20% at normal atmospheric pressure. For this reason, the culture of helicobacter is not a routine procedure. Helicobacter felis proved the easiest to isolate but some Helicobacter species have not yet been successfully cultured (Jalava et al 1998).

PCR . Certain species-specific DNA sequences lend themselves to amplification-based techniques, eg, different feline GHLOs have different urease genes (ureA and ureB) (Handt et al 1994, Jalava et al 1998, Neiger et al 1998) which can be differentiated by analysing PCR products thereby showing which kind of bacterium and which species are present in the sample. Unfortunately, recent data show that the levels of 16S rDNA sequence similarity between H felis, H bizzozeronii and H heilmannii are extremely high, and this widely used gene does not seem suitable as a target for species-specific PCR (Jalava et al 1997).

Indirect methods

[¹³C]-urea respiratory test . The [¹³C]-urea respiratory test is an indirect diagnostic test based on the high level of urease activity in Helicobacter. The test was known to be both sensitive and specific for diagnosing human H pylori infections, has been shown to have sensitivity and specificity levels of over 95% in dogs (Ballèvre et al 1997) and has recently been validated for use in cats with its results correlating closely with those of other methods (Neiger et al 1998). The maximum change in ¹³C over baseline values was found 30 min post-dosing. This test is particularly useful for post-treatment follow-up and for high-volume epidemiological investigations.

Serology . Serum samples can be evaluated by kinetic enzyme-linked immunosorbent assay (ELISA) in the detection of the presence of H felis. High-molecular-weight cell-associated protein, purified from a detergent extraction of H felis ATCC 49179 has been used in a recent study (Simpson et al 1999).

Treating GHLO infections

The discovery of the pathogenicity of H pylori in humans led to the development of treatment strategies designed to eliminate the bacterium. The first therapeutic regimes were based on combinations of bismuth salts with one or two antibiotics, but nowadays triple antibiotic therapy is considered the most effective way of sterilising the bacterium. The concomitant prescription of antisecretories (especially proton pump inhibitors) is necessary to guarantee antibiotic activity which would otherwise be inhibited by the low pH. The combination of antimicrobial drugs with different sites of action (eg, local together with systemic) not only reduces the treatment time (to 7–14 days) and the amounts of drugs needed but also reduces the risk of the development of drug resistance. Various different combinations have been approved in humans, mostly based on an imidazole antibiotic (metronidazole or tinidazole) together with a macrolide (erythromycin or clarithromycin) and amoxicillin (Vincent 1996).

Because GHLO infection is so prevalent in animals, yet no pathogenic role has been defined, the decision whether or not to treat the infection is a difficult one. In our opinion, various different considerations should be taken into account including whether or not there are any problems in the upper digestive tract, histological evidence of moderate to severe gastritis and confirmation of high numbers of infecting GHLOs.

Few controlled studies of the treatment of GHLO infection have been performed in carnivorous pets. Most veterinarians have directly adapted the kind of treatment regime used against H pylori in humans (Vincent 1994, Novo et al 1995, Lecoindre et al 1998a). We use the combination of metronidazole (methyl-nitroimidazol-ethanol group) 30 mg/kg/day, spiramycin (erythromicin group) 15000 iu/5 kg/day and omeprazole (proton group inhibitor) 1 mg/kg/day, over 7 days. The results of this study in dogs indicate that this treatment is effective (clearance 100%, eradication 80% 40 days after treatment) and without side-effects (Lecoindre et al 1998b). The regression of chronic fundic gastritis was 50%, but these results could not be proved in cats.

In brief, the important questions regarding the treatment of GHLO infection in cats that justify further investigation are: the appropriateness of treating GHLO infection; the eradication rate following treatment; and the reinfection rates after treatment.

Can GHLOs Be transmitted from cats to humans?

The zoonotic transmission of gastric helicobacter organisms is the subject of much active discussion and many alternative hypotheses, but it is true to say that spiral bacteria resembling feline helicobacter (‘H heilmannii-like’ and H felis) have been found in gastritic lesions in the stomachs of human subjects (Flejou et al 1990, Heilmann et al 1991). A recent report suggests that ‘H heilmannii’ infection is an example of zoonosis. The authors conclude that human and animal H heilmannii strains are closely related and that the humans can be infected by more than one H heilmannii strain, as has been observed for H pylori (Dietrich et al 1998).

More recently, the detection of H pylori in cats in the same niche could indicate that cats could act as a reservoir for the bacterium (Handt et al 1994). Since other work has shown that the saliva, feces and gastric juice of H pylori-infected cats can contain viable pathogens (Fox et al 1995) and given that cats are continuously licking their fur, that they vomit frequently and that humans regularly come into contact with their feces when changing their litter, the presence of H pylori in these feline excretions means that transmission to a human host may be possible. However, the actual frequency of H pylori infection in cats has not yet been properly determined and could be minimal because, on present evidence, it seems that cats in their natural environment (not raised in contact with humans) are rarely infected (Eaton et al 1996).

Conclusions

In the light of the results from a wide variety of studies, it is clear that GHLOs infect a large proportion of all cats and that, in certain conditions, these bacteria can induce a local mucosal inflammatory response which is probably chronic. Just like H pylori, these bacteria possess certain features, such as high urease activity and motility, which confer on them the ability to establish infection in the gastric mucosa. However, many questions still need answering. What role do these bacteria play in the pathogenesis of inflammatory gastric conditions in cats? Are some species more pathogenic than others? Are combinations of different species more damaging to the gastric epithelium?

Footnotes

Acknowledgements

We would like to thank the Laboratoire Merial and the Unisabi Company for their financial and technical contributions towards this work.

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