The non-H pylori helicobacters in humans: New developments
Institute of Digestive Diseases
Koste Todorovica 6 St.
YU-11000 Beograd, Serbia, Yugoslavia
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Non-Helicobacter pylori and alimentary tract Gastroenteroloska sekcija SLD-
01722, 2001.
The discovery
of Helicobacter pylori increased
interest in the range of other spiral bacteria in the stomach, but also in the
other parts of the alimentary tract (1,2). The polymerase chain reaction (PCR)
has provided to us to define new members of Helicobacter
family. Table 1.
Today, at least 24 formally named Helicobacters have been identified and an additional 35 or more
novel Helicobacters await formal
naming. Helicobacter pylori is
the best known and the most important in terms of global impact on human
disease. However, two other gastric Helicobacters,
H.heilmannii and
H.felis, are
associated with gastric disease in humans and are worthy of discussion.
Nineteen named
species colonise the lower intestinal tract of animals, many of which also
colonise humans (3,4,5,6,7).
In 1987, Dent et al described the presence of a novel
bacterium in 3/1300 gastric biopsies (8). The initial differentiation was based
on morphology, the bacterium having a larger tight helical shape compared to
the S shape of H.pylori. Subsequent
studies have shown that while rarely found in humans it is the dominant gastric
organism in a number of animal species including primates, pigs, cats, and
dogs. Although first given the name Gastrospirillum
hominis this gastric bacterium has subsequently been shown to belong to the
Helicobacter genus and has been given
the provisional name of Helicobacter
heilmannii (9,10,11,12,13).
The gastritis
observed with H.heilmannii infection
tends to be less severe than that due to H.
pylori, but infection has been
found in association with duodenal ulceration, gastric ulceration, gastric
carcinoma and mucosa associated lymphoid tissue (MALT) lymphoma. Indeed, a
surprisingly high rate (3.4%) of MALT
lymphomas in H.heilmannii infected
patients was noted (14). The majority of patients are asymptomatic; however,
epigastric pain or discomfort, nausea, vomiting, anorexia, weight loss, diarrhoea,
and occasionally gastrointestinal bleeding may occur. At gastroscopy, findings
range from a normal appearance to antral erythema, erosive gastritis, gastric
ulceration, duodenal erosions, and ulceration.
Gastric
lymphoid nodules have been reported in cases of H.heilmannii infection in children as is the case with H.pylori. The gastritis is characterised
histologically by an infiltrate of polymorphonuclear leukocytes, lymphocytes,
and plasma cells in the lamina propria.
Serology for H.pylori and rapid urease tests can be
relatively insensitive, the later probably related to the patchy nature of H.heilmannii colonisation and low
numbers of bacteria present when compared with H.pylori. Large numbers of attempts to culture this bacterium using
a variety of media and growth conditions have
been unsuccessful.
One
group has reported on culture of a similar organism from humans, though
molecular studies indicate this bacterium is Helicobacter bizzozeronii, an organism normally found in canine
gastric mucosa. H.heilmannii can
however be readily maintained by in vivo culture techniques in mice. As it is generally easier to eradicate H.heilmannii than H.pylori the best approach would be to over a standard course of
anti H.pylori therapy to any patient
in which a non-H.pylori gastric helicobacter is detected. wide range of
very distinct bacterial populations. Although varying in size and amplitude,
all had in common a spiral shape . We reasoned that this morphology gave the
bacteria a selective advantage in the viscous mucous environment. Following the
discovery of H.pylori the bacterium’s morphology led us to suggest
that its natural habitat was the gastric mucous. Many of these spiral bacteria
have since been classified as belonging to the Helicobacter genus, which is hardly surprising given that gut
mucous is their natural habitat. These species include Helicobacter bilis, Helicobacter hepaticus,and Helicobacter muridarum that are naturally found in s.mall rodents, Helicobacter cinaedi and Helicobacter cholecystus in gerbils and
hamsters (hrcak), Helicobacter pullorum and
Helicobacter pametensis in chickens
and birds, and Helicobacter canis in
dogs.
It is possible
that Helicobacter species are under
recognized causes of infective diarrhoea in humans today due to the specialised
methods required for their isolation. Helicobacters
cultured from human diarrhoeal samples include H. cinaedi, H.canis, H.pullorum, H.fennelliae, H.canadensis, H.rappini and other unclassified but
related organisms. The presence of Helicobacter
species in a diarrhoeal specimen is not proof of causality.
Helicobacter cinaedi and Helicobacter fennelliae Initially these bacteria were isolated
from faeces of HIV infected
homosexual man suffering from colitis and proctitis. The sigmoidoscopic and
histopathologic findings were similar to those with Campylobacter jejuni infection. Although most additional bacteria
have since been isolated from immunocompromised patients, H.cinaedi and H. fennelliae were
also recovered from stools of immunocompetent heterosexual men, women, and
children. It is likely that this
cluster of H cinaedi and H fennelliae cases was first recognised
in homosexual men because of sexual behaviours that increase the risk of
faecal–oral and mucosa– mucosa transmission. As the natural hosts for H cinaedi are thought to be gerbils
(rodent, vrsta glodara) and hamsters (hrcak), the authors speculate that a
zoonosis resulting from contact with these animals may have been the initial
source.
Helicobacter pullorum This campylobacter-like
organism is originally isolated from intestinal content of asymptomatic
poultry, and from the livers and faeces of hens (zivine) presented with hepatic
lesions. Later on H.pullorum was
discovered from the carcasses ( telo zaklane zivine) with a prevalence of 60%.
This bacteria is isolated from patients suffering from mild to severe diarrhoea
suggesting a possible zoonosis. Recent detailed analysis of four H.pullorum isolates from Canadian
patients presenting with diarrhoea showed they possessed atypical biochemical
features and could be differentiated from H.pullorum
on the basis of 16S rRNA sequencing and restriction fragment length
polymorphism (RFLP) analysis. Based on this data the name Helicobacter canadensis has been proposed for this group of
organisms.
Helicobacter rappini This bacterium ( originally named: Flexispira rappini) was originally isolated from aborted sheep
foetuses. H.rappini was later shown to be part of the faecal flora of dogs,
cats, and rabbits. In humans, is has been isolated from patients suffering from
either mild chronic diarrhoea, bacteriemia, or pneumonia involving both
immunocompetent and immunocompromised individuals.
In summary, H.cinaedi and H.fennelliae are helicobacters
species most frequently isolated from human colonic samples and for which
there is definite evidence of pathogenicity. The role of the four other Helicobacter species in human disease
has to be determined.
A substantial body of evidence suggests
that bacterial antigens are key contributors to the development of inflammatory
bowel disease (IBD) in a genetically or immunologically predisposed host.
Recently, murine models have clearly shown that if the normal immune balances
are altered then mucosa associated Helicobacter
species induce a pathology similar
to human IBD. This is possibly due to their location in mucous, the microbial
niche closest to the susceptible mucosa. Whether an analogous process occurs in humans is unclear. Helicobacter species have not consistently been isolated from IBD
patients.
In recent
years, new Helicobacter species have
been islolated from the livers of wide variety of animals and have been
associated with hepatic disease. It is
possible that intestinal Helicobacter species
can enter the bloodstream, particularly in immunocompromised individuals, and
thus it would be expected that these organisms could end up in the liver
(18,19).
In murine
models, the intestinal Helicobacters
have been observed to translocate to the liver where viable infection may be
associated with inflammation and/or neoplastic change. The hypothesis that Helicobacters infect the human
intestine, liver, or biliary tree and may be responsible for previously
unexplained human pathology is certainly very attractive. However, despite
detection of helicobacter 16s ribosomal DNA (16s rDNA) by multiple
investigators in human hepatic and biliary tissue by polymerase chain reaction
(PCR) there have been no published accounts of the culture or consistent
ultrastructural identification of Helicobacters
from these tissues. This is in contrast to the relative ease with which Helicobacters have been cultured from
animal liver tissue. In the absence of the direct isolation of bacteria there
are several reasons to be cautious in the interpretation of these PCR based
studies. Firstly, the results of these studies have often been conflicting. For
example, Fox et al detected Helicobacter 16s rDNA in 13 of 23 bile
samples and 9 of 23 resected gall bladder tissues from Chilean women with
chronic cholecystitis (20). In contrast, Rudi et al were not able to detect any helicobacter DNA in bile samples
from 73 Germans with biliary disease (21). Nilsson et al reported positive Helicobacter
PCR in 11 of 12 patients with primary biliary cirrhosis whereas Tanaka et al demonstrated Helicobacter DNA in only 1 of 29 PBC cases and Harada et al in 0 of 5 cases using a PCR
cloning methodology (23,24). The main exception to this criticism has been the
detection of helicobacter DNA in a majority of primary hepatic and biliary
cancers. Some of these anomalies may be explained by geographic and clinical
differences in the populations studied. In addition, many of these studies do
not report the results of PCR for other bacterial species and, when they do so,
a plethora of other (possibly contaminating) bacterial species is discovered.
Interestingly, the gene sequence obtained from positive Helicobacter species specific 16s rDNA PCRs is usually most
analogous to H.pylori. This raises
the possibility that the presence of helicobacter
DNA in human liver tissue is a reflection of the transport of H.pylori of gastric origin or its DNA to
the liver. At present this hypothesis is speculative. It is important to note that this region of the
16S rRNA gene is not highly variable amongst different Helicobacter species and so the evidence to date does not preclude
the presence of another human gut Helicobacter
species. Two studies did however indicate that intestinal Helicobacters may be implicated in
hepatobiliary disease. Accurate species
determination was only reported in the study by Fox et al where they were able to identify H.bilis, H.pullorum, and H.rappini with no detection of H.pylori. To make further progress, future studies should include an attempt
to culture and directly identify Helicobacters
ultrastructurally in the hepatobiliary system, in addition to assessing gastric
Helicobacter status.
Over the past
20 years, the genus Helicobacter has
evolved rapidly due to isolation of novel species from a wide range of animals
and humans. The genus now includes at least 24 formally named species as well
as numerous other Helicobacters not
formally named. Nineteen of these formally named Helicobacters are found in the intestinal mucus of animals, eight
in humans, and two in birds.
The situation
in the stomach is clear. Like H.pylori in
the human, animals have highly specialised populations of Helicobacters that have evolved to inhabit the ecological niche of gastric
mucous. These animal organisms can transmit to humans and it is likely they
cause symptomatic disease. There is strong evidence that pet (kucni ljubimci)
carnivores are possible sourse for this infection.
The recent
recovery of different Helicobacter species from both immunocompromised and
immunocompetent patients suffering from enteric and hepatic disease raises the
question about the origin and the impact of these infections. Most animals also
have highly adapted populations of Helicobacter
species inhabiting their intestinal mucous. In some circumstances, if these
bacteria move outside their natural niche they can cause disease—for example,
hepatitis in the mouse. If normal homeostasis is altered they can cause severe
pathology within their natural niche—for example, inflammatory bowel disease in
immunocompromised mice. Yet the intestinal Helicobacters
of animals have been found in humans where they are able to induce
gastrointestinal symptoms and translocate into the bloodstream. The implication
is that these bacteria are transmitted to humans from animals. Systematic study
of these bacteria using appropriate isolation and identification methods is
needed in both health and disease. Only then will we know whether the discovery
of these bacteria will influence the management of intestinal and systemic
disease in the dramatic way that the discovery of H.pylori impacted on the management of gastroduodenal disease.
Many of the Helicobacters can also colonise the
biliary tract of the liver and induce hepatitis (and in some cases hepatic
cancer) or cause bacteraemia and systemic disease in immunocompromised hosts.
Discovery of these Helicobacters
provides the scientific community with an excellent opportunity to study and
better understand the finely balanced ecological relationship between these
bacteria which persistently colonise the gastrointestinal tract and their
effect on the host. Infection with Helicobacter
species and their associated diseases in numerous hosts allow us the means
to assess pathogenic mechanisms. In vivo models are also being used to develop
various therapeutic and prophylactic modalities to eradicate or prevent Helicobacter induced gastrointestinal
disease in humans. In addition, it is important to study the epidemiology of Helicobacters and their zoonotic
potential as well as to identify novel Helicobacter
species and their possible associations.
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Table 1.
Non-
Helicobacter pylori helicobacters isolated from humans (as of 2001)
“H.
rappini”* Sheep, dog, mice intestine, blood (humans); liver (sheep); stomach
(dogs)
H.canis* Dog, cat intestine, blood
(humans); liver (dog)
H.cinaedi* Hamster, rhesus monkey, dog
intestine, blood, soft tissue, joints (humans); liver (monkey)
H.fennelliae Dog, macaque intestine, blood
H.pullorum* Chicken intestine, liver
(chicken)
H.canadensis NR** Intestine NR
H.westmeadii NR NR Blood
H.winghamensis NR Intestine NR
“H.heilmannii”* Dogs, cats, monkeys,
cheetahs, wild rats, swine stomach NR
H.felis* Dogs, cats, cheetahs stomach, NR
*Potentially zoonosis
NR, not recorded.