Helicobacter pylori
.
In 1875,
German scientists found spiral bacteria in the lining of the human stomach; the bacteria could not be grown in culture and the results were eventually forgotten
.
In 1892, the
Italian researcher
Giulio Bizzozero described spiral bacteria living in the acidic environment of the stomach of dogs.
Professor
Walery Jaworski of the
Jagiellonian University in
Kraków investigated sediments of gastric washings obtained from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called
Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogeny of gastric diseases. This work was included in the "Handbook of Gastric Diseases" but it did not have much impact as it was written in Polish
.
The bacterium was rediscovered in 1979 by
Australian physician
Robin Warren, who did further research on it with
Barry Marshall beginning in 1981; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them
. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by colonization with this bacterium, not by
stress or
spicy food as had been assumed before
.
The medical community was slow to recognize the role of this bacterium in stomach ulcers and gastritis, believing that no bacterium could survive for long in the acidic environment of the stomach. The community began to come around after further studies were done, including one in which Marshall drank a Petri dish of
H. pylori, developed gastritis, and the bacteria were recovered from his stomach lining, thereby satisfying three out of the four
Koch's postulates. Marshall's gastritis later resolved without treatment. Marshall and Warren went on to show that antibiotics are effective in the treatment of gastritis. In 1994, the
National Institutes of Health published an opinion stating that most recurrent gastric ulcers were caused by
H. pylori, and recommended that antibiotics be included in the treatment regimen
. In 2005, Warren and Marshall were awarded the
Nobel Prize in Medicine for their work on
H. pylori[The Nobel Prize in Physiology or Medicine 2005 awarded to Barry J. Marshall and J. Robin Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease".].
Before the appreciation of the bacterium's role, stomach ulcers were typically treated with medicines that neutralize stomach acid or decrease its production. While this worked well, the ulcers very often reappeared. A traditional medication against gastritis was
bismuth subsalicylate. It was often effective, but fell out of use, since its mechanism of action was a mystery. Nowadays it is quite clear that it is due to the bismuth salt acting as an antibiotic. Today, many stomach ulcers are treated with antibiotics effective against
H. pylori.
The bacterium was initially named
Campylobacter pyloridis, then
C. pylori (after a correction to the
Latin grammar) and in 1989, after
DNA sequencing and other data showed that the bacterium did not belong in the
Campylobacter genus, it was placed in its own
genus,
Helicobacter. The name
pylori comes from the
Latin word
pylorus, which means
gatekeeper, and refers to the
pyloric valve (the circular opening leading from the stomach into the
duodenum).
While
H. pylori remain the most important known bacteria to inhabit the human stomach, several other species of the
Helicobacter genus have now been identified in other
mammals and some
birds, and some of these can infect humans.
Helicobacter species have also been found to infect the
livers of certain mammals and to cause liver disease.
H. pylori is a spiral-shaped
gram-negative bacterium, about
3 micrometres long with a diameter of about 0.5 micrometre. It has 4–6
flagella. It is
microaerophilic, i.e. it requires
oxygen but at lower levels than those contained in the
atmosphere. It uses
hydrogen methanogenesis as an energy source. It tests positive for
oxidase and
catalase.
 |
Molecular model of H. pylori urease enzyme |
With its flagella and its spiral shape, the bacterium drills into the mucus layer of the stomach, and then can either be found suspended in the gastric mucosa or attached to
epithelial cells. It produces
adhesins which bind to membrane-associated lipids and carbohydrates and help its adhesion to epithelial cells. It excretes the
enzyme urease, which converts
urea into
ammonia and
bicarbonate. The release of ammonia is beneficial to the bacterium since it partially neutralizes the very acidic environment of the stomach (whose very purpose is to kill bacteria). Ammonia is, however, toxic to the epithelial cells, and with other products of
H. pylori, including
protease,
catalase, and
phospholipases, causes damage to those cells.
A recent finding is that some strains of the bacteria have a particular mechanism for "injecting" the
inflammatory agent
peptidoglycan from their own
cell wall into epithelial stomach cells. (See below for "cagA pathogenicity island" in the section "Genome studies of different strains".) It remains unknown how this mechanism is advantageous to the bacterium
[, PMID 15489856}}].
Under conditions of environmental stress, Helicobacter will convert from the spiral to a
coccoid form. This coccoid form of the organism has not been cultured, but has been found in the water supply in the US and is apparently involved in the epidemiology of the bacterium. The coccoid form has also been found to be able to adhere to gastric epithelial cells
in vitro.
Infection may be symptomatic or asymptomatic (without visible ill effects). It is estimated that up to 70% of infection is asymptomatic.
The bacteria have been isolated from
feces,
saliva and dental
plaque of infected patients, which suggests gastro-oral or fecal-oral as possible transmission routes.
It is estimated that about 2/3 of the world population are infected by the bacterium. Actual infection rates vary from nation to nation - the West (Western Europe, North America, Australasia) having rates around 25% and the Third World much higher. In the latter, it is common, probably due to poor sanitary conditions, to find infections in children. In the
United States, infection is primarily in the older generations (about 50% for those over the age of 60 compared with 20% under 40 years) and the poorest. This is largely attributed to higher hygiene standards and widespread use of antibiotics. However,
antibiotic resistance is appearing in
H. pylori. There are already
metronidazole resistant strains present in the
UK population.
In the absence of antibiotic based treatments,
H. pylori infection apparently persists for life; the human
immune system is not able to eradicate it.
One can test for
H. pylori infection with
blood antibody or stool
antigen tests, or with the
carbon urea breath test (in which the patient drinks
14C- or
13C-labelled
urea, which the bacterium metabolizes producing labelled
carbon dioxide that can be detected in the breath), or
endoscopy to provide a biopsy sample for testing for the presence of urease "
rapid urease test",
histology or microbial culture.
None of these test methods are completely failsafe. Blood antibody tests, for example, range from 76% to 84%
sensitivity. Medication can affect
H. pylori urease activity and give "false negatives" with the urea-based tests.
|
H. pylori colonized on the surface of regenerative epithelium (Warthin-Starry's silver) |
In patients who are asymptomatic, treatment is not usually recommended.
In
gastric ulcer patients where
H. pylori is detected, normal procedure is eradication to allow the ulcer to heal. The standard first-line therapy is a one week
triple-therapy. The Sydney gastroenterolgist
Thomas Borody invented the first triple therapy in 1987. Today the standard triple therapy is
amoxicillin,
clarithromycin and
omeprazole – though sometimes a different
proton pump inhibitor is substituted, or
metronidazole is used in place of amoxicillin in those
allergic to
penicillin. Such a therapy has revolutionised the treatment of gastric ulcers and has made a cure to the disease possible, where previously symptom-control using
antacids,
H2-antagonists or
proton pump inhibitors alone was the only option.
Unfortunately, an increasing number of infected individuals are found to harbour bacteria
resistant to first-line antibiotics. This results in initial treatment failure and requires additional rounds of antibiotic therapy.For resistant cases, a quadruple therapy may be used.
Bismuth compounds are also effective in combination with the above drugs. For the treatment of
clarithromycin- resistant strains of
H. pylori the use of
levofloxacin as part of the therapy has been recommended.
There is some preliminary evidence that regular consumption of
broccoli might eradicate
H. pylori.
Giaconda, an Australian biotechnology company in which Thomas Borody is the major shareholder, is working on a new therapy for drug resistant
H. pylori.
As
explained below, some authors suggest that an
H. pylori infection may be protective against certain diseases of the esophagus and cardia. Therefore, a more cautious approach than complete eradication may be necessary in some cases.
Gastric cancer & gastric
MALT lymphoma (lymphoma of the
mucosa-associated lymphoid tissue) have been associated with
H. pylori, and the bacterium has been categorized as a group I
carcinogen by the
International Agency for Research on Cancer (IARC). While the association is reasonably strong, it is not entirely clear that there is a
causal relationship involved.
Two related mechanisms by which
H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of
free radicals near
H. pylori and an increased rate of host cell
mutation. The other proposed mechanism has been called a "perigenetic pathway"
and involves enhancement of the transformed host cell phenotype by means of alterations in cell
proteins such as
adhesion proteins. It has been proposed that
H. pylori induces
inflammation and locally high levels of
TNF-alpha and/or
interleukin 6. According to the proposed perigenetic mechanism, inflammation-associated signaling molecules such as TNF-alpha can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in
tumor suppressor genes such as genes that code for cell adhesion proteins.
The infection rate with
H. pylori has been decreasing in developing countries, presumably because of improved hygiene and increased antibiotics use. Accordingly, the incidence of gastric cancer in the U.S. has fallen by 80 percent from 1900 to 2000. However,
gastroesophageal reflux disease (GORD or GERD depending on the use of British or American English, respectively) and
cancer of the esophagus (BE: oesophagus) have increased dramatically during the same period. In 1996,
Martin J. Blaser put forward the theory that
H. pylori might also have a beneficial effect: by regulating the acidity of the stomach contents, it lowers the impact of regurgitation of stomach acids into the esophagus. While some favorable evidence has been accumulated,
as of 2005 the theory is not universally accepted.
|
EM photograph of H. pylori |
Several strains are known, and the
genomes of two have been completely
sequenced[The Pylori Gene website allows access to genome information for the H. pylori 26695 and J99 strains. Another genome interface is provided by the National Center for Biotechnology Information; 26695, J99.]. The genome of the strain "26695" consists of about 1.7 million base pairs, with some 1550 genes. The two sequenced strains show large genetic differences, with up to 6% of the nucleotides differing.
Study of the
H. pylori genome is centered on attempts to understand
pathogenesis, the ability of this organism to cause disease. There are 62 genes in the "pathogenesis" category of the genome database. Both sequenced strains have an approximately 40 kb long Cag
pathogenicity island (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. This pathogenicity island is usually absent from
H. pylori strains isolated from humans who are carriers of
H. pylori but remain asymptomatic.
The cagA gene codes for one of the major
H. pylori virulence proteins. Bacterial strains that have the cagA gene are associated with an ability to cause severe ulcers. The cagA gene codes for a relatively long (1186
amino acid) protein. The CagA protein is transported into human cells where it may disrupt the normal functioning of the
cytoskeleton. The Cag pathogenicity island has about 30 genes that code for a complex
type IV secretion system. After attachment of
H.pylori to stomach epithelial cells, the CagA protein is injected into the epithelial cells by the type IV secretion system. The CagA protein is
phosphorylated on
tyrosine residues by a host cell membrane-associated
tyrosine kinase. Pathogenic strains of
H. pylori have been shown to activate the
epidermal growth factor receptor (EGFR), a membrane protein with a tyrosine kinase domain. Activation of the EGFR by
H. pylori is associated with altered
signal transduction and
gene expression in host epithelial cells that may contribute to pathogenesis. It has also been suggested that a
c-terminal region of the CagA protein (amino acids 873-1002) can regulate host cell gene transcription independent of protein tyrosine phosphorylation. It is thought, due to cagA's low GC content relative to the rest of the helicobacter genome, that the gene was acquired by horizontal transfer from another cagA+ bacterial species.
Each human population has a characteristic distribution of
H. pylori strains that typically infect members of that population. This allows researchers to use
H. pylori to study human migration patterns. It could be established that
H. pylori in
Amazon Indians has East Asian rather than European origins, suggesting that it arrived with the original immigrants at least 11,000 years ago.
*
Gastritis*
Peptic ulcer*
Stomach
*
Helicobacter Pylori and other Gastric Helicobacter-Like Organisms: direct link to appropriate section.
*
NB: link is to partial text unless subscribed
*
*
The Helicobacter Foundation provides information on
Helicobacter pylori and its effects - founded by Dr. Barry J. Marshall, one of the discoverers of
H. pylori*
Helicobacter pylori persistence: biology and disease by Martin J. Blaser and John C. Atherton in
Journal of Clinical Investigations (2004) Volume 113 pages 321â€"333.
*Helicobacter pylori
: Physiology and Genetics Online text of the Mobley et al book (via NCBI).
*European Helicobacter Study Group sponsors annual international workshop, yearbook, and clinical guidelines
** The Year in Helicobacter pylori
2005 Helicobacter journal Sept 2005 - Free content
**The Year in Helicobacter pylori
2004 Helicobacter journal August 2004 - Free Content on line
* Atwood KC. Bacteria, Ulcers, and Ostracism?: H. pylori and the Making of a Myth.
Skeptical Inquirer November 2004. Fulltext Claims that medicine's purported ostracism of the discovery of H. pylori
has achieved a mythological quality, but isn't true: after appropriate initial scientific skepticism, the hypothesis was accepted right "on schedule".
* Microscopic image of H. pylori
* List of species in the genus Helicobacter''
