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Helicobacter pylori
From Wikipedia, the free encyclopedia
Helicobacter pylori
Synonym Campylobacter pylori
Immunohistochemical detection of Helicobacter (1) histopatholgy.jpg
Immunohistochemical staining of H. pylori from a gastric biopsy
Pronunciation
/'h?l?ko??b�kt?r pa?'l??ra?, p?-, -ri/[1][2]
Specialty Infectious disease, gastroenterology
Symptoms None, abdominal pain, nausea[3][4]
Complications Stomach ulcer, stomach cancer[5]
Causes Helicobacter pylori spread by fecal oral route[4]
Diagnostic method Urea breath test, fecal antigen assay, tissue biopsy[4]
Medication Proton pump inhibitor, clarithromycin, amoxicillin, metronidazole[4]
Frequency >50%[6]
[edit on Wikidata]
Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative,
microaerophilic bacterium usually found in the stomach. It was identified in 1982
by Australian scientists Barry Marshall and Robin Warren, who found that it was
present in a person with chronic gastritis and gastric ulcers, conditions not
previously believed to have a microbial cause. It is also linked to the development
of duodenal ulcers and stomach cancer. However, over 80% of individuals infected
with the bacterium are asymptomatic, and it may play an important role in the
natural stomach ecology.[7]

More than 50% of the world's population have H. pylori in their upper
gastrointestinal tract.[6] Infection is more common in developing countries than
Western countries.[4] H. pylori's helical shape (from which the genus name derives)
is thought to have evolved to penetrate the mucoid lining of the stomach.[8][9]

Contents
1 Signs and symptoms
2 Microbiology
2.1 Morphology
2.2 Physiology
2.3 Genome
2.4 Transcriptome
3 Pathophysiology
3.1 Adaptation to the stomach
3.2 Inflammation, gastritis, and ulcer
3.3 Cag pathogenicity island
3.4 Cancer
3.5 Survival of H. pylori
4 Diagnosis
5 Prevention
6 Treatment
7 Prognosis
8 Epidemiology
9 History
10 Research
11 See also
12 References
13 External links
Signs and symptoms
Up to 85% of people infected with H. pylori never experience symptoms or
complications.[10] Acute infection may appear as an acute gastritis with abdominal
pain (stomach ache) or nausea.[3] Where this develops into chronic gastritis, the
symptoms, if present, are often those of non-ulcer dyspepsia: stomach pains,
nausea, bloating, belching, and sometimes vomiting or black stool.[11][12]

Individuals infected with H. pylori have a 10 to 20% lifetime risk of developing

peptic ulcers and a 1 to 2% risk of acquiring stomach cancer.[5][13] Inflammation
of the pyloric antrum is more likely to lead to duodenal ulcers, while inflammation
of the corpus (body of the stomach) is more likely to lead to gastric ulcers and
gastric carcinoma.[14][15] However, H. pylori possibly plays a role only in the
first stage that leads to common chronic inflammation, but not in further stages
leading to carcinogenesis.[9] A meta-analysis conducted in 2009 concluded the
eradication of H. pylori reduces gastric cancer risk in previously infected
individuals, suggesting the continued presence of H. pylori constitutes a relative
risk factor of 65% for gastric cancers; in terms of absolute risk, the increase was
from 1.1% to 1.7%.[16]

H. pylori has been associated with colorectal polyps and colorectal cancer.[17] It
may also be associated with eye disease.[18]

Pain typically occurs when the stomach is empty, between meals and in the early
morning hours, but it can also occur at other times. Less common ulcer symptoms
include nausea, vomiting, and loss of appetite. Bleeding can also occur; prolonged
bleeding may cause anemia leading to weakness and fatigue. If bleeding is heavy,
hematemesis, hematochezia, or melena may occur.[19]

Microbiology
Helicobacter pylori
EMpylori.jpg
Scientific classification
Domain: Bacteria
Phylum: Proteobacteria
Class: Epsilonproteobacteria
Order: Campylobacterales
Family: Helicobacteraceae
Genus: Helicobacter
Species: H. pylori
Binomial name
Helicobacter pylori
(Marshall et al. 1985) Goodwin et al., 1989
Morphology
H. pylori is a helix-shaped (classified as a curved rod, not spirochaete) Gram-
negative bacterium about 3 �m long with a diameter of about 0.5�m. H. pylori can be
demonstrated in tissue by Gram stain, Giemsa stain, haematoxylin�eosin stain,
Warthin�Starry silver stain, acridine orange stain, and phase-contrast microscopy.
It is capable of forming biofilms[20] and can convert from spiral to a possibly
viable but nonculturable coccoid form.[21]

H. pylori has four to six flagella at the same spot; all gastric and enterohepatic
Helicobacter species are highly motile owing to flagella.[22] The characteristic
sheathed flagellar filaments of Helicobacter are composed of two copolymerized
flagellins, FlaA and FlaB.[23]

Physiology
H. pylori is microaerophilic�that is, it requires oxygen, but at lower
concentration than in the atmosphere. It contains a hydrogenase that can produce
energy by oxidizing molecular hydrogen (H2) made by intestinal bacteria.[24] It
produces oxidase, catalase, and urease.

Outer membrane. H. pylori possesses five major outer membrane protein families.[13]
The largest family includes known and putative adhesins. The other four families
are porins, iron transporters, flagellum-associated proteins, and proteins of
unknown function. Like other typical Gram-negative bacteria, the outer membrane of
H. pylori consists of phospholipids and lipopolysaccharide (LPS). The O antigen of
LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric
epithelium.[13] The outer membrane also contains cholesterol glucosides, which are
present in few other bacteria.[13]

Genome
H. pylori consists of a large diversity of strains, and hundreds of genomes have
been completely sequenced.[25][26][27][28][29][30] The genome of the strain "26695"
consists of about 1.7 million base pairs, with some 1,576 genes. The pan-genome,
that is a combined set of 30 sequenced strains, encodes 2,239 protein families
(orthologous groups, OGs). Among them, 1248 OGs are conserved in all the 30
strains, and represent the universal core. The remaining 991 OGs correspond to the
accessory genome in which 277 OGs are unique (i.e., OGs present in only one
strain).[31]

Transcriptome
In 2010, Sharma et al. presented a comprehensive analysis of transcription at
single-nucleotide resolution by differential RNA-seq that confirmed the known acid
induction of major virulence loci, such as the urease (ure) operon or the cag
pathogenicity island (see below).[32] More importantly, this study identified a
total of 1,907 transcriptional start sites, 337 primary operons, and 126 additional
suboperons, and 66 monocistrons. Until 2010, only about 55 transcriptional start
sites (TSSs) were known in this species. Notably, 27% of the primary TSSs are also
antisense TSSs, indicating that�similar to E. coli�antisense transcription occurs
across the entire H. pylori genome. At least one antisense TSS is associated with
about 46% of all open reading frames, including many housekeeping genes.[32] Most
(about 50%) of the 5' UTRs are 20�40 nucleotides (nt) in length and support the
AAGGag motif located about 6 nt (median distance) upstream of start codons as the
consensus Shine�Dalgarno sequence in H. pylori.[32]

Genes involved in virulence and pathogenesis

Study of the H. pylori genome is centered on attempts to understand pathogenesis,
the ability of this organism to cause disease. About 29% of the loci have a
colonization defect when mutated. Two of sequenced strains have an around 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.[33]

The cagA gene codes for one of the major H. pylori virulence proteins. Bacterial
strains with the cagA gene are associated with an ability to cause ulcers.[34] The
cagA gene codes for a relatively long (1186-amino acid) protein. The cag
pathogenicity island (PAI) has about 30 genes, part of which code for a complex
type IV secretion system. The low GC-content of the cag PAI relative to the rest of
the Helicobacter genome suggests the island was acquired by horizontal transfer
from another bacterial species.[25]

Pathophysiology
Adaptation to the stomach

Diagram showing how H. pylori reaches the epithelium of the stomach

To avoid the acidic environment of the interior of the stomach (lumen), H. pylori
uses its flagella to burrow into the mucus lining of the stomach to reach the
epithelial cells underneath, where it is less acidic.[35] H. pylori is able to
sense the pH gradient in the mucus and move towards the less acidic region
(chemotaxis). This also keeps the bacteria from being swept away into the lumen
with the bacteria's mucus environment, which is constantly moving from its site of
creation at the epithelium to its dissolution at the lumen interface.[36]

H. pylori urease enzyme diagram

H. pylori is found in the mucus, on the inner surface of the epithelium, and
occasionally inside the epithelial cells themselves.[37] It adheres to the
epithelial cells by producing adhesins, which bind to lipids and carbohydrates in
the epithelial cell membrane. One such adhesin, BabA, binds to the Lewis b antigen
displayed on the surface of stomach epithelial cells.[38] H. pylori adherence via
BabA is acid sensitive and can be fully reversed by increased pH. It has been
proposed that BabA's acid responsiveness enables adherence while also allowing an
effective escape from unfavorable environment at pH that is harmful to the
organism.[39] Another such adhesin, SabA, binds to increased levels of sialyl-Lewis
x antigen expressed on gastric mucosa.[40]

In addition to using chemotaxis to avoid areas of low pH, H. pylori also

neutralizes the acid in its environment by producing large amounts of urease, which
breaks down the urea present in the stomach to carbon dioxide and ammonia. These
react with the strong acids in the environment to produce a neutralized area around
H. pylori.[41] Urease knockout mutants are incapable of colonization. In fact,
urease expression is not only required for establishing initial colonization but
also for maintaining chronic infection.[42]

Inflammation, gastritis, and ulcer

H. pylori harms the stomach and duodenal linings by several mechanisms. The ammonia
produced to regulate pH is toxic to epithelial cells, as are biochemicals produced
by H. pylori such as proteases, vacuolating cytotoxin A (VacA) [this damages
epithelial cells, disrupts tight junctions and causes apoptosis, and certain
phospholipases.[43] Cytotoxin associated gene CagA can also cause inflammation and
is potentially a carcinogen.[44]

Colonization of the stomach by H. pylori can result in chronic gastritis, an

inflammation of the stomach lining, at the site of infection. Helicobacter
cysteine-rich proteins (Hcp), particularly HcpA (hp0211), are known to trigger an
immune response, causing inflammation.[45] Chronic gastritis is likely to underlie
H. pylori-related diseases.[46]

Ulcers in the stomach and duodenum result when the consequences of inflammation
allow stomach acid and the digestive enzyme pepsin to overwhelm the mechanisms that
protect the stomach and duodenal mucous membranes. The location of colonization of
H. pylori, which affects the location of the ulcer, depends on the acidity of the
stomach.[47] In people producing large amounts of acid, H. pylori colonizes near
the pyloric antrum (exit to the duodenum) to avoid the acid-secreting parietal
cells at the fundus (near the entrance to the stomach).[13] In people producing
normal or reduced amounts of acid, H. pylori can also colonize the rest of the
stomach.

The inflammatory response caused by bacteria colonizing near the pyloric antrum
induces G cells in the antrum to secrete the hormone gastrin, which travels through
the bloodstream to parietal cells in the fundus.[48] Gastrin stimulates the
parietal cells to secrete more acid into the stomach lumen, and over time increases
the number of parietal cells, as well.[49] The increased acid load damages the
duodenum, which may eventually result in ulcers forming in the duodenum.

When H. pylori colonizes other areas of the stomach, the inflammatory response can
result in atrophy of the stomach lining and eventually ulcers in the stomach. This
also may increase the risk of stomach cancer.[50]
Cag pathogenicity island
The pathogenicity of H. pylori may be increased by genes of the cag pathogenicity
island; about 50�70% of H. pylori strains in Western countries carry it.[51]
Western people infected with strains carrying the cag PAI have a stronger
inflammatory response in the stomach and are at a greater risk of developing peptic
ulcers or stomach cancer than those infected with strains lacking the island.[13]
Following attachment of H. pylori to stomach epithelial cells, the type IV
secretion system expressed by the cag PAI "injects" the inflammation-inducing
agent, peptidoglycan, from their own cell walls into the epithelial cells. The
injected peptidoglycan is recognized by the cytoplasmic pattern recognition
receptor (immune sensor) Nod1, which then stimulates expression of cytokines that
promote inflammation.[52]

The type-IV secretion apparatus also injects the cag PAI-encoded protein CagA into
the stomach's epithelial cells, where it disrupts the cytoskeleton, adherence to
adjacent cells, intracellular signaling, cell polarity, and other cellular
activities.[53] Once inside the cell, the CagA protein is phosphorylated on
tyrosine residues by a host cell membrane-associated tyrosine kinase (TK). CagA
then allosterically activates protein tyrosine phosphatase/protooncogene Shp2.[54]
Pathogenic strains of H. pylori have been shown to activate the epidermal growth
factor receptor (EGFR), a membrane protein with a TK 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. A C-terminal region of
the CagA protein (amino acids 873�1002) has also been suggested to be able to
regulate host cell gene transcription, independent of protein tyrosine
phosphorylation.[33][34] A great deal of diversity exists between strains of H.
pylori, and the strain that infects a person can predict the outcome.

Cancer
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",[55] and involves enhancement of the
transformed host cell phenotype by means of alterations in cell proteins, such as
adhesion proteins. H. pylori has been proposed to induce inflammation and locally
high levels of TNF-a and/or interleukin 6 (IL-6). According to the proposed
perigenetic mechanism, inflammation-associated signaling molecules, such as TNF-a,
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.[56]

The strain of H. pylori a person is exposed to may influence the risk of developing
gastric cancer. Strains of H. pylori that produce high levels of two proteins,
vacuolating toxin A (VacA) and the cytotoxin-associated gene A (CagA), appear to
cause greater tissue damage than those that produce lower levels or that lack those
genes completely. These proteins are directly toxic to cells lining the stomach and
signal strongly to the immune system that an invasion is under way. As a result of
the bacterial presence, neutrophils and macrophages set up residence in the tissue
to fight the bacteria assault.[57]

Survival of H. pylori
The pathogenesis of H. pylori depends on its ability to survive in the harsh
gastric environment characterized by acidity, peristalsis, and attack by phagocytes
accompanied by release of reactive oxygen species.[58] In particular, H. pylori
elicits an oxidative stress response during host colonization. This oxidative
stress response induces potentially lethal and mutagenic oxidative DNA adducts in
the H. pylori genome.[59]

Vulnerability to oxidative stress and oxidative DNA damage occurs commonly in many
studied bacterial pathogens, including Neisseria gonorrhoeae, Hemophilus
influenzae, Streptococcus pneumoniae, S. mutans, and H. pylori.[60] For each of
these pathogens, surviving the DNA damage induced by oxidative stress appears
supported by transformation-mediated recombinational repair. Thus, transformation
and recombinational repair appear to contribute to successful infection.

Transformation (the transfer of DNA from one bacterial cell to another through the
intervening medium) appears to be part of an adaptation for DNA repair. H. pylori
is naturally competent for transformation. While many organisms are competent only
under certain environmental conditions, such as starvation, H. pylori is competent
throughout logarithmic growth.[61] All organisms encode genetic programs for
response to stressful conditions including those that cause DNA damage.[61] In H.
pylori, homologous recombination is required for repairing DNA double-strand breaks
(DSBs). The AddAB helicase-nuclease complex resects DSBs and loads RecA onto
single-strand DNA (ssDNA), which then mediates strand exchange, leading to
homologous recombination and repair. The requirement of RecA plus AddAB for
efficient gastric colonization suggests, in the stomach, H. pylori is either
exposed to double-strand DNA damage that must be repaired or requires some other
recombination-mediated event. In particular, natural transformation is increased by
DNA damage in H. pylori, and a connection exists between the DNA damage response
and DNA uptake in H. pylori,[61] suggesting natural competence contributes to
persistence of H. pylori in its human host and explains the retention of competence
in most clinical isolates.

RuvC protein is essential to the process of recombinational repair, since it

resolves intermediates in this process termed Holliday junctions. H. pylori mutants
that are defective in RuvC have increased sensitivity to DNA-damaging agents and to
oxidative stress, exhibit reduced survival within macrophages, and are unable to
establish successful infection in a mouse model.[62] Similarly, RecN protein plays
an important role in DSB repair in H. pylori.[63] An H. pylori recN mutant displays
an attenuated ability to colonize mouse stomachs, highlighting the importance of
recombinational DNA repair in survival of H. pylori within its host.[63]

Diagnosis

H. pylori colonized on the surface of regenerative epithelium (Warthin-Starry

silver stain)
Colonization with H. pylori is not a disease in and of itself, but a condition
associated with a number of disorders of the upper gastrointestinal tract.[13]
Testing for H. pylori is recommended if peptic ulcer disease or low-grade gastric
MALT lymphoma is present, after endoscopic resection of early gastric cancer,
first-degree relatives with gastric cancer, and in certain cases of dyspepsia,[64]
not routinely.[13] Several ways of testing exist. One can test noninvasively for H.
pylori infection with a blood antibody test, stool antigen test, 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).[64] Also, a urine ELISA test with a 96% sensitivity and 79%
specificity is available. None of the test methods is completely failsafe. Even
biopsy is dependent on the location of the biopsy. Blood antibody tests, for
example, range from 76% to 84% sensitivity. Some drugs can affect H. pylori urease
activity and give false negatives with the urea-based tests. The most accurate
method for detecting H. pylori infection is with a histological examination from
two sites after endoscopic biopsy, combined with either a rapid urease test or
microbial culture.[65]

Prevention
H. pylori is a major cause of certain diseases of the upper gastrointestinal tract.
Rising antibiotic resistance increases the need to search for new therapeutic
strategies; this might include prevention in the form of vaccination.[66] Much work
has been done on developing viable vaccines aimed at providing an alternative
strategy to control H. pylori infection and related diseases, including stomach
cancer.[67] Researchers are studying different adjuvants, antigens, and routes of
immunization to ascertain the most appropriate system of immune protection;
however, most of the research only recently moved from animal to human trials.[68]
An economic evaluation of the use of a potential H. pylori vaccine in babies found
its introduction could, at least in the Netherlands, prove cost-effective for the
prevention of peptic ulcer and stomach cancer.[69] A similar approach has also been
studied for the United States.[70]

The presence of bacteria in the stomach may be beneficial, reducing the prevalence
of asthma,[71] rhinitis,[71] dermatitis,[71] inflammatory bowel disease,[71]
gastroesophageal reflux disease,[72] and esophageal cancer[72] by influencing
systemic immune responses.[71][73]

Recent evidence suggests that nonpathogenic strains of H. pylori may be beneficial,

e.g., by normalizing stomach acid secretion,[74] and may play a role in regulating
appetite, since its presence in the stomach results in a persistent but reversible
reduction in the level of ghrelin.[74]

Treatment
Further information: Helicobacter pylori eradication protocols
Once H. pylori is detected in a person with a peptic ulcer, the normal procedure is
to eradicate it and allow the ulcer to heal. The standard first-line therapy is a
one-week "triple therapy" consisting of proton pump inhibitors such as omeprazole
and the antibiotics clarithromycin and amoxicillin.[75] Variations of the triple
therapy have been developed over the years, such as using a different proton pump
inhibitor, as with pantoprazole or rabeprazole, or replacing amoxicillin with
metronidazole for people who are allergic to penicillin.[76] In areas with higher
rates of clarithromycin resistance, other options are recommended.[77] Such a
therapy has revolutionized the treatment of peptic ulcers and has made a cure to
the disease possible. Previously, the only option was symptom control using
antacids, H2-antagonists or proton pump inhibitors alone.[78][79]

An increasing number of infected individuals are found to harbor antibiotic-

resistant bacteria. This results in initial treatment failure and requires
additional rounds of antibiotic therapy or alternative strategies, such as a
quadruple therapy, which adds a bismuth colloid, such as bismuth subsalicylate.[64]
[80][81] For the treatment of clarithromycin-resistant strains of H. pylori, the
use of levofloxacin as part of the therapy has been suggested.[82][83]

Ingesting lactic acid bacteria exerts a suppressive effect on H. pylori infection

in both animals and humans, and supplementing with Lactobacillus- and
Bifidobacterium-containing yogurt improved the rates of eradication of H. pylori in
humans.[84] Symbiotic butyrate-producing bacteria which are normally present in the
intestine are sometimes used as probiotics to help suppress H. pylori infections as
an adjunct to antibiotic therapy.[85] Butyrate itself is an antimicrobial which
destroys the cell envelope of H. pylori by inducing regulatory T cell expression
(specifically, FOXP3) and synthesis of an antimicrobial peptide called LL-37, which
arises through its action as a histone deacetylase inhibitor.[86][87][88]

The substance sulforaphane, which occurs in broccoli and cauliflower, has been
proposed as a treatment.[89][90][91] Periodontal therapy or scaling and root
planing has also been suggested as an additional treatment.[92]

Prognosis
H. pylori colonizes the stomach and induces chronic gastritis, a long-lasting
inflammation of the stomach. The bacterium persists in the stomach for decades in
most people. Most individuals infected by H. pylori never experience clinical
symptoms, despite having chronic gastritis. About 10�20% of those colonized by H.
pylori ultimately develop gastric and duodenal ulcers.[13] H. pylori infection is
also associated with a 1�2% lifetime risk of stomach cancer and a less than 1% risk
of gastric MALT lymphoma.[13]

In the absence of treatment, H. pylori infection�once established in its gastric

niche�is widely believed to persist for life.[9] In the elderly, however, infection
likely can disappear as the stomach's mucosa becomes increasingly atrophic and
inhospitable to colonization. The proportion of acute infections that persist is
not known, but several studies that followed the natural history in populations
have reported apparent spontaneous elimination.[93][94]

Mounting evidence suggests H. pylori has an important role in protection from some
diseases.[95] The incidence of acid reflux disease, Barrett's esophagus, and
esophageal cancer have been rising dramatically at the same time as H. pylori's
presence decreases.[96] In 1996, Martin J. Blaser advanced the hypothesis that H.
pylori has a beneficial effect: by regulating the acidity of the stomach contents.
[48][96] The hypothesis is not universally accepted as several randomized
controlled trials failed to demonstrate worsening of acid reflux disease symptoms
following eradication of H. pylori.[97][98] Nevertheless, Blaser has reasserted his
view that H. pylori is a member of the normal flora of the stomach.[99] He
postulates that the changes in gastric physiology caused by the loss of H. pylori
account for the recent increase in incidence of several diseases, including type 2
diabetes, obesity, and asthma.[99][100] His group has recently shown that H. pylori
colonization is associated with a lower incidence of childhood asthma.[101]

Epidemiology
At least half the world's population is infected by the bacterium, making it the
most widespread infection in the world.[102] Actual infection rates vary from
nation to nation; the developing world has much higher infection rates than the
West (Western Europe, North America, Australasia), where rates are estimated to be
around 25%.[102]

The age when someone acquires this bacterium seems to influence the pathologic
outcome of the infection. People infected at an early age are likely to develop
more intense inflammation that may be followed by atrophic gastritis with a higher
subsequent risk of gastric ulcer, gastric cancer, or both. Acquisition at an older
age brings different gastric changes more likely to lead to duodenal ulcer.[9]
Infections are usually acquired in early childhood in all countries.[13] However,
the infection rate of children in developing nations is higher than in
industrialized nations, probably due to poor sanitary conditions, perhaps combined
with lower antibiotics usage for unrelated pathologies. In developed nations, it is
currently uncommon to find infected children, but the percentage of infected people
increases with age, with about 50% infected for those over the age of 60 compared
with around 10% between 18 and 30 years.[102] The higher prevalence among the
elderly reflects higher infection rates in the past when the individuals were
children rather than more recent infection at a later age of the individual.[13] In
the United States, prevalence appears higher in African-American and Hispanic
populations, most likely due to socioeconomic factors.[103][104] The lower rate of
infection in the West is largely attributed to higher hygiene standards and
widespread use of antibiotics. Despite high rates of infection in certain areas of
the world, the overall frequency of H. pylori infection is declining.[105] However,
antibiotic resistance is appearing in H. pylori; many metronidazole- and
clarithromycin-resistant strains are found in most parts of the world.[106]

H. pylori is contagious, although the exact route of transmission is not known.

[107][108] Person-to-person transmission by either the oral�oral or fecal�oral
route is most likely. Consistent with these transmission routes, the bacteria have
been isolated from feces, saliva, and dental plaque of some infected people.
Findings suggest H. pylori is more easily transmitted by gastric mucus than saliva.
[9] Transmission occurs mainly within families in developed nations, yet can also
be acquired from the community in developing countries.[109] H. pylori may also be
transmitted orally by means of fecal matter through the ingestion of waste-tainted
water, so a hygienic environment could help decrease the risk of H. pylori
infection.[9]

History
See also: Timeline of peptic ulcer disease and Helicobacter pylori
H. pylori migrated out of Africa along with its human host circa 60,000 years ago.
[110] Recent research states that genetic diversity in H. pylori, like that of its
host, decreases with geographic distance from East Africa. Using the genetic
diversity data, researchers have created simulations that indicate the bacteria
seem to have spread from East Africa around 58,000 years ago. Their results
indicate modern humans were already infected by H. pylori before their migrations
out of Africa, and it has remained associated with human hosts since that time.
[111]

H. pylori was first discovered in the stomachs of patients with gastritis and
ulcers in 1982 by Drs. Barry Marshall and Robin Warren of Perth, Western Australia.
At the time, the conventional thinking was that no bacterium could live in the acid
environment of the human stomach. In recognition of their discovery, Marshall and
Warren were awarded the 2005 Nobel Prize in Physiology or Medicine.[112]

Before the research of Marshall and Warren, German scientists found spiral-shaped
bacteria in the lining of the human stomach in 1875, but they were unable to
culture them, and the results were eventually forgotten.[96] The Italian researcher
Giulio Bizzozero described similarly shaped bacteria living in the acidic
environment of the stomach of dogs in 1893.[113] Professor Walery Jaworski of the
Jagiellonian University in Krak�w investigated sediments of gastric washings
obtained by lavage 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 pathogenesis of
gastric diseases. His work was included in the Handbook of Gastric Diseases, but it
had little impact, as it was written in Polish.[114] Several small studies
conducted in the early 20th century demonstrated the presence of curved rods in the
stomachs of many people with peptic ulcers and stomach cancers.[115] Interest in
the bacteria waned, however, when an American study published in 1954 failed to
observe the bacteria in 1180 stomach biopsies.[116]

Interest in understanding the role of bacteria in stomach diseases was rekindled in

the 1970s, with the visualization of bacteria in the stomachs of people with
gastric ulcers.[117] The bacteria had also been observed in 1979, by Robin Warren,
who researched it further with Barry Marshall from 1981. After unsuccessful
attempts at culturing the bacteria from the stomach, they finally succeeded in
visualizing colonies in 1982, when they unintentionally left their Petri dishes
incubating for five days over the Easter weekend. In their original paper, Warren
and Marshall contended that most stomach ulcers and gastritis were caused by
bacterial infection and not by stress or spicy food, as had been assumed before.
[118]

Some skepticism was expressed initially, but within a few years multiple research
groups had verified the association of H. pylori with gastritis and, to a lesser
extent, ulcers.[119] To demonstrate H. pylori caused gastritis and was not merely a
bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea
and vomiting several days later. An endoscopy 10 days after inoculation revealed
signs of gastritis and the presence of H. pylori. These results suggested H. pylori
was the causative agent. Marshall and Warren went on to demonstrate antibiotics are
effective in the treatment of many cases of gastritis. In 1987, the Sydney
gastroenterologist Thomas Borody invented the first triple therapy for the
treatment of duodenal ulcers.[120] In 1994, the National Institutes of Health
stated most recurrent duodenal and gastric ulcers were caused by H. pylori, and
recommended antibiotics be included in the treatment regimen.[121]

The bacterium was initially named Campylobacter pyloridis, then renamed C. pylori
in 1987 (pylori being the genitive of pylorus, the circular opening leading from
the stomach into the duodenum, from the Ancient Greek word p??????, which means
gatekeeper.[122]).[123] When 16S ribosomal RNA gene sequencing and other research
showed in 1989 that the bacterium did not belong in the genus Campylobacter, it was
placed in its own genus, Helicobacter from the ancient Greek helix/???? "spiral" or
"coil".[122][124]

In October 1987, a group of experts met in Copenhagen to found the European

Helicobacter Study Group (EHSG), an international multidisciplinary research group
and the only institution focused on H. pylori.[125] The Group is involved with the
Annual International Workshop on Helicobacter and Related Bacteria,[126] the
Maastricht Consensus Reports (European Consensus on the management of H. pylori),
[127][128][129][130] and other educational and research projects, including two
international long-term projects:

European Registry on H. pylori Management (Hp-EuReg) � a database systematically

registering the routine clinical practice of European gastroenterologists.[131]
Optimal H. pylori management in primary care (OptiCare) � a long-term educational
project aiming to disseminate the evidence based recommendations of the Maastricht
IV Consensus to primary care physicians in Europe, funded by an educational grant
from United European Gastroenterology.[132]
Research
Results from in vitro studies suggest that fatty acids, mainly polyunsaturated
fatty acids, have a bactericidal effect against H. pylori, but their in vivo
effects have not been proven.[133]

See also
List of oncogenic bacteria
Infectious causes of cancer
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External links
Classification V � T � D
ICD-10: B98.0 ICD-9-CM: 041.86 OMIM: 600263 MeSH: D016481 DiseasesDB: 5702
External resources
MedlinePlus: 000229 eMedicine: med/962 Patient UK: Helicobacter pylori

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Categories: Conditions diagnosed by stool testHelicobacter pyloriInfectious causes
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