Helicobacter pylori

Helicobacter pylori (/ˌhɛlɪkɵˈbæktərpaɪˈlɔəraɪ/), previ-ously named Campylobacter pylori, is a Gram-negative,microaerophilic bacterium found in the stomach, andmay be present in other parts of the body, such as theeye.[1][2][3] It was identified in 1982 by Australian sci-entists Barry Marshall and Robin Warren with furtherresearch led by British scientist Stewart Goodwin, whofound that it was present in patients with chronic gastritisand gastric ulcers, conditions not previously believed tohave a microbial cause. It is also linked to the develop-ment of duodenal ulcers and stomach cancer. However,over 80% of individuals infected with the bacterium areasymptomatic and it may play an important role in thenatural stomach ecology.[4]

More than 50% of the world’s population harbor H. py-lori in their upper gastrointestinal tract. Infection is moreprevalent in developing countries, and incidence is de-creasing in Western countries. H. pylori's helical shape(from which the generic name is derived) is thoughtto have evolved to penetrate the mucoid lining of thestomach.[5][6]

1 Signs and symptoms

Up to 85% of people infected withH. pylori never experi-ence symptoms or complications.[7] Acute infection mayappear as an acute gastritis with abdominal pain (stom-ach ache) or nausea.[8] Where this develops into chronicgastritis, the symptoms, if present, are often those ofnon-ulcer dyspepsia: stomach pains, nausea, bloating,belching, and sometimes vomiting or black stool.[9][10]

Individuals infected with H. pylori have a 10 to 20%lifetime risk of developing peptic ulcers and a 1 to2% risk of acquiring stomach cancer.[11] [12] Inflam-mation of the pyloric antrum is more likely to lead toduodenal ulcers, while inflammation of the corpus (bodyof the stomach) is more likely to lead to gastric ulcersand gastric carcinoma.[13] However, H. pylori possiblyplays a role only in the first stage that leads to commonchronic inflammation, but not in further stages leadingto carcinogenesis.[6] A meta-analysis conducted in 2009concluded the eradication of H. pylori reduces gastriccancer risk in previously infected individuals, suggestingthe continued presence of H. pylori constitutes a relativerisk factor of 65% for gastric cancers; in terms of absoluterisk, the increase was from 1.1% to 1.7%.[14]

H. pylori has also been associated with colorectal polyps

and colorectal cancer.[15]

2 Microbiology

Scanning electron micrograph of H. pylori

H. pylori is a helix-shaped (classified as a curved rod, notspirochaete) Gram-negative bacterium about 3 μm longwith a diameter of about 0.5 μm. It is microaerophilic;that is, it requires oxygen, but at lower concentration thanis found in the atmosphere. It contains a hydrogenasewhich can be used to obtain energy by oxidizing molec-ular hydrogen (H2) produced by intestinal bacteria.[16]It produces oxidase, catalase, and urease. It is capa-ble of forming biofilms[17] and can convert from spiralto a possibly viable but nonculturable coccoid form,[18]both likely to favor its survival and be factors in theepidemiology of the bacterium.H. pylori possesses five major outer membrane pro-tein families.[12] The largest family includes known andputative adhesins. The other four families are porins,

1

2 3 PATHOPHYSIOLOGY

iron transporters, flagellum-associated proteins, and pro-teins of unknown function. Like other typical Gram-negative bacteria, the outer membrane of H. pylori con-sists of phospholipids and lipopolysaccharide (LPS). TheO antigen of LPS may be fucosylated and mimic Lewisblood group antigens found on the gastric epithelium.[12]The outer membrane also contains cholesterol glucosides,which are found in few other bacteria.[12] H. pylori hasfour to six lophotrichous flagella; all gastric and entero-hepatic Helicobacter species are highly motile owing toflagella.[19] The characteristic sheathed flagellar filamentsofHelicobacter are composed of two copolymerized flag-ellins, FlaA and FlaB.[20]

2.1 Microscopy

H. pylori can be demonstrated in tissue by Gram stain,Giemsa stain, haematoxylin-eosin stain, Warthin-Starrysilver stain, acridine-orange stain, and phase-contrast mi-croscopy.

2.2 Genome

H. pylori consists of a large diversity of strains,and the genomes of three have been completelysequenced.[21][22][23][24][25] The genome of the strain“26695” consists of about 1.7 million base pairs, withsome 1,550 genes. The two sequenced strains show largegenetic differences, with up to 6% of the nucleotidesdiffering.[23]

Study of the H. pylori genome is centered on attemptsto understand pathogenesis, the ability of this organismto cause disease. About 29% of the loci are in the“pathogenesis” category of the genome database. Twoof sequenced strains have an around 40-kb-long Cagpathogenicity island (a common gene sequence believedresponsible for pathogenesis) that contains over 40 genes.This pathogenicity island is usually absent from H. pyloristrains isolated from humans who are carriers ofH. pyloribut remain asymptomatic.[26]

The cagA gene codes for one of the major H. pylorivirulence proteins. Bacterial strains with the cagA geneare associated with an ability to cause ulcers.[27] The cagAgene codes for a relatively long (1186-amino acid) pro-tein. The cag pathogenicity island (PAI) has about 30genes, part of which code for a complex type IV secre-tion system. The low GC-content of the cag PAI relativeto the rest of the Helicobacter genome suggests the islandwas acquired by horizontal transfer from another bacte-rial species.[21]

3 Pathophysiology

3.1 Adaptation to the stomach’s acidic en-vironment

Diagram showing how H. pylori reaches the epithelium of thestomach

To avoid the acidic environment of the interior of thestomach (lumen), H. pylori uses its flagella to burrow intothe mucus lining of the stomach to reach the epithelialcells underneath, where the pH is more neutral.[28] H. py-lori is able to sense the pH gradient in the mucus andmove towards the less acidic region (chemotaxis). Thisalso keeps the bacteria from being swept away into thelumen with the bacteria’s mucus environment, which isconstantly moving from its site of creation at the epithe-lium to its dissolution at the lumen interface.[29]

H. pylori is found in the mucus, on the inner surfaceof the epithelium, and occasionally inside the epithelialcells themselves.[30] It adheres to the epithelial cells byproducing adhesins, which bind to lipids and carbohy-drates in the epithelial cell membrane. One such adhe-sion, BabA, binds to the Lewis b antigen displayed on thesurface of stomach epithelial cells.[31] Another such ad-hesion, SabA, binds to increased levels of sialyl-Lewis xantigen expressed on gastric mucosa.[32]

In addition to using chemotaxis to avoid areas of low pH,H. pylori also neutralizes the acid in its environment byproducing large amounts of urease, which breaks downthe urea present in the stomach to carbon dioxide andammonia. The ammonia, which is basic, then neutralizesstomach acid.

3.2 Inflammation, gastritis, and ulcer

H. pylori harms the stomach and duodenal linings byseveral mechanisms. The ammonia produced to reg-ulate pH is toxic to epithelial cells, as are biochem-icals produced by H. pylori such as proteases, vac-uolating cytotoxin A (VacA) [this damages epithelialcells, disrupts tight junctions and causes apoptosis],and certain phospholipases.[33] Cytotoxin associated geneCagA can also cause inflammation and is potentially acarcinogen.[34]

Colonization of the stomach by H. pylori can result in

3.4 Cancer 3

chronic gastritis, an inflammation of the stomach lining,at the site of infection. Helicobacter cysteine-rich proteins(Hcp), particularly HcpA (hp0211), are known to triggeran immune response, causing inflammation.[35] Chronicgastritis is likely to underlie H. pylori-related diseases.[36]

Ulcers in the stomach and duodenum result when the con-sequences of inflammation allow stomach acid and the di-gestive enzyme pepsin to overwhelm the mechanisms thatprotect the stomach and duodenal mucous membranes.The location of colonization of H. pylori, which affectsthe location of the ulcer, depends on the acidity of thestomach.[37] In people producing large amounts of acid,H. pylori colonizes near the pyloric antrum (exit to theduodenum) to avoid the acid-secreting parietal cells at thefundus (near the entrance to the stomach).[12] In peopleproducing normal or reduced amounts of acid, H. pylorican also colonize the rest of the stomach.The inflammatory response caused by bacteria coloniz-ing near the pyloric antrum induces G cells in the antrumto secrete the hormone gastrin, which travels through thebloodstream to parietal cells in the fundus.[38] Gastrinstimulates the parietal cells to secrete more acid into thestomach lumen, and over time increases the number ofparietal cells, as well.[39] The increased acid load dam-ages the duodenum, which may eventually result in ulcersforming in the duodenum.When H. pylori colonizes other areas of the stomach, theinflammatory response can result in atrophy of the stom-ach lining and eventually ulcers in the stomach. This alsomay increase the risk of stomach cancer.[40]

3.3 The Cag pathogenicity island

The pathogenicity ofH. pylorimay be increased by genesof the cag pathogenicity island. About 50–70% of H. py-lori strains inWestern countries carry the cag pathogenic-ity island (cag PAI).[41] Western patients infected withstrains carrying the cag PAI have a stronger inflamma-tory response in the stomach and are at a greater risk ofdeveloping peptic ulcers or stomach cancer than those in-fected with strains lacking the island.[12] Following at-tachment of H. pylori to stomach epithelial cells, thetype IV secretion system expressed by the cag PAI “in-jects” the inflammation-inducing agent, peptidoglycan,from their own cell wall into the epithelial cells. Theinjected peptidoglycan is recognized by the cytoplas-mic pattern recognition receptor (immune sensor) Nod1,which then stimulates expression of cytokines that pro-mote inflammation.[42]

The type-IV secretion apparatus also injects the cagPAI-encoded protein CagA into the stomach’s epithe-lial cells, where it disrupts the cytoskeleton, adherenceto adjacent cells, intracellular signaling, cell polarity,and other cellular activities.[43] Once inside the cell, theCagA protein is phosphorylated on tyrosine residues bya host cell membrane-associated tyrosine kinase (TK).

CagA then allosterically activates protein tyrosine phos-phatase/protooncogene Shp2.[44] Pathogenic strains ofH.pylori have been shown to activate the epidermal growthfactor receptor (EGFR), a membrane protein with a TKdomain. Activation of the EGFR by H. pylori is associ-ated with altered signal transduction and gene expressionin host epithelial cells that may contribute to pathogen-esis. A C-terminal region of the CagA protein (aminoacids 873–1002) has also been suggested to be able toregulate host cell gene transcription, independent of pro-tein tyrosine phosphorylation.[26][27] A great deal of di-versity exists between strains of H. pylori, and the strainwith which one is infected is predictive of the outcome.

3.4 Cancer

Two related mechanisms by which H. pylori could pro-mote cancer are under investigation. One mechanisminvolves the enhanced production of free radicals nearH. pylori and an increased rate of host cell mutation.The other proposed mechanism has been called a “peri-genetic pathway”,[45] and involves enhancement of thetransformed host cell phenotype by means of alterationsin cell proteins, such as adhesion proteins. H. pylori hasbeen proposed to induce inflammation and locally highlevels of TNF-α and/or interleukin 6 (IL-6). Accordingto the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF-α, can altergastric epithelial cell adhesion and lead to the dispersionand migration of mutated epithelial cells without the needfor additional mutations in tumor suppressor genes, suchas genes that code for cell adhesion proteins.[46]

The strain of H. pylori to which a person is exposed mayinfluence the risk of developing gastric cancer. Strains ofH. pylori that produce high levels of two proteins, vacuo-lating toxin A (VacA) and the cytotoxin-associated geneA (CagA), appear to cause greater tissue damage thanthose that produce lower levels or that lack those genescompletely.These proteins are directly toxic to cells lin-ing the stomach and signal strongly to the immune systemthat an invasion is underway. As a result of the bacterialpresence, neutrophils and macrophages set up residencein the tissue to fight the bacteria assault. [47]

4 Diagnosis

Colonization with H. pylori is not a disease in and of it-self, but a condition associated with a number of disor-ders of the upper gastrointestinal tract.[12] Testing for H.pylori is recommended if there is peptic ulcer disease,low grade gastric MALT lymphoma, after endoscopicresection of early gastric cancer, if there are first de-gree relatives with gastric cancer, and in certain casesof dyspepsia,[48] not routinely.[12] Several ways of testingexist. One can test noninvasively for H. pylori infection

4 6 TREATMENT

H. pylori colonized on the surface of regenerative epithelium (im-age from Warthin-Starry’s silver stain)

with a blood antibody test, stool antigen test, or with thecarbon 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 inthe breath).[48] Also, a urine ELISA test with a 96% sen-sitivity and 79% specificity is available. None of the testmethods is completely failsafe. Even biopsy is dependenton the location of the biopsy. Blood antibody tests, for ex-ample, range from 76% to 84% sensitivity. Some drugscan affectH. pylori urease activity and give false negativeswith the urea-based tests. The most reliable method fordetecting H. pylori infection is with a histological exami-nation from two sites after endoscopic biopsy, combinedwith either a rapid urease test or microbial culture.[49]

5 Prevention

H. pylori is a major cause of certain diseases of the up-per gastrointestinal tract. Rising antibiotic resistance in-creases the need to search for new therapeutic strate-gies; this might include prevention in form of vaccina-tion. [50] Much work has been done on developing vi-able vaccines aimed at providing an alternative strategy tocontrol H. pylori infection and related diseases, includingstomach cancer. [51] Researchers are studying differentadjuvants, antigens, and routes of immunization to ascer-tain the most appropriate system of immune protection;however, most of the research only recently moved fromanimal to human trials. [52] An economic evaluation ofthe use of a potential H. pylori vaccine in babies foundits introduction could, at least in the Netherlands, provecost-effective for the prevention of peptic ulcer and stom-ach cancer. [53] A similar approach has also been studiedfor the United States. [54]

The presence of bacteria in the stomach may be ben-eficial, reducing the prevalence of asthma, [55] rhinitis,[55] dermatitis, [55] inflammatory bowel disease, [55]

gastroesophageal reflux disease, [56] and esophageal can-cer [56] by influencing systemic immune responses. [55][57]

Recent evidence suggests that H. pylorimay be beneficial“by helping regulate levels of stomach acids, thus creatingan environment that suits itself and its host. If the stom-ach churns out too much acid for the bacteria to thrive,for example, strains of the bacteria that contain a genecalled cagA start producing proteins that signal the stom-ach to tone down the flow of acid, in susceptible people,however, cagA has an unwelcome side effect: provokingthe ulcers that earned H. pylori its nasty rap.”[58]

H. pylori may play a role in regulating appetite — “Whenyou have H. pylori, you have a postprandial decrease inghrelin. When you eradicate H. pylori, you lose that.”Ghrelin is a hormone “which tells the brain that the bodyneeds to eat.” [58]

6 Treatment

Further information: Helicobacter pylori eradicationprotocols

Once H. pylori is detected in a person with a peptic ulcer,the normal procedure is to eradicate it and allow the ul-cer to heal. The standard first-line therapy is a one-week“triple therapy” consisting of proton pump inhibitors suchas omeprazole and the antibiotics clarithromycin andamoxicillin.[59] Variations of the triple therapy have beendeveloped over the years, such as using a different protonpump inhibitor, as with pantoprazole or rabeprazole, orreplacing amoxicillin with metronidazole for people whoare allergic to penicillin.[60] Such a therapy has revolu-tionized the treatment of peptic ulcers and has made acure to the disease possible. Previously, the only optionwas symptom control using antacids, H2-antagonists orproton pump inhibitors alone.[61][62]

An increasing number of infected individuals are foundto harbor antibiotic-resistant bacteria. This results ininitial treatment failure and requires additional roundsof antibiotic therapy or alternative strategies, such asa quadruple therapy, which adds a bismuth colloid,such as bismuth subsalicylate.[48][63][64] For the treat-ment of clarithromycin-resistant strains of H. pylori, theuse of levofloxacin as part of the therapy has beensuggested.[65][66]

Ingesting lactic acid bacteria exerts a suppressive effecton H. pylori infection in both animals and humans, andsupplementing with Lactobacillus- and Bifidobacterium-containing yogurt improved the rates of eradication of H.pylori in humans.[67]

The substance sulforaphane, which occurs in broccoli andcauliflower, has been proposed as a treatment.[68][69][70]

5

7 Prognosis

H. pylori colonizes the stomach and induces chronicgastritis, a long-lasting inflammation of the stomach. Thebacterium persists in the stomach for decades in mostpeople. Most individuals infected by H. pylori will neverexperience clinical symptoms despite having chronic gas-tritis. About 10–20% of those colonized by H. pyloriwill ultimately develop gastric and duodenal ulcers.[12] H.pylori infection is also associated with a 1–2% lifetimerisk of stomach cancer and a less than 1% risk of gastricMALT lymphoma.[12]

In the absence of treatment,H. pylori infection—once es-tablished in its gastric niche—is widely believed to per-sist for life.[6] In the elderly, however, infection likely candisappear as the stomach’s mucosa becomes increasinglyatrophic and inhospitable to colonization. The proportionof acute infections that persist is not known, but severalstudies that followed the natural history in populationshave reported apparent spontaneous elimination.[71][72]

Mounting evidence suggests H. pylori has an importantrole in protection from some diseases. The incidence ofacid reflux disease, Barrett’s esophagus, and esophagealcancer have been rising dramatically at the same timeas H. pylori's presence decreases.[73] In 1996, MartinJ. Blaser advanced the hypothesis that H. pylori has abeneficial effect: by regulating the acidity of the stom-ach contents.[38][73] The hypothesis is not universally ac-cepted as several randomized controlled trials failed todemonstrate worsening of acid reflux disease symptomsfollowing eradication of H. pylori.[74][75] Nevertheless,Blaser has reasserted his view that H. pylori is a memberof the normal flora of the stomach.[76] He postulates thatthe changes in gastric physiology caused by the loss ofH. pylori account for the recent increase in incidence ofseveral diseases, including type 2 diabetes, obesity, andasthma.[76][77] His group has recently shown that H. py-lori colonization is associated with a lower incidence ofchildhood asthma.[78]

8 Survival of H. pylori

The pathogenesis of H. pylori depends on its ability tosurvive in the harsh gastric environment characterized byacidity, peristalsis, and attack by phagocytes accompa-nied by release of reactive oxygen species.[79] In partic-ular, H. pylori elicits an oxidative stress response duringhost colonization. This oxidative stress response inducespotentially lethal and mutagenic oxidative DNA adductsin the H. pylori genome.[80]

Vulnerability to oxidative stress and oxidative DNAdamage occurs commonly in many studied bacterialpathogens, including Neisseria gonorrhoeae, Hemophilusinfluenzae, Streptococcus pneumoniae, Streptococcus mu-tans and Helicobacter pylori.[81] For each of these

pathogens, surviving the DNA damage induced by ox-idative stress appears to be supported by transformation-mediated recombinational repair. Thus, transformationand recombinational repair appear to contribute to suc-cessful infection.Transformation (the transfer of DNA from one bacte-rial cell to another through the intervening medium) ap-pears to be part of an adaptation for DNA repair. H.pylori is naturally competent for transformation. Whilemany organisms are competent only under certain envi-ronmental conditions, such as starvation,H. pylori is com-petent throughout logarithmic growth.[82] All organismsencode genetic programs for response to stressful con-ditions including those that cause DNA damage.[82] InH. pylori, homologous recombination is required for re-pairing DNA double-strand breaks (DSBs). The AddABhelicase-nuclease complex resects DSBs and loads RecAonto single-strand DNA (ssDNA), which then mediatesstrand exchange, leading to homologous recombinationand repair. The requirement of RecA plus AddABfor efficient gastric colonization suggests, in the stom-ach, H. pylori is either exposed to double-strand DNAdamage that must be repaired or requires some otherrecombination-mediated event. In particular, naturaltransformation is increased by DNA damage in H. py-lori, and a connection exists between the DNA damageresponse and DNA uptake inH. pylori,[82] suggesting nat-ural competence contributes to persistence ofH. pylori inits human host and explains the retention of competencein most clinical isolates.RuvC protein is essential to the process of recombina-tional repair since it resolves intermediates in this pro-cess termed Holliday junctions. H. pylori mutants thatare defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reducedsurvival within macrophages, and are unable to estab-lish successful infection in a mouse model.[83] Similarly,RecN protein plays an important role in DSB repair in H.pylori.[84] An H. pylori recN mutant displays an attenu-ated ability to colonize mouse stomachs, highlighting theimportance of recombinational DNA repair in survival ofH. pylori within its host.[84]

9 Epidemiology

At least half the world’s population is infected by thebacterium, making it the most widespread infection inthe world.[85] Actual infection rates vary from nationto nation; the developing world has much higher infec-tion rates than the West (Western Europe, North Amer-ica, Australasia), where rates are estimated to be around25%.[85] The age at which this bacterium is acquiredseems to influence the possible pathologic outcome of theinfection : people infected with it at an early age are likelyto develop more intense inflammation that may be fol-lowed by atrophic gastritis with a higher subsequent risk

6 11 HISTORY

of gastric ulcer, gastric cancer, or both. Acquisition at anolder age brings different gastric changes more likely tolead to duodenal ulcer.[6] Infections are usually acquiredin early childhood in all countries.[12] However, the in-fection rate of children in developing nations is higherthan in industrialized nations, probably due to poor sani-tary conditions, perhaps combined with lower antibioticsusage for unrelated pathologies. In developed nations, itis currently uncommon to find infected children, but thepercentage of infected people increases with age, withabout 50% infected for those over the age of 60 com-pared with around 10% between 18 and 30 years.[85] Thehigher prevalence among the elderly reflects higher infec-tion rates in the past when the individuals were childrenrather than more recent infection at a later age of theindividual.[12] In the United States, prevalence appearsto be higher in African-American and Hispanic popu-lations, most likely due to socioeconomic factors.[86][87]The lower rate of infection in the West is largely at-tributed to higher hygiene standards and widespread useof antibiotics. Despite high rates of infection in cer-tain areas of the world, the overall frequency of H. py-lori infection is declining.[88] However, antibiotic resis-tance is appearing in H. pylori; many metronidazole- andclarithromycin-resistant strains are found in most parts ofthe world.[89]

H. pylori is contagious, although the exact route of trans-mission is not known.[90][91] Person-to-person transmis-sion by either the oral-oral or fecal-oral route is mostlikely. Consistent with these transmission routes, the bac-teria have been isolated from feces, saliva, and dentalplaque of some infected people. Findings suggest H.pylori is more easily transmitted by gastric mucus thansaliva[6] Transmission occurs mainly within families indeveloped nations, yet can also be acquired from the com-munity in developing countries.[92] H. pylori may also betransmitted orally by means of fecal matter through theingestion of waste-tainted water, so a hygienic environ-ment could help decrease the risk ofH. pylori infection.[6]

10 Evolution

H. pylori migrated out of Africa along with its humanhost circa 60,000 years ago.[93] Its subsequent evolutioncreated seven prototypes—Europe (isolated from Eu-rope, the Middle East, India, and Iran), NE Africa (fromnortheast Africa), Africa1 (from countries in WesternAfrica and South Africa), Africa2 (from South Africa),Asia2 (from Northern India and among isolates fromBangladesh, Thailand, and Malaysia), Sahul (from Aus-tralian Aboriginals and Papua New Guineans) and EastAsia with the subpopulations E Asia (from East Asians),Maori (from Taiwanese Aboriginals, Melanesians andPolynesians) and Amerind (Native Americans). The pre-cursors of these prototypes have been named ancestralEurope1, ancestral Europe2, ancestral East Asia, an-

cestral Africa1, ancestral Africa2, and ancestral Sahul.These ancestral prototypes appear to have originated inAfrica and Central and East Asia. European and Africanstrains were introduced into the Americas along with itscolonisation—both thousands of years ago and more re-cently in the slave trade.Recent research states that genetic diversity in H. pyloridecreases with geographic distance from East Africa, thebirthplace of modern humans. Using the genetic diversitydata, researchers have created simulations that indicatethe bacteria seem to have spread from East Africa around58,000 years ago. Their results indicate modern humanswere already infected byH. pylori before their migrationsout of Africa, and it has remained associated with humanhosts since that time.[94]

11 History

See also: Timeline of peptic ulcer disease and Heli-cobacter pylori

H. pylori was first discovered in the stomachs of pa-tients with gastritis and ulcers in 1982 by Drs. BarryMarshall and Robin Warren of Perth, Australia. At thetime, the conventional thinking was that no bacteriumcould live in the acid environment of the human stom-ach. In recognition of their discovery, Marshall andWar-ren were awarded the 2005 Nobel Prize in Physiology orMedicine.[95]

Before the research of Marshall and Warren, Germanscientists found spiral-shaped bacteria in the lining ofthe human stomach in 1875, but they were unable toculture them, and the results were eventually forgotten.[73]The Italian researcher Giulio Bizzozero described simi-larly shaped bacteria living in the acidic environment ofthe stomach of dogs in 1893.[96] Professor Walery Ja-worski of the Jagiellonian University in Kraków inves-tigated sediments of gastric washings obtained from hu-mans in 1899. Among some rod-like bacteria, he alsofound bacteria with a characteristic spiral shape, whichhe called Vibrio rugula. He was the first to suggest apossible role of this organism in the pathogenesis of gas-tric diseases. His work was included in the Handbook ofGastric Diseases, but it had little impact, as it was writtenin Polish.[97] Several small studies conducted in the early20th century demonstrated the presence of curved rodsin the stomach of many patients with peptic ulcers andstomach cancer.[98] Interest in the bacteria waned, how-ever, when an American study published in 1954 failedto observe the bacteria in 1180 stomach biopsies.[99]

Interest in understanding the role of bacteria in stomachdiseases was rekindled in the 1970s, with the visualizationof bacteria in the stomachs of gastric ulcer patients.[100]The bacteria had also been observed in 1979, by RobinWarren, who researched it further with Barry Marshall

7

from 1981. After unsuccessful attempts at culturing thebacteria from the stomach, they finally succeeded in vi-sualizing colonies in 1982, when they unintentionally lefttheir Petri dishes incubating for five days over the Easterweekend. In their original paper, Warren and Marshallcontended that most stomach ulcers and gastritis werecaused by bacterial infection and not by stress or spicyfood, as had been assumed before.[101]

Although some skepticism was expressed initially, withinseveral years multiple research groups had verified the as-sociation of H. pylori with gastritis and, to a lesser extent,ulcers.[102] To demonstrate H. pylori caused gastritis andwas not merely a bystander, Marshall drank a beaker ofH. pylori culture. He became ill with nausea and vomit-ing several days later. An endoscopy 10 days after inoc-ulation revealed signs of gastritis and the presence of H.pylori. These results suggestedH. pyloriwas the causativeagent. Marshall and Warren went on to demonstrate an-tibiotics are effective in the treatment of many cases ofgastritis. In 1987, the Sydney gastroenterologist ThomasBorody invented the first triple therapy for the treatmentof duodenal ulcers.[103] In 1994, the National Institutes ofHealth stated most recurrent duodenal and gastric ulcerswere caused by H. pylori, and recommended antibioticsbe included in the treatment regimen.[104]

The bacterium was initially named Campylobacter py-loridis, then renamed C. pylori (pylori being the genitiveof pylorus, the circular opening leading from the stom-ach into the duodenum, from the Ancient Greek wordπυλωρός, which means gatekeeper.[105]). When 16Sribosomal RNA gene sequencing and other researchshowed in 1989 that the bacterium did not belong in thegenus Campylobacter, it was placed in its own genus,Helicobacter from the ancient Greek hělix/έλιξ “spiral”or “coil”.[105]

In October 1987, a group of experts met in Copen-hagen to found the European Helicobacter Study Group(EHSG), an international multidisciplinary researchgroup and the only institution focused on H. pylori.[106]The Group is involved with the Annual InternationalWorkshop on Helicobacter and Related Bacteria,[107] theMaastricht Consensus Reports (European Consensus onthe management of H. pylori),[108][109][110][111] and othereducational and research projects, including two interna-tional long-term projects:

• European Registry on H. pylori Management(Hp-EuReg) – a database systematically regis-tering the routine clinical practice of Europeangastroenterologists.[112]

• OptimalH. pylorimanagement in primary care (Op-tiCare) – a long-term educational project aimingto disseminate the evidence based recommenda-tions of the Maastricht IV Consensus to primarycare physicians in Europe, funded by an educationalgrant from United European Gastroenterology.[113]

12 See also

• List of oncogenic bacteria

• Infectious causes of cancer

13 References

[1] Giusti C (2004). “Association of Helicobacter pyloriwith central serous chorioretinopathy: Hypotheses re-garding pathogenesis”. Medical Hypotheses 63 (3): 524–7. doi:10.1016/j.mehy.2004.02.020. PMID 15288381.

[2] Ahnoux-Zabsonre A, Quaranta M, Mauget-Faÿsse M(2004). “Prévalence de l'Helicobacter pylori dans lachoriorétinopathie séreuse centrale et l'épithéliopathierétinienne diffuse” [Prevalence of Helicobacter pyloriin central serous chorioretinopathy and diffuse reti-nal epitheliopathy: a complementary study]. Jour-nal Français d'Ophtalmologie (in French) 27 (10):1129–33. doi:10.1016/S0181-5512(04)96281-X. PMID15687922.

[3] Cotticelli L, Borrelli M, D'Alessio AC, Menzione M, Vil-lani A, Piccolo G, Montella F, Iovene MR, Romano M(2006). “Central serous chorioretinopathy and Helicobac-ter pylori”. European journal of ophthalmology 16 (2):274–8. PMID 16703546.

[4] Blaser MJ (2006). “Who are we? Indigenous microbesand the ecology of human diseases” (PDF). EMBOReports7 (10): 956–60. doi:10.1038/sj.embor.7400812. PMC1618379. PMID 17016449.

[5] Yamaoka, Yoshio (2008). Helicobacter pylori: Molecu-lar Genetics and Cellular Biology. Caister Academic Pr.ISBN 1-904455-31-X.

[6] Brown LM (2000). "Helicobacter pylori: epidemiologyand routes of transmission” (PDF). Epidemiol Rev 22 (2):283–97. doi:10.1093/oxfordjournals.epirev.a018040.PMID 11218379.

[7] Bytzer P, Dahlerup JF, Eriksen JR, Jarbøl DE, Rosen-stock S, Wildt S (April 2011). “Diagnosis and treatmentof Helicobacter pylori infection”. Dan Med Bull 58 (4):C4271. PMID 21466771. Retrieved 7 August 2013.

[8] Butcher, Graham P. (2003). Gastroenterology: An Illus-trated Colour Text. Elsevier Health Sciences. p. 25. ISBN0-443-06215-3.

[9] Butcher 2003, pp. 24–5

[10] Ryan, Kenneth (2010). Sherris Medical Microbiology.McGraw-Hill. pp. 573, 576. ISBN 978-0-07-160402-4.

[11] Chang, A. H.; Parsonnet, J. (2010). “Role of Bacte-ria in Oncogenesis”. Clinical Microbiology Reviews 23(4): 837–857. doi:10.1128/CMR.00012-10. ISSN 0893-8512.

8 13 REFERENCES

[12] Kusters JG, van Vliet AH, Kuipers EJ (July 2006).“Pathogenesis of Helicobacter pylori Infection”. Clin Mi-crobiol Rev 19 (3): 449–90. doi:10.1128/CMR.00054-05. PMC 1539101. PMID 16847081.

[13] Suerbaum S, Michetti P (October 2002). "Helicobacterpylori infection”. N. Engl. J. Med. 347 (15): 1175–86.doi:10.1056/NEJMra020542. PMID 12374879.

[14] Fuccio L, Zagari RM, Eusebi LH, Laterza L, Cen-namo V, Ceroni L, Grilli D, Bazzoli F (2009). “Meta-analysis: can Helicobacter pylori eradication treatment re-duce the risk for gastric cancer?". Ann Intern Med 151(2): 121–8. doi:10.7326/0003-4819-151-2-200907210-00009. PMID 19620164.

[15] Wu Q, Yang ZP, Xu P, Gao LC, Fan DM (2013).“Association between Helicobacter pylori infection andthe risk of colorectal neoplasia: a systematic reviewand meta-analysis”. Colorectal Dis 15 (7): e352–64.doi:10.1111/codi.12284. PMID 23672575.

[16] Olson JW, Maier RJ (November 2002). “Molec-ular hydrogen as an energy source for Heli-cobacter pylori". Science 298 (5599): 1788–90.doi:10.1126/science.1077123. PMID 12459589.

[17] Stark RM, Gerwig GJ, Pitman RS, Potts LF, WilliamsNA, Greenman J, Weinzweig IP, Hirst TR, MillarMR (February 1999). “Biofilm formation by Heli-cobacter pylori". Lett Appl Microbiol 28 (2): 121–6. doi:10.1046/j.1365-2672.1999.00481.x. PMID10063642.

[18] Chan WY, Hui PK, Leung KM, Chow J, Kwok F, Ng CS(October 1994). “Coccoid forms of Helicobacter pylori inthe human stomach”. Am J Clin Pathol 102 (4): 503–7.PMID 7524304.

[19] Josenhans C, Eaton KA, Thevenot T, Suerbaum S (Au-gust 2000). “Switching of Flagellar Motility in He-licobacter pylori by Reversible Length Variation of aShort Homopolymeric Sequence Repeat in fliP, a GeneEncoding a Basal Body Protein”. Infect Immun 68(8): 4598–603. doi:10.1128/IAI.68.8.4598-4603.2000.PMC 98385. PMID 10899861.

[20] Rust M, Schweinitzer T, Josenhans C (2008).“Helicobacter Flagella, Motility and Chemotaxis”.In Yamaoka Y. Helicobacter pylori: Molecular Geneticsand Cellular Biology. Caister Academic Press. ISBN1-904455-31-X.

[21] Tomb JF, White O, Kerlavage AR, Clayton RA, SuttonGG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S,Dougherty BA, Nelson K, Quackenbush J, Zhou L, Kirk-ness EF, Peterson S, Loftus B, Richardson D, Dodson R,Khalak HG, Glodek A, McKenney K, Fitzegerald LM,Lee N, Adams MD, Hickey EK, Berg DE, Gocayne JD,Utterback TR, Peterson JD, Kelley JM, Cotton MD, Wei-dman JM, Fujii C, Bowman C, Watthey L, Wallin E,Hayes WS, Borodovsky M, Karp PD, Smith HO, FraserCM, Venter JC (August 1997). “The complete genomesequence of the gastric pathogenHelicobacter pylori". Na-ture 388 (6642): 539–47. doi:10.1038/41483. PMID9252185.

[22] “Genome information for the H. pylori 26695 and J99strains”. Institut Pasteur. 2002. Retrieved 1 September2008.

[23] "Helicobacter pylori 26695, complete genome”. Na-tional Center for Biotechnology Information. Retrieved1 September 2008.

[24] "Helicobacter pylori J99, complete genome”. NationalCenter for Biotechnology Information. Retrieved 1September 2008.

[25] Oh JD, Kling-Bäckhed H, Giannakis M, Xu J, Fulton RS,Fulton LA, Cordum HS, Wang C, Elliott G, Edwards J,Mardis ER, Engstrand LG, Gordon JI (June 2006). “Thecomplete genome sequence of a chronic atrophic gastritisHelicobacter pylori strain: Evolution during disease pro-gression”. Proc Natl Acad Sci U.S.A. 103 (26): 9999–10004. doi:10.1073/pnas.0603784103. PMC 1480403.PMID 16788065.

[26] Baldwin DN, Shepherd B, Kraemer P, Hall MK, SycuroLK, Pinto-Santini DM, Salama NR (February 2007).“Identification of Helicobacter pylori Genes That Con-tribute to Stomach Colonization”. Infect Immun 75 (2):1005–16. doi:10.1128/IAI.01176-06. PMC 1828534.PMID 17101654.

[27] Broutet N, Marais A, Lamouliatte H, de Mascarel A,Samoyeau R, Salamon R, Mégraud F (April 2001).“cagA Status and Eradication Treatment Outcome ofAnti-Helicobacter pylori Triple Therapies in Patientswith Nonulcer Dyspepsia” (PDF). J Clin Microbiol 39(4): 1319–22. doi:10.1128/JCM.39.4.1319-1322.2001.PMC 87932. PMID 11283049.

[28] Amieva MR, El-Omar EM (January 2008). “Host-bacterial interactions in Helicobacter pylori in-fection”. Gastroenterology 134 (1): 306–23.doi:10.1053/j.gastro.2007.11.009. PMID 18166359.

[29] Schreiber S, Konradt M, Groll C, Scheid P, Hanauer G,Werling HO, Josenhans C, Suerbaum S (April 2004).“The spatial orientation of Helicobacter pylori in the gas-tric mucus”. Proc. Natl. Acad. Sci. U.S.A. 101 (14):5024–9. doi:10.1073/pnas.0308386101. PMC 387367.PMID 15044704.

[30] Petersen AM, Krogfelt KA (May 2003). "Helicobac-ter pylori: an invading microorganism? A review”.FEMS Immunol. Med. Microbiol. 36 (3): 117–26.doi:10.1016/S0928-8244(03)00020-8. PMID 12738380.

[31] Ilver D, Arnqvist A, Ogren J, Frick IM, KersulyteD, Incecik ET, Berg DE, Covacci A, Engstrand L,Borén T (January 1998). "Helicobacter pylori ad-hesin binding fucosylated histo-blood group antigens re-vealed by retagging”. Science 279 (5349): 373–7.doi:10.1126/science.279.5349.373. PMID 9430586.

[32] Mahdavi J, Sondén B, Hurtig M, Olfat FO, Forsberg L,Roche N, Angstrom J, Larsson T, Teneberg S, Karls-son KA, Altraja S, Wadström T, Kersulyte D, Berg DE,Dubois A, Petersson C,Magnusson KE, Norberg T, LindhF, Lundskog BB, Arnqvist A, Hammarström L, BorénT (July 2002). "Helicobacter pylori SabA Adhesin in

9

Persistent Infection and Chronic Inflammation”. Science297 (5581): 573–8. doi:10.1126/science.1069076. PMC2570540. PMID 12142529.

[33] Smoot DT (December 1997). “How does Helicobac-ter pylori cause mucosal damage? Direct mechanisms”.Gastroenterology 113 (6 Suppl): S31–4; discussion S50.doi:10.1016/S0016-5085(97)80008-X. PMID 9394757.

[34] Hatakeyama M, Higashi H (2005). “Helicobacter py-lori CagA: A new paradigm for bacterial carcinogenesis”.Cancer Science 96 (12): 835–43. doi:10.1111/j.1349-7006.2005.00130.x. PMID 16367902.

[35] Dumrese C, Slomianka L, Ziegler U, Choi SS, KaliaA, Fulurija A, Lu W, Berg DE, Benghezal M, Mar-shall B, Mittl PR (May 2009). “The secreted Heli-cobacter cysteine-rich protein A causes adherence of hu-man monocytes and differentiation into a macrophage-like phenotype”. FEBS Letters 583 (10): 1637–43. doi:10.1016/j.febslet.2009.04.027. PMC 2764743.PMID 19393649.

[36] Shiotani A, Graham DY (November 2002). “Patho-genesis and therapy of gastric and duodenal ulcer dis-ease”. Med. Clin. North Am. 86 (6): 1447–66, viii.doi:10.1016/S0025-7125(02)00083-4. PMID 12510460.

[37] Dixon MF (February 2000). “Patterns of inflammationlinked to ulcer disease”. Baillieres Best Pract Res Clin Gas-troenterol 14 (1): 27–40. doi:10.1053/bega.1999.0057.PMID 10749087.

[38] Blaser MJ, Atherton JC (February 2004). "Helicobacterpylori persistence: biology and disease”. J. Clin. Invest.113 (3): 321–33. doi:10.1172/JCI20925. PMC 324548.PMID 14755326.

[39] Schubert ML, Peura DA (June 2008). “Control of gastricacid secretion in health and disease”. Gastroenterology134 (7): 1842–60. doi:10.1053/j.gastro.2008.05.021.PMID 18474247.

[40] Suerbaum S, Michetti P (October 2002). "Helicobacterpylori infection”. N. Engl. J. Med. 347 (15): 1175–86.doi:10.1056/NEJMra020542. PMID 12374879.

[41] Peek RM, Crabtree JE (January 2006). "Helicobacter in-fection and gastric neoplasia”. J. Pathol. 208 (2): 233–48.doi:10.1002/path.1868. PMID 16362989.

[42] Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE,Moran AP, Athman R, Mémet S, Huerre MR, Coyle AJ,DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, PhilpottDJ, Ferrero RL (November 2004). “Nod1 responds topeptidoglycan delivered by the Helicobacter pylori cagpathogenicity island”. Nat. Immunol. 5 (11): 1166–74.doi:10.1038/ni1131. PMID 15489856.

[43] Backert S, Selbach M (August 2008). “Role of typeIV secretion in Helicobacter pylori pathogenesis”. Cell.Microbiol. 10 (8): 1573–81. doi:10.1111/j.1462-5822.2008.01156.x. PMID 18410539.

[44] Hatakeyama M (Sep 2004). “Oncogenic mechanisms ofthe Helicobacter pylori CagA protein”. Nat Rev Cancer(United States) 4 (9): 688–94. doi:10.1038/nrc1433.PMID 15343275.

[45] Tsuji S, Kawai N, Tsujii M, Kawano S, Hori M (July2003). “Review article: inflammation-related promo-tion of gastrointestinal carcinogenesis--a perigenetic path-way”. Aliment. Pharmacol. Ther. 18 (Suppl 1): 82–9.doi:10.1046/j.1365-2036.18.s1.22.x. PMID 12925144.

[46] Suganuma M, Yamaguchi K, Ono Y, Matsumoto H,Hayashi T, Ogawa T, Imai K, Kuzuhara T, NishizonoA, Fujiki H (July 2008). “TNF-α-inducing protein, acarcinogenic factor secreted from H. pylori, enters gas-tric cancer cells”. Int. J. Cancer 123 (1): 117–22.doi:10.1002/ijc.23484. PMID 18412243.

[47] Kim, W. & Moss, S.F. (December 2008). “The role ofH. pylori in the development of stomach cancer”. Oncol-ogy Review. 1 (Suppl 1): 165–168. Retrieved 25 August2014.

[48] Stenström B, Mendis A, Marshall B (August 2008). "He-licobacter pylori—The latest in diagnosis and treatment”.Aust Fam Physician 37 (8): 608–12. PMID 18704207.

[49] Logan RP, Walker MM (October 2001). “Epidemiologyand diagnosis of Helicobacter pylori infection”. BMJ 323(7318): 920–2. doi:10.1136/bmj.323.7318.920. PMC1121445. PMID 11668141.

[50] Selgrad M, Malfertheiner P (October 2008). “New strate-gies for Helicobacter pylori eradication”. Curr Opin Phar-macol 8 (5): 593–7. doi:10.1016/j.coph.2008.04.010.PMID 18555746.

[51] Blanchard, T G; Nedrud, J G (2010). “9. Helicobac-ter pylori Vaccines”. In Sutton, Philip; Mitchell, Hazel.Helicobacter Pylori in the 21st Century. Mitchell, Hazel.CABI. pp. 167–189. ISBN 978-1-84593-594-8. Re-trieved 7 August 2013.

[52] Kabir S (April 2007). “The current status of Helicobac-ter pylori vaccines: a review”. Helicobacter 12 (2): 89–102. doi:10.1111/j.1523-5378.2007.00478.x. PMID17309745.

[53] de Vries R, Klok RM, Brouwers JR, Postma MJ (Febru-ary 2009). “Cost-effectiveness of a potential future He-licobacter pylori vaccine in the Netherlands: the impactof varying the discount rate for health”. Vaccine 27(6): 846–52. doi:10.1016/j.vaccine.2008.11.081. PMID19084566.

[54] Rupnow MF, Chang AH, Shachter RD, Owens DK, Par-sonnet J (October 2009). “Cost-effectiveness of a po-tential prophylactic Helicobacter pylori vaccine in theUnited States”. J. Infect. Dis. 200 (8): 1311–7.doi:10.1086/605845. PMID 19751153.

[55] Salama N. R. et al. (2013). “Life in the human stomach:persistence strategies of the bacterial pathogen Helicobac-ter pylori”. Nature Reviews Microbiology 11: 385–399.doi:10.1038/nrmicro3016.

[56] Blaser M (2011). “Antibiotic overuse: Stop the killingof beneficial bacteria”. Nature 476 (7361): 393–4.doi:10.1038/476393a. PMID 21866137.

[57] Willyard, C. Gut reaction. Nature 479, S5–S7 (2011)

10 13 REFERENCES

[58] Ackerman, Jennifer; Blaser, Martin (2012-06-01). “HowBacteria in Our Bodies Protect Our Health” (PDF). Scien-tific American (Scientific American, a division of NatureAmerica, Inc.) (June 1, 2012): 42. Retrieved 2014-11-18.

[59] Malfertheiner P, Megraud F, O'Morain CA, Atherton J,Axon AT, Bazzoli F, Gensini GF, Gisbert JP, GrahamDY, Rokkas T, El-Omar EM, Kuipers EJ (May 2012).“Management ofHelicobacter pylori infection—theMaas-tricht IV/ Florence Consensus Report”. Gut 61 (5): 646–64. doi:10.1136/gutjnl-2012-302084. PMID 22491499.

[60] Malfertheiner P, Megraud F, O'Morain C, Bazzoli F,El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N,Kuipers EJ (June 2007). “Current concepts in the man-agement of Helicobacter pylori infection: the Maas-tricht III Consensus Report”. Gut 56 (6): 772–81.doi:10.1136/gut.2006.101634. PMC 1954853. PMID17170018.

[61] Rauws EA, Tytgat GN (May 1990). “Cure of duode-nal ulcer associated with eradication of Helicobacter py-lori". Lancet 335 (8700): 1233–5. doi:10.1016/0140-6736(90)91301-P. PMID 1971318.

[62] Graham DY, Lew GM, Evans DG, Evans DJ, Klein PD(August 1991). “Effect of triple therapy (antibiotics plusbismuth) on duodenal ulcer healing. A randomized con-trolled trial”. Ann. Intern. Med. 115 (4): 266–9.doi:10.7326/0003-4819-115-4-266. PMID 1854110.

[63] Fischbach L, Evans EL (August 2007). “Meta-analysis:the effect of antibiotic resistance status on the effi-cacy of triple and quadruple first-line therapies for He-licobacter pylori". Aliment. Pharmacol. Ther. 26 (3):343–57. doi:10.1111/j.1365-2036.2007.03386.x. PMID17635369.

[64] Graham DY, Shiotani A (June 2008). “Newer conceptsregarding resistance in the treatment Helicobacter pyloriinfections”. Nat Clin Pract Gastroenterol Hepatol 5 (6):321–31. doi:10.1038/ncpgasthep1138. PMC 2841357.PMID 18446147.

[65] Perna F, Zullo A, Ricci C, Hassan C, Morini S, VairaD (November 2007). “Levofloxacin-based triple ther-apy for Helicobacter pylori re-treatment: role of bac-terial resistance”. Dig Liver Dis 39 (11): 1001–5.doi:10.1016/j.dld.2007.06.016. PMID 17889627.

[66] Hsu PI, Wu DC, Chen A, Peng NJ, Tseng HH, Tsay FW,Lo GH, Lu CY, Yu FJ, Lai KH (June 2008). “Quadru-ple rescue therapy for Helicobacter pylori infection aftertwo treatment failures”. Eur. J. Clin. Invest. 38 (6):404–9. doi:10.1111/j.1365-2362.2008.01951.x. PMID18435764.

[67] Wang KY, Li SN, Liu CS, Perng DS, Su YC,Wu DC, JanCM, Lai CH, Wang TN, Wang WM (September 2004).“Effects of ingesting Lactobacillus- and Bifidobacterium-containing yogurt in subjects with colonized Helicobacterpylori" (PDF). The American Journal of Clinical Nutrition80 (3): 737–41. PMID 15321816.

[68] Moon JK, Kim JR, Ahn YJ, Shibamoto T (2010). “Anal-ysis and anti-Helicobacter activity of sulforaphane and re-lated compounds present in broccoli ( Brassica oleraceaL.) sprouts”. J. Agric. Food Chem. 58 (11): 6672–7.doi:10.1021/jf1003573. PMID 20459098.

[69] Fahey JW, Haristoy X, Dolan PM, Kensler TW, Schol-tus I, Stephenson KK, Talalay P, Lozniewski A (2002).“Sulforaphane inhibits extracellular, intracellular, andantibiotic-resistant strains of Helicobacter pylori and pre-vents benzo[a]pyrene-induced stomach tumors”. Proc.Natl. Acad. Sci. U.S.A. 99 (11): 7610–5.doi:10.1073/pnas.112203099. PMC 124299. PMID12032331.

[70] Haristoy X, Angioi-Duprez K, Duprez A, Lozniewski A(2003). “Efficacy of sulforaphane in eradicating Heli-cobacter pylori in human gastric xenografts implanted innude mice”. Antimicrob. Agents Chemother. 47 (12):3982–4. doi:10.1128/aac.47.12.3982-3984.2003. PMC296232. PMID 14638516.

[71] Goodman KJ, O'rourke K, Day RS, Wang C, NurgalievaZ, Phillips CV, Aragaki C, Campos A, de la RosaJM (December 2005). “Dynamics of Helicobacter py-lori infection in a US-Mexico cohort during the firsttwo years of life”. Int J Epidemiol 34 (6): 1348–55.doi:10.1093/ije/dyi152. PMID 16076858.

[72] Goodman KJ, Cockburn M (March 2001). “The roleof epidemiology in understanding the health effectsof Helicobacter pylori". Epidemiology 12 (2): 266–71. doi:10.1097/00001648-200103000-00023. PMID11246592.

[73] Blaser MJ (February 2005). “An endangered speciesin the stomach”. Sci. Am. 292 (2): 38–45. doi:10.1038/scientificamerican0205-38. PMID15715390.

[74] Graham DY, Yamaoka Y, Malaty HM (November2007). “Contemplating the Future without Helicobac-ter pylori and the Dire Consequences Hypothesis”. He-licobacter 12 (Suppl 2): 64–8. doi:10.1111/j.1523-5378.2007.00566.x. PMC 3128250. PMID 17991179.

[75] Delaney B, McColl K (August 2005). “Review arti-cle: Helicobacter pylori and gastro-oesophageal refluxdisease”. Aliment. Pharmacol. Ther. 22 (Suppl 1):32–40. doi:10.1111/j.1365-2036.2005.02607.x. PMID16042657.

[76] Blaser MJ (October 2006). “Who are we? Indigenousmicrobes and the ecology of human diseases”. EMBOReports 7 (10): 956–60. doi:10.1038/sj.embor.7400812.PMC 1618379. PMID 17016449.

[77] Blaser MJ, Chen Y, Reibman J (May 2008). “Does Heli-cobacter pylori protect against asthma and allergy?". Gut57 (5): 561–7. doi:10.1136/gut.2007.133462. PMID18194986.

[78] Chen Y, Blaser MJ (August 2008). "Helicobacterpylori colonization is inversely associated with child-hood asthma”. J. Infect. Dis. 198 (4): 553–60.doi:10.1086/590158. PMID 18598192.

11

[79] Olczak AA, Olson JW, Maier RJ (June 2002).“Oxidative-stress resistance mutants of Helicobac-ter pylori". J. Bacteriol. 184 (12): 3186–93.doi:10.1128/JB.184.12.3186-3193.2002. PMC 135082.PMID 12029034.

[80] O'Rourke EJ, Chevalier C, Pinto AV, Thiberge JM, IelpiL, Labigne A, Radicella JP (March 2003). “PathogenDNA as target for host-generated oxidative stress: rolefor repair of bacterial DNA damage in Helicobacter py-lori colonization”. Proc. Natl. Acad. Sci. U.S.A. 100 (5):2789–94. doi:10.1073/pnas.0337641100. PMC 151419.PMID 12601164.

[81] Michod RE, Bernstein H, Nedelcu AM (May2008). “Adaptive value of sex in microbialpathogens”. Infect. Genet. Evol. 8 (3): 267–85.doi:10.1016/j.meegid.2008.01.002. PMID 18295550.

[82] Dorer MS, Fero J, Salama NR (2010). Blanke,Steven R, ed. “DNA damage triggers genetic ex-change in Helicobacter pylori". PLoS Pathog. 6 (7):e1001026. doi:10.1371/journal.ppat.1001026. PMC2912397. PMID 20686662.

[83] LoughlinMF, Barnard FM, Jenkins D, Sharples GJ, JenksPJ (April 2003). "Helicobacter pylori mutants defec-tive in RuvC Holliday junction resolvase display reducedmacrophage survival and spontaneous clearance from themurine gastric mucosa”. Infect. Immun. 71 (4): 2022–31.doi:10.1128/IAI.71.4.2022-2031.2003. PMC 152077.PMID 12654822.

[84] Wang G, Maier RJ (January 2008). “Critical role ofRecN in recombinational DNA repair and survival ofHelicobacter pylori". Infect. Immun. 76 (1): 153–60. doi:10.1128/IAI.00791-07. PMC 2223656. PMID17954726.

[85] Pounder RE, Ng D (1995). “The prevalence ofHelicobac-ter pylori infection in different countries”. Aliment. Phar-macol. Ther. 9 (Suppl 2): 33–9. PMID 8547526.

[86] Smoak BL, Kelley PW, Taylor DN (March 1994). “Sero-prevalence of Helicobacter pylori infections in a cohort ofUS Army recruits”. Am. J. Epidemiol. 139 (5): 513–9.PMID 8154475.

[87] Everhart JE, Kruszon-Moran D, Perez-Perez GI, TralkaTS, McQuillan G (April 2000). “Seroprevalence andethnic differences in Helicobacter pylori infection amongadults in the United States”. J. Infect. Dis. 181 (4): 1359–63. doi:10.1086/315384. PMID 10762567.

[88] Malaty HM (2007). “Epidemiology ofHelicobacter pyloriinfection”. Best Pract Res Clin Gastroenterol 21 (2): 205–14. doi:10.1016/j.bpg.2006.10.005. PMID 17382273.

[89] Mégraud F (September 2004). “H pylori antibiotic resis-tance: prevalence, importance, and advances in testing”.Gut 53 (9): 1374–84. doi:10.1136/gut.2003.022111.PMC 1774187. PMID 15306603.

[90] Mégraud F (1995). “Transmission of Helicobacter pylori:faecal–oral versus oral–oral route”. Aliment. Pharmacol.Ther. 9 (Suppl 2): 85–91. PMID 8547533.

[91] Cave DR (May 1996). “Transmission and epidemiologyof Helicobacter pylori". Am. J. Med. 100 (5A): 12S–17S;discussion 17S–18S. PMID 8644777.

[92] Delport W, van der Merwe SW (2007). “Thetransmission of Helicobacter pylori: the effects ofanalysis method and study population on inference”.Best Pract Res Clin Gastroenterol 21 (2): 215–36.doi:10.1016/j.bpg.2006.10.001. PMID 17382274.

[93] Correa P, Piazuelo MB (January 2012). “EvolutionaryHistory of the Helicobacter pylori Genome: Implicationsfor Gastric Carcinogenesis”. Gut Liver 6 (1): 21–8.doi:10.5009/gnl.2012.6.1.21. PMC 3286735. PMID22375167.

[94] Linz B, Balloux F, Moodley Y, Manica A, Liu H, Rou-magnac P, Falush D, Stamer C, Prugnolle F, van derMerwe SW, Yamaoka Y, Graham DY, Perez-TralleroE, Wadstrom T, Suerbaum S, Achtman M (February2007). “An African origin for the intimate associa-tion between humans and Helicobacter pylori". Nature445 (7130): 915–8. doi:10.1038/nature05562. PMC1847463. PMID 17287725.

[95] “The Nobel Prize in Physiology or Medicine 2005”. Re-trieved 2 August 2008.

[96] Bizzozero G (1893). “Ueber die schlauchförmigenDrüsen des Magendarmkanals und die Beziehungen ihresEpitheles zu dem Oberflächenepithel der Schleimhaut”.Archiv für mikroskopische Anatomie 42: 82–152.doi:10.1007/BF02975307.

[97] Konturek JW (December 2003). “Discovery by Jaworskiof Helicobacter pylori and its pathogenetic role in pep-tic ulcer, gastritis and gastric cancer” (PDF). J. Physiol.Pharmacol. 54 (Suppl 3): 23–41. PMID 15075463.Archived from the original (PDF) on 30 September 2004.Retrieved 25 August 2008.

[98] Egan BJ, O'Morain CA (2007). “A historical perspec-tive of Helicobacter gastroduodenitis and its complica-tions”. Best Pract Res Clin Gastroenterol 21 (2): 335–46.doi:10.1016/j.bpg.2006.12.002. PMID 17382281.

[99] Palmer ED (August 1954). “Investigation of the gastricmucosa spirochetes of the human”. Gastroenterology 27(2): 218–20. PMID 13183283.

[100] Steer HW (August 1975). “Ultrastructure of cell mi-gration through the gastric epithelium and its relation-ship to bacteria” (PDF). J. Clin. Pathol. 28 (8): 639–46. doi:10.1136/jcp.28.8.639. PMC 475793. PMID1184762.

[101] Marshall BJ, Warren JR (June 1984). “Unidentifiedcurved bacilli in the stomach of patients with gastri-tis and peptic ulceration”. Lancet 1 (8390): 1311–5.doi:10.1016/S0140-6736(84)91816-6. PMID 6145023.

[102] Atwood IV KC (2004). “Bacteria, Ulcers, and Ostracism?H. pylori and the making of a myth”. Retrieved 2 August2008.

12 14 EXTERNAL LINKS

[103] Borody TJ, Cole P, Noonan S, Morgan A, Lenne J, Hy-land L, Brandl S, Borody EG, George LL (October 1989).“Recurrence of duodenal ulcer and Campylobacter pyloriinfection after eradication”. Med. J. Aust. 151 (8): 431–5. PMID 2687668.

[104] "Helicobacter pylori in peptic ulcer disease”. NIH Consen-sus Statement Online 12 (1). January 7–9, 1994. pp. 1–23.Retrieved December 21, 2004.

[105] Liddell HG, Scott R (1966). A Lexicon: Abridged fromLiddell and Scott’s Greek-English Lexicon. Oxford [Ox-fordshire]: Oxford University Press. ISBN 0-19-910207-4.

[106] Buckley MJ, O'Morain CA (1998). “Helicobacterbiology—discovery”. Br Med Bull 54 (1): 7–16.

[107] Mégraud F (Nov 2007). “European Helicobacter StudyGroup. Evolution of Helicobacter pylori research as ob-served through the workshops of the European Helicobac-ter Study Group”. Helicobacter 12 (Suppl 2): 1–5.

[108] Malfertheiner P, Megraud F, O'Morain CA, AthertonJ, Axon AT, Bazzoli F, Gensini GF, Gisbert JP, Gra-ham DY, Rokkas T, El-Omar EM, Kuipers EJ (May2012). “European Helicobacter Study Group. Manage-ment of Helicobacter pylori infection—the MaastrichtIV/ Florence Consensus Report”. Gut 61 (5): 646–64.doi:10.1136/gutjnl-2012-302084. PMID 22491499.

[109] Malfertheiner P, Megraud F, O'Morain C, Bazzoli F,El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N,Kuipers EJ (Jun 2007). “Current concepts in the man-agement of Helicobacter pylori infection: the Maas-tricht III Consensus Report”. Gut 56 (6): 772–81.doi:10.1136/gut.2006.101634. PMC 1954853. PMID17170018.

[110] Malfertheiner P, Mégraud F, O'Morain C, Hungin AP,Jones R, Axon A, Graham DY, Tytgat G (Feb 2002).“European Helicobacter Pylori Study Group (EHPSG).Current concepts in the management of Helicobac-ter pylori infection—the Maastricht 2-2000 Consen-sus Report”. Aliment Pharmacol Ther 16 (2): 167–80. doi:10.1046/j.1365-2036.2002.01169.x. PMID11860399..

[111] Malfertheiner P, Mégraud F, O'Morain C, Bell D, BianchiPorro G, Deltenre M, Forman D, Gasbarrini G, Jaup B,Misiewicz JJ, Pajares J, Quina M, Rauws E (Jan 1997).“Current European concepts in the management of Heli-cobacter pylori infection—the Maastricht Consensus Re-port. The European Helicobacter Pylori Study Group(EHPSG)". Eur J Gastroenterol Hepatol 9 (1): 1–2.

[112] McNicholl AG, Gasbarrini A, Tepes B, et al. (September2014). “Pan-European Registry onH. pyloriManagement(Hp-EuReg): Interim Analysis of 5,792 Patients”. Heli-cobacter 2014: 69.

[113] "Management of Helicobacter pylori infection" and"Annual Report 2012", United European Gastroenterol-ogy

14 External links• Information on tests for H. pylori from the NationalInstitutes of Health

• European Helicobacter Study Group (EHSG)

13

15 Text and image sources, contributors, and licenses

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