View source for Helicobacter pylori

{{Taxobox | color = lightgrey
| name = ''Helicobacter pylori''
| image = EMpylori.jpg
| image_width=200px
| regnum = [[Bacteria]]
| phylum = [[Proteobacteria]]
| classis = Epsilon Proteobacteria
| ordo = [[Campylobacterales]]
| familia = [[Helicobacteraceae]]
| genus = ''[[Helicobacter]]''
| species = '''''H. pylori'''''
| binomial = ''Helicobacter pylori''
| binomial_authority = ((Marshall ''et al.'' 1985) Goodwin ''et al.'' 1989)
ICD-9 code: 041.86
}}
{{SI}}
{{CMG}}



==Overview==
'''''Helicobacter pylori''''' ({{pronEng|ˌhɛl<s>ɪ</s>kəˈbæktɚ paɪˈlɔəraɪ}}) is a [[gram-negative]], [[microaerophile|microaerophilic]], and [[acidophile|acidophilic]] [[bacterium]] that [[infection|infects]] various areas of the [[stomach]] and [[duodenum]]. Many cases of [[peptic ulcer]]s, [[gastritis]], [[duodenitis]], and perhaps some [[cancer bacteria|cancer]]s are caused by ''H. pylori'' infections.  However, many who are infected do not show any symptoms of [[disease]].  ''Helicobacter'' spp. are the only known microorganisms that can thrive in the highly [[acid]]ic environment of the stomach.  ''H. pylori'''s helical shape (from which the [[genus]] name is derived) is thought to have evolved to penetrate and favor its [[motility]] in the [[mucus]] gel layer.<ref>[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.1336 Chapter 23: ''Campylobacter'' and ''Helicobacter''] from [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed ''Medical Microbiology'', 4th ed.], by Samuel Baron (editor), 1996</ref>

==History==
{{see also|Timeline of peptic ulcer disease and Helicobacter pylori}}

In 1875, [[Germany|German]] scientists found [[helical]] shaped [[bacteria]] in the lining of the human [[stomach]].  The bacteria could not be grown in [[Microbiological culture|culture]] and the results were eventually forgotten.<ref name=Blaser_2005>{{cite journal|author=Blaser MJ|title=An Endangered Species in the Stomach|journal=[[Scientific American]]|year=2005|volume=292|issue=2|pages=38–45|url=http://www.sciam.com/article.cfm?articleID=00024948-2764-11E8-A28583414B7F0000&ref=sciam&chanID=sa006|id=PMID 15715390}}</ref> 

In 1893, the [[Italy|Italian]] researcher [[Giulio Bizzozero]] described helical shaped bacteria living in the acidic environment of the stomach of [[dog]]s.<ref>{{cite journal |last=Bizzozero |first=Giulio |authorlink=Giulio Bizzozero |year=1893 |title=Ueber die schlauchförmigen Drüsen des Magendarmkanals und die Beziehungen ihres Epitheles zu dem Oberflächenepithel der Schleimhaut |journal=Archiv für mikroskopische Anatomie |volume=42 |pages=82–152
}}</ref>

Professor [[Walery Jaworski]] of the [[Jagiellonian University]] in [[Kraków]] investigated sediments of [[gastric]] washings obtained from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic helical shape, which he called ''Vibrio rugula''. He was the first to suggest a possible role of this organism in the pathogeny of gastric diseases. This work was included in the "Handbook of Gastric Diseases" but it did not have much impact as it was written in [[Polish language|Polish]].<ref>{{cite journal|author=Konturek JW|title=Discovery by Jaworski of Helicobacter pylori and its pathogenetic role in peptic ulcer, gastritis and gastric cancer|journal=J Physiol Pharmacol. |year=2003 Dec|volume=54 Suppl 3|pages=23–41|url=http://www.jpp.krakow.pl/journal/archive/1203_s3/articles/03_article.html|id=PMID 15075463}}</ref>

The bacterium was rediscovered in 1979 by [[Australia]]n pathologist [[Robin Warren]], who did further research on it with [[Barry Marshall]] beginning in 1981; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them.<ref>[http://www.tallpoppies.net.au/cavalcade/marshall.htm Barry Marshall biography], The Tall Poppy Campaign. Accessed 9 September 2006.</ref> In their original paper,<ref>{{cite journal|author=Marshall BJ|title=Unidentified curved bacillus on gastric epithelium in active chronic gastritis|journal=[[Lancet]]|year=1983|volume=1|issue=8336|pages=1273–1275|id=PMID 6134060}}</ref> Warren and Marshall contended that most stomach ulcers and gastritis were caused by infection by this bacterium and not by [[stress (medicine)|stress]] or [[spicy food]] as had been assumed before.<ref>{{cite journal|author=Marshall BJ, Warren JR|title=Unidentified curved bacilli in the stomach patients with gastritis and peptic ulceration|journal=Lancet|year=1984|volume=1|issue=8390|pages=1311–1315|id=PMID 6145023}}</ref>

The medical community was slow to recognize the role of this [[bacterium]] in [[stomach ulcer]]s and [[gastritis]], believing that no [[microorganism]] could survive for long in the acidic environment of the stomach.  The community began to come around after further studies were done, including one in which Marshall drank a Petri dish of ''H. pylori'', developed gastritis, and the bacteria were recovered from his stomach lining, thereby satisfying three out of the four [[Koch's postulates]]. The fourth was satisfied after a second endoscopy ten days after inoculation revealed signs of gastritis and the presence of "H. pylori".  Marshall was then able to treat himself using a fourteen day dual therapy with [[bismuth]] salts and [[metronidazole]]. Marshall and Warren went on to show that antibiotics are effective in the treatment of many cases of gastritis. In 1994, the [[National Institutes of Health]] (USA) published an opinion stating that most recurrent gastric ulcers were caused by ''H. pylori'', and recommended that [[antibiotics]] be included in the treatment regimen.<ref>{{cite web|title=Helicobacter pylori in peptic ulcer disease|work=NIH Consensus Statement Online Jan 7–9;12(1):1-23|accessdate=2004-12-21|url=http://consensus.nih.gov/1994/1994HelicobacterPyloriUlcer094html.htm}}</ref>   Evidence has been accumulating to suggest that [[duodenal ulcer]]s are also associated with ''H. pylori'' infection.<ref>{{cite journal|author=Pietroiusti A, Luzzi I, Gomez MJ, Magrini A, Bergamaschi A, Forlini A, Galante A.|title=Helicobacter pylori duodenal colonization is a strong risk factor for the development of duodenal ulcer.|month=April|year=2005|id=PMID 15801926}}</ref><ref>[http://gut.bmjjournals.com/cgi/content/abstract/52/6/797 Helicobacter pylori infection induces duodenitis and superficial duodenal ulcer in Mongolian gerbils]</ref> In 2005, Warren and Marshall were awarded the [[Nobel Prize in Medicine]] for their work on ''H. pylori''.<ref>[http://nobelprize.org/medicine/laureates/2005/index.html The Nobel Prize in Physiology or Medicine 2005] awarded to Barry J. Marshall and J. Robin Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease".</ref>

Before the appreciation of the bacterium's role, stomach ulcers were typically treated with [[medicine]]s that neutralize [[gastric acid]] or decrease its production. While this worked well, the ulcers very often reappeared. A very often used medication against gastritis and peptic ulcers was [[bismuth subsalicylate]]. It was often effective, but fell out of use, since its mechanism of action was a mystery.  Nowadays it is quite clear that it is due to the bismuth salt acting as an antibiotic. Today, many stomach ulcers are treated with antibiotics effective against ''H. pylori''.

The bacterium was initially named '''''Campylobacter pyloridis''''', then '''''C. pylori''''' (after a correction to the [[Latin grammar]]) and in 1989, after [[DNA sequencing]] and other data showed that the bacterium did not belong in the ''[[Campylobacter]]'' genus, it was placed in its own [[genus]], ''[[Helicobacter]]''.  The name ''pylōri'' means "of the pylorus" or [[pyloric valve]] (the circular opening leading from the stomach into the [[duodenum]]), from the [[Greek language|Greek]] word ''πυλωρός'', which means [[gatekeeper]].

While ''H. pylori'' remains the most [[medical]]ly important [[bacterial]] inhabitant of the human stomach, other species of the ''Helicobacter'' genus have been identified in other [[mammal]]s and some [[bird]]s, and some of these can infect humans.<ref>{{cite book |title=Helicobacter Pylori: Physiology and Genetics |last=Mobley |first=Harry L. T. |coauthors=George L. Mendz, Stuart L. Hazell |year=2001 |publisher=ASM Press |isbn=1555812139 }}</ref> ''Helicobacter'' species have also been found to infect the [[liver]]s of certain mammals and to cause liver disease.<ref name=Starzyñska_2006>{{cite journal |author=Starzyñska T, Malfertheiner P |title=''Helicobacter'' and digestive malignancies |journal=Helicobacter |volume=11 Suppl 1 |issue= |pages=32-5 |year=2006 |id=PMID 16925609}}</ref>

==Structure==
''H. pylori'' is a helical shaped [[Gram-negative]] bacterium, about [[1 E-6 m|3 micrometres]] long with a diameter of about 0.5 micrometre. It has 4&ndash;6 [[flagellum|flagella]]. It is [[microaerophilic]], i.e. it requires [[oxygen]] but at lower levels than those contained in the [[earth's atmosphere|atmosphere]]. It contains a [[hydrogenase]] which can be used to obtain energy by oxidizing molecular [[hydrogen]] (H<sub>2</sub>) that is produced by other intestinal bacteria.<ref>Jonathan W. Olson and Robert J. Maier. Molecular Hydrogen as an energy source for Helicobacter pylori. ''Science'' 298.5599 (Nov 29, 2002): pp.1788–1790. PMID 12459589</ref> It tests positive for [[oxidase test|oxidase]], [[catalase]], and [[urease]]. It is capable of forming [[biofilm]]s<ref>{{cite journal|author=Stark RM, Gerwig GJ, Pitman RS, Potts LF, Williams NA, Greenman J, Weinzweig IP, Hirst TR, Millar MR |title=Biofilm formation by Helicobacter pylori.|year=1999|id=PMID 10063642}}</ref> and conversion from helical to [[coccus|coccoid]] form<ref>{{cite journal|author=Chan WY, Hui PK, Leung KM, Chow J, Kwok F, Ng CS|title=Coccoid forms of Helicobacter pylori in the human stomach.|year=1994|id=PMID 7524304}}</ref>, both likely to favor its survival and be factors in the [[epidemiology]] of the bacterium.  The coccoid form of the organism has not been cultured, but has been found in the water supply in the US. This form has also been found to be able to adhere to gastric epithelial cells ''[[in vitro]]''.

[[Image:Helicobacter Pylori Urease.png|thumb|250px|left|Molecular model of ''H. pylori'' urease enzyme]]

==Colonization==

With its [[flagella]], the bacterium moves through the stomach lumen and drills into the [[mucus]] [[gel]] [[layer]] of the stomach.  It then finds ways to live in various areas of the stomach. The known areas include: inside the mucus gel layer (with a preference for the [[superficial]] area), above [[epithelial]] [[cell (biology)|cell]]s, and inside [[vacuole]]s formed by ''H. pylori'' in epithelial cells. It produces [[adhesin]]s which bind to membrane-associated [[lipids]] and [[carbohydrates]] and help its adhesion to epithelial cells. An example of this is the Lewis b antigen. It produces large amounts of [[urease]] [[enzyme]]s which are localized inside and outside of the bacterium.  Urease metabolizes [[urea]] (which is normally  secreted into the stomach) to [[carbon dioxide]] and [[ammonia]] (which neutralizes gastric acid). The survival of ''H. pylori'' in the acidic stomach is dependent on urease, and it would eventually die without it.  The ammonia that is produced is [[toxic]] to the epithelial cells, and, along with the other products of ''H. pylori''—including [[protease]], [[catalase]] and certain [[phospholipase]]s—causes [[damage]] to those cells. 

Some [[Strain (biology)|strains]] of the bacterium have a particular mechanism for "injecting" the [[inflammation|inflammatory]] inducing agents [[peptidoglycan]] from their own [[cell wall]] into epithelial stomach cells. (See below for "cagA pathogenicity island" in the section [[Helicobacter pylori#Genome studies of different strains|Genome studies of different strains]]) This factor may play a role in allowing certain strains to invade [[Host (biology)|host]] [[tissue]].<ref>{{cite journal|author=Viala, Jérôme; Chaput, Catherine; Boneca, Ivo G; Cardona, Ana; Girardin, Stephen E; Moran, Anthony P; Athman, Rafika; Memet, Sylvie; Huerre, Michel R; Coyle, Anthony J; DiStefano, Peter S; Sansonetti, Philippe J; Labigne, Agnès; Bertin, John; Philpott, Dana J; Ferrero, Richard L|title=Nod1 responds to peptidoglycan delivered by the ''Helicobacter pylori'' cag pathogenicity island|journal=Nature Immunol|year=2004|volume=5|pages=1166–74|url=http://www.nature.com/ni/journal/v5/n11/abs/ni1131.html|id={{doi|10.1038/ni1131}}, PMID 15489856}}</ref>

== Causes of infection ==
''H. pylori'' is a contagious bacterium. Many researchers think that ''H. pylori'' is transmitted orally by means of fecal matter through the ingestion of waste tainted food or water. A clean and hygienic environment can help decrease the risk of ''H. pylori'' infection.

==Diagnosis of infection==
[[Image:Immunohistochemical detection of Helicobacter (1) histopatholgy.jpg|thumb|190px|left|[[Immunohistochemistry|Immunohistochemical]] staining of ''H. pylori'' from a [[stomach|gastric]] [[biopsy]].]]

Diagnosis of infection is usually made by checking for [[dyspepsia|dyspeptic]] symptoms and then doing tests which can suggest ''H. pylori'' infection.  One can test noninvasively for ''H. pylori'' infection with a [[blood]] [[antibody]] test, stool [[antigen]] [[stool test|test]], or with the [[Urea breath test|carbon urea breath test]] (in which the patient drinks [[carbon-14|<sup>14</sup>C]]- or [[carbon-13|<sup>13</sup>C]]-labelled [[urea]], which the bacterium metabolizes producing labelled [[carbon dioxide]] that can be detected in the breath).  However, the most reliable method for detecting ''H. pylori'' infection is a [[biopsy]] check during [[endoscopy]] with a [[rapid urease test]], [[histological]] examination, and microbial culture.  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 (tests)|sensitivity]]. Some drugs can affect ''H. pylori'' urease activity and give "false negatives" with the urea-based tests.

Infection may be symptomatic or asymptomatic (without perceptible ill effects).  It is estimated that up to 70% of infection is asymptomatic and that about 2/3 of the world population are infected by the bacterium, making it the most widespread infection in the world.  Actual infection rates vary from nation to nation - the West (Western Europe, North America, Australasia) having rates around 25% and much higher in the Third World. In the latter, it is common, probably due to poor sanitary conditions, to find infections in children. In the [[United States]], infection is primarily in the older generations (about 50% for those over the age of 60 compared with 20% under 40 years) and the poorest.

This is largely attributed to higher hygiene standards and widespread use of antibiotics. However, [[antibiotic resistance]] is appearing in ''H. pylori''.<ref>[http://gut.bmjjournals.com/cgi/content/full/53/9/1374 H pylori antibiotic resistance: prevalence, importance, and advances in testing]</ref> There are already many [[metronidazole]] resistant strains in [[Europe]], the [[United States]], and developing countries.

The bacteria have been isolated from [[feces]], [[saliva]] and [[dental plaque]] of infected patients, which suggests gastro-oral or fecal-oral as possible transmission routes.

It is widely believed that in the absence of treatment, ''H. pylori'' infection—once established in its gastric niche—persists for life.  In the elderly, however, it is likely infection 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.<ref name=Goodman_2005>{{cite journal | author = Goodman K, O'rourke K, Day R, Wang C, Nurgalieva Z, Phillips C, Aragaki C, Campos A, de la Rosa J | title = Dynamics of ''Helicobacter pylori'' infection in a US-Mexico cohort during the first two years of life. | journal = Int J Epidemiol | volume = 34 | issue = 6 | pages = 1348–55 | year = 2005 | id = PMID 16076858}}</ref><ref name=Goodman_2001>{{cite journal | author = Goodman K, Cockburn M | title = The role of epidemiology in understanding the health effects of ''Helicobacter pylori''. | journal = Epidemiology | volume = 12 | issue = 2 | pages = 266-71 | year = 2001 | id = PMID 11246592}}</ref>

==Treatment of infection==
[[Image:pylorigastritis.jpg|thumb|left|300 px|''H. pylori'' colonized on the surface of regenerative epithelium (image from Warthin-Starry's silver stain)]]
In [[peptic ulcer]] patients where [[infection]] is detected, the normal procedure is eradicating ''H. pylori'' to allow the [[ulcer]] to heal. The standard first-line therapy is a one week ''triple therapy''. The Sydney gastroenterolgist [[Thomas Borody]] invented the first triple therapy in 1987.<ref name=Borody_1989>{{cite journal | last = Borody | first = Thomas J. | coauthors = | P. Cole, S. Noonan, A. Morgan, J. Lenne, L. Hyland, S. Brandl, E. G. Borody, and L. L. George | date = [[October 16]], [[1989]] | title = Recurrence of duodenal ulcer and Campylobacter pylori infection after eradication | journal = Medical Journal of Australia | volume = 151 | issue = 8 | pages = 431–435 | id = {{PMID|2687668}} }}</ref> Today, the standard triple therapy is [[amoxicillin]], [[clarithromycin]] and a [[proton pump inhibitor]] such as [[omeprazole]].<ref name=Mirbagheri_et_al_2006>{{cite journal | last = Mirbagheri | first = Seyed Amir | coauthors = Mehrdad Hasibi, Mehdi Abouzari, and Armin Rashidi | date = [[August 14]], [[2006]] | title = Triple, standard quadruple and [[ampicillin]]-[[sulbactam]]-based quadruple therapies for H pylori eradication: A comparative three-armed randomized clinical trial | journal = World Journal of Gastroenterology | volume = 12 | issue = 30 | pages = 4888–4891
 | id = {{PMID|16937475}} | url = http://www.wjgnet.com/1007-9327/12/4888.asp | accessdate = 2006-09-30}}</ref> 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 using [[metronidazole]] instead of amoxicillin in those [[allergy|allergic]] to [[penicillin]].<ref name=Maastricht_2_Consensus_Report>{{cite web | url = http://www.noster.com/fReport.htm | title = 
Current Concepts in the Management of Helicobacter pylori Infection | accessmonthday = September 30 | accessyear = 2006 | author = European Helicobacter Pylori Study Group | work = The Maastricht 2-2000 Consensus Report }}</ref> Such a therapy has revolutionised the treatment of peptic ulcers and has made a cure to the [[disease]] possible, where previously symptom control using [[antacids]], [[H2 antagonist|H<sub>2</sub>-antagonists]] or [[proton pump inhibitor]]s alone was the only option.<ref name="pmid1971318">{{cite journal |author=Rauws EA, Tytgat GN |title=Cure of duodenal ulcer associated with eradication of Helicobacter pylori |journal=Lancet |volume=335 |issue=8700 |pages=1233-5 |year=1990 |pmid=1971318 |doi=}}</ref><ref name="pmid1854110">{{cite journal |author=Graham DY, Lew GM, Evans DG, Evans DJ, Klein PD |title=Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. A randomized controlled trial |journal=Ann. Intern. Med. |volume=115 |issue=4 |pages=266-9 |year=1991 |pmid=1854110 |doi=}}</ref>

A [[meta-analysis]] of [[randomized controlled trials]] suggests that supplementation with [[probiotics]] can improve eradication rates and reduce adverse events.<ref name="pmid17229240">{{cite journal |author=Tong JL, Ran ZH, Shen J, Zhang CX, Xiao SD |title=Meta-analysis: the effect of supplementation with probiotics on eradication rates and adverse events during Helicobacter pylori eradication therapy |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=2 |pages=155-68 |year=2007 |pmid=17229240 |doi=10.1111/j.1365-2036.2006.03179.x}} [http://www.acpjc.org/Content/146/3/issue/ACPJC-2007-146-3-063.htm ACP Journal Club]</ref>

Unfortunately, an increasing number of infected individuals are found to harbour [[antibiotic resistance|antibiotic-resistant]] bacteria. This results in initial treatment failure and requires additional rounds of antibiotic therapy or alternative strategies such as a quadruple therapy.   [[Bismuth]] compounds are also effective in combination with the above drugs. For the treatment of [[clarithromycin]]-resistant strains of ''H. pylori'' the use of [[levofloxacin]] as part of the therapy has been suggested.

Some studies show that consumption of [[broccoli]] sprouts can be effective at inhibiting ''H. pylori'' growth<ref>{{cite journal|author=Galan MV, Kishan AA, Silverman AL|title=Oral broccoli sprouts for the treatment of ''Helicobacter pylori'' infection: a preliminary report|journal=Dig Dis Sci.|month=August | year = 2004|volume=49|issue=7–8|pages=1088–90|id=PMID 15387326}}</ref> with [[sulforaphane]] being at least one of the active agents<ref>{{cite journal|author=|title=Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors.|author=Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A|year=2002|month=May|id=PMID 12032331}}</ref>.

Some studies show that [[mastic]] gum can destroy ''H. pylori'' ''[[in vitro]]'', but studies done ''[[in vivo]]'' have shown it to be ineffective.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&term=%22gum+mastic%22%5BSubstance+Name%5D+AND+%22Helicobacter+pylori%22%5BMeSH%5D PubMed search for "gum mastic" and "H. pylori"], accessed 9 September 2006.</ref>

A study done on Mongolian gerbils indicates that [[green tea]] extract can suppress ''H. pylori'' growth.<ref>{{cite journal|author=Matsubara S, Shibata H, Ishikawa F, Yokokura T, Takahashi M, Sugimura T, Wakabayashi K.|title=Suppression of Helicobacter pylori-induced gastritis by green tea extract in Mongolian gerbils.|month=October |year = 2003|id=PMID 14550260}}</ref> Another study done in South Korea suggests that an acidic [[polysaccharide]] found in green tea is significantly effective in preventing adhesion of ''H. pylori'' to human cultures of epithelial cells.<ref name=Lee_2006>{{cite journal |author=Lee J, Shim J, Lee J, Kim J, Yang I, Chung M, Kim K |title=Inhibition of pathogenic bacterial adhesion by acidic polysaccharide from green tea (Camellia sinensis) |journal=J Agric Food Chem |volume=54 |issue=23 |pages=8717–23 |year=2006 |id=PMID 17090112}}</ref>

As [[#Acid reflux and esophageal cancer|explained below]], some authors suggest that some strains of ''H. pylori'' may be protective against certain diseases of the esophagus and cardia. Therefore, a more cautious approach than complete eradication may be necessary in some cases.

==''Helicobacter'' and cancer==

While the [[incidence (epidemiology)|incidence]] of ''H. pylori'' infection in humans is decreasing in developing countries,<!-- several statements in this paragraph need citation --> presumably because of improving sanitation and increasing use of antibiotics, in the United States the incidence of gastric cancer has decreased by 80 percent from 1900 to 2000.  This apparent correlation is consistent with an epidemiological link between ''H. pylori'' and cancer.  Specifically, both [[gastric cancer]] and gastric [[MALT lymphoma]] (lymphoma of the [[mucosa-associated lymphoid tissue]]) have been associated with ''H. pylori'', and the bacterium has been categorized as a group I [[carcinogen]] by the [[International Agency for Research on Cancer]] (IARC).  Despite these associations, a direct [[causality|causal]] relationship has not been demonstrated.  Nonetheless, among [[cancer bacteria|bacteria suspected to cause cancer]], ''H. pylori'' is the leading contender.

Two related mechanisms by which ''H. pylori'' could promote [[cancer]] are under investigation. One mechanism involves the enhanced production of [[free radical]]s near ''H. pylori'' and an increased rate of host cell [[mutation]]. The other proposed mechanism has been called a "perigenetic pathway"<ref>{{cite journal|author=Tsuji S, Kawai N, Tsujii M, Kawano S, Hori M|title=Review article: inflammation-related promotion of gastrointestinal carcinogenesis - a perigenetic pathway|journal=Aliment Pharmacol Ther|year=2003|volume=18|issue=Suppl 1|pages=82–9|id=PMID 12925144}}</ref> and involves enhancement of the transformed host cell phenotype by means of alterations in cell [[protein]]s such as [[cell adhesion|adhesion]] proteins. It has been proposed that ''H. pylori'' induces [[inflammation]] and locally high levels of [[TNF-alpha]] and/or [[interleukin 6]]. According to the proposed perigenetic mechanism, inflammation-associated signaling molecules such as TNF-alpha can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in [[tumor suppressor gene]]s such as [[genes]] that code for cell adhesion proteins.

===Acid reflux and esophageal cancer===<!-- *otheus* intra-wiki link to here exists. do not remove section without changing "explained below" link in previous lvl2 section. -->
As the incidence of gastric cancer has decreased, the incidences of [[gastroesophageal reflux disease]] and [[esophageal cancer]] have increased dramatically. In 1996, [[Martin J. Blaser]] put forward the theory that ''H. pylori'' might also have a beneficial effect: by regulating the acidity of the stomach contents, it lowers the impact of regurgitation of gastric acid into the esophagus.<ref name = Blaser_2005 /> While some favorable evidence has been accumulated, [[as of 2005]] the theory is not universally accepted.

==Genome studies of different strains==<!-- This section is linked from [[Helicobacter pylori]] -->
[[Image:Helicobacter pylori.jpg|thumb|left|EM photograph of ''H. pylori'']]
Several strains are known, and the [[genome]]s of two have been completely [[sequencing|sequenced]].<ref>{{cite journal|author=Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S, Dougherty BA, Nelson K, Quackenbush J, Zhou LX, Kirkness 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, Weldman JM, Fujii C, Bowman C, Watthey L, Wallin E, Hayes WS, Weidman JM, Fujii C, Borodovsky M, Karp PD, Smith HO, Fraser CM, Venter JC|title=The complete genome sequence of the gastric pathogen ''Helicobacter pylori''|journal=Nature|year=1997|volume=288|issue=6642|pages=539-547|id=PMID 9252185}}</ref><ref>The [http://genolist.pasteur.fr/PyloriGene/ Pylori Gene] website allows access to genome information for the ''H. pylori'' 26695 and J99 strains. Another [[genome]] interface is provided by the [[National Center for Biotechnology Information]]; [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genome&cmd=Retrieve&dopt=Overview&list_uids=128 26695], [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genome&cmd=Retrieve&dopt=Overview&list_uids=139 J99].</ref> The genome of the strain "26695" consists of about 1.7 million [[base pair]]s, with some 1550 genes. The two sequenced strains show large genetic differences, with up to 6% of the [[nucleosides]] differing.

Study of the ''H. pylori'' genome is centered on attempts to understand [[pathogenesis]], the ability of this [[organism]] to cause disease. There are 62 genes in the "pathogenesis" category of the genome database. Both sequenced strains have an approximately 40 kb long Cag [[pathogenicity island]] (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. This pathogenicity island is usually absent from ''H. pylori'' strains isolated from humans who are carriers of ''H. pylori'' but remain [[asymptomatic]]. 

The cagA gene codes for one of the major ''H. pylori'' [[virulence]] proteins. Bacterial strains that have the cagA gene are associated with an ability to cause severe ulcers. The cagA gene codes for a relatively long (1186 [[amino acid]]) protein. The cagA protein is transported into human cells where it may disrupt the normal functioning of the [[cytoskeleton]]. The Cag pathogenicity island has about 30 genes that code for a complex [[type IV secretion system]]. After attachment of ''H.pylori'' to stomach epithelial cells, the cagA protein is injected into the epithelial cells by the type IV secretion system. The cagA protein is [[Phosphorylation|phosphorylated]] on [[Protein kinase#Tyrosine-specific protein kinases|tyrosine residues]] by a host cell membrane-associated [[tyrosine kinase]]. Pathogenic strains of ''H. pylori'' have been shown to activate the [[epidermal growth factor receptor]] (EGFR), a membrane protein with a tyrosine kinase domain. Activation of the EGFR by ''H. pylori'' is associated with altered [[signal transduction]] and [[gene expression]] in host epithelial cells that may contribute to pathogenesis. It has also been suggested that a [[C-terminus|c-terminal]] region of the cagA protein (amino acids 873–1002) can regulate host cell gene transcription independent of protein tyrosine phosphorylation.  It is thought, due to cagA's low GC content relative to the rest of the helicobacter genome, that the gene was acquired by horizontal transfer from another cagA+ bacterial species.

==Gallery==
<gallery>
Image: Helicobacter pylori05.jpeg| Scanning electron micrograph depicts a Flexispira rappini bacteria (13,951x mag). <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>

Image: Helicobacter pylori04.jpeg| Scanning electron micrograph depicts a Flexispira rappini bacteria (6976x mag). <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>

Image: Helicobacter pylori03.jpeg| Scanning electron micrograph depicts a Flexispira rappini bacteria (13951x mag). <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>

</gallery>
==See also==
* [[Gastritis]]
* [[Peptic ulcer]]
* [[Stomach]]

==Notes==
{{Reflist|2}}

==References==
* {{cite web|title=''Helicobacter pylori'' and peptic ulcer|work=Centers for Disease Control and Prevention|accessdate= 2004-12-21|url=http://www.cdc.gov/ulcer/}}
* {{cite journal|author=Logan, Robert P H; Walker, Marjorie M|title=Clinical review: ABC of the upper gastrointestinal tract. Epidemiology and diagnosis of ''Helicobacter pylori'' infection|journal=BMJ|year=20 October 2001|volume=323|pages=920–922|url=http://bmj.bmjjournals.com/cgi/content/full/323/7318/920|id= PMID 11668141}}

==External links==
{{wikispecies}}
{{Commonscat|Helicobacter pylori}}
*[http://www.h-pylori-symptoms.com/ Helicobacter pylori - Natural solutions] Offers guidance and natural programmes for H Pylori sufferers
*[http://www.helico.com/ The Helicobacter Foundation] provides information on ''Helicobacter pylori'' and its effects - founded by Dr. Barry J. Marshall, one of the discoverers of ''H. pylori''
*[http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=14755326 ''Helicobacter pylori'' persistence: biology and disease] by Martin J. Blaser and John C. Atherton in ''Journal of Clinical Investigations (2004) Volume 113 pages 321–333.
*[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hp ''Helicobacter pylori'': Physiology and Genetics] Online text of the Mobley et al book (via NCBI).
*[http://www.helicobacter.org/ European Helicobacter Study Group] sponsors annual international workshop, yearbook, and clinical guidelines
**[http://www.helicobacter.org/content/publications/helicobacter_2006/yih2006.pdf The Year in ''Helicobacter pylori'' 2006] Helicobacter journal Supplement Oct 2006 - Free content 
**[http://www.helicobacter.org/content/publications/publications.htm 1994–2005 back issues]
* Atwood KC. ''Bacteria, Ulcers, and Ostracism?: H. pylori and the Making of a Myth.'' Skeptical Inquirer November 2004. [http://www.csicop.org/si/2004-11/bacteria.html Fulltext] Claims that medicine’s purported ostracism of the discovery of ''H. pylori'' has achieved a mythological quality, but isn't true: after appropriate initial scientific skepticism, the hypothesis was accepted right "on schedule".
* [http://www.pathologyatlas.ro/Helicobacter%20pylori.html Microscopic image of ''H. pylori'']
* [http://www.hpylori.com.au/picturebook.html ''H. pylori'' Picture Book]
* [http://www.dsmz.de/bactnom/nam3637.htm List of species in the genus ''Helicobacter'']
* [http://www.sciencedaily.com/releases/2007/02/070215134529.htm ''Out Of Africa -- Bacteria, As Well:'' Homo Sapiens ''And'' H. Pylori ''Jointly Spread Across The Globe''] ScienceDaily (Feb. 16, 2007) — When man made his way out of Africa some 60,000 years ago to populate the world, he was not alone: He was accompanied by the bacterium ''Helicobacter pylori''....



[[Category:Proteobacteria]]
[[Category:Gastroenterology]]
[[Category:IARC Group 1 carcinogens]]
[[Category:Conditions diagnosed by stool test]]

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