Helicobacter pylori


Helicobacter pylori

Taxobox | name = "Helicobacter pylori"



image_width=190px
regnum = Bacteria
phylum = Proteobacteria
classis = Epsilon Proteobacteria
ordo = Campylobacterales
familia = Helicobacteraceae
genus = "Helicobacter"
species = "H. pylori"
binomial = "Helicobacter pylori"
binomial_authority =
Infobox_Disease
Name = Helicobacter pylori infection

| Caption = Immunohistochemical staining of "H. pylori" from a gastric biopsy
DiseasesDB = 5702
ICD10 = | ICD9 = ICD9|533 | ICDO =
OMIM =
MedlinePlus = 000229
eMedicineSubj = med
eMedicineTopic = 962
eMedicine_mult = | MeshID = D016481
"Helicobacter pylori" (pron-en|ˌhɛlɪkəˈbæktɚ pɪˈlɔəraɪ) is a gram-negative, microaerophilic bacterium that inhabits various areas of the stomach and duodenum. It causes a chronic low-level inflammation of the stomach lining and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer. Over 80% of individuals infected with the bacterium are asymptomatic.

The bacterium was initially named "Campylobacter pyloridis", then renamed "C. pylori" to fix a Latin grammar error. When 16S rRNA 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". The genus derived from the Ancient Greek "hělix"/έλιξ "spiral" or "coil".cite book
author=Liddell HG and Scott R
title=A Lexicon: Abridged from Liddell and Scott's Greek-English Lexicon
publisher=Oxford University Press
location=Oxford [Oxfordshire]
year=1966
isbn=0-19-910207-4
] The specific epithet "pylōri" means "of the pylorus" or pyloric valve (the circular opening leading from the stomach into the duodenum), from the Ancient Greek word "πυλωρός", which means gatekeeper.

More than 50% of the world's population harbour "H. pylori" in their upper gastrointestinal tract. Infection is more prevalent in developing countries. The route of transmission is unknown, although individuals become infected in childhood. "H. pylori"'s helix shape (from which the generic name is derived) is thought to have evolved to penetrate the mucoid lining of the stomach.cite book
author=Yamaoka, Yoshio
title=Helicobacter pylori: Molecular Genetics and Cellular Biology
publisher=Caister Academic Pr
year=2008
isbn=1-904455-31-X
] cite journal
author=Brown LM
title="Helicobacter pylori": epidemiology and routes of transmission
journal=Epidemiol Rev
volume=22
issue=2
pages=283–97
year=2000
pmid=11218379
doi=
url=http://epirev.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11218379
]

igns and symptoms

Most individuals with chronic "H. pylori" infection have no symptoms. Some individuals develop more serious problems, including stomach or duodenal ulcers. Ulcers can cause a variety of symptoms or no symptoms at all. Common complaints include pain or discomfort (usually in the upper abdomen), bloating, feeling full after eating a small amount of food, lack of appetite, nausea, vomiting, and dark or tar-colored stools. Ulcers that bleed can cause a low blood count and fatigue.cite journal
author=Suerbaum S, Michetti P
title="Helicobacter pylori" infection
journal=N. Engl. J. Med.
volume=347
issue=15
pages=1175–86
year=2002
month=October
pmid=12374879
doi=10.1056/NEJMra020542
url=
]

Microbiology

"H. pylori" is a helix-shaped Gram-negative bacterium, about 3 micrometres long with a diameter of about 0.5 micrometre. It is microaerophilic; it requires oxygen although at lower concentration than is found in the atmosphere. It contains a hydrogenase which can be used to obtain energy by oxidizing molecular hydrogen (H2) that is produced by intestinal bacteria. [cite journal
author=Olson JW, Maier RJ
title=Molecular hydrogen as an energy source for "Helicobacter pylori"
journal=Science (journal)
volume=298
issue=5599
pages=1788–90
year=2002
month=November
pmid=12459589
doi=10.1126/science.1077123
url=
] It produces oxidase, catalase, and urease. It is capable of forming biofilms [cite journal |author=Stark RM, Gerwig GJ, Pitman RS, "et al" |title=Biofilm formation by "Helicobacter pylori" |journal=Lett. Appl. Microbiol. |volume=28 |issue=2 |pages=121–6 |year=1999 |month=February |pmid=10063642] and can convert from spiral to a possibly viable but nonculturable coccoid form, [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
journal=Am. J. Clin. Pathol.
volume=102
issue=4
pages=503–7
year=1994
month=October
pmid=7524304
doi=
url=
] both likely to favor its survival and be factors in the epidemiology of the bacterium. The coccoid form can adhere to gastric epithelial cells "in vitro". [cite journal
author=Liu ZF, Chen CY, Tang W, Zhang JY, Gong YQ, Jia JH
title=Gene-expression profiles in gastric epithelial cells stimulated with spiral and coccoid "Helicobacter pylori"
journal=J. Med. Microbiol.
volume=55
issue=Pt 8
pages=1009–15
year=2006
month=August
pmid=16849720
doi=10.1099/jmm.0.46456-0
url=
]

"H. pylori" possesses five major outer membrane protein (OMP) families.cite journal
author=Kusters JG, van Vliet AH, Kuipers EJ
title=Pathogenesis of "Helicobacter pylori" infection
journal=Clin. Microbiol. Rev.
volume=19
issue=3
pages=449–90
year=2006
month=July
pmid=16847081
pmc=1539101
doi=10.1128/CMR.00054-05
url=
] The largest family includes known and putative adhesins. The other four families include 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. The outer membrane also contains cholesterol glucosides, which is found in few other bacteria. "H. pylori" has 4–6 flagella; all gastric and enterohepatic "Helicobacter" species are highly motile due to flagella. [cite journal
author=Josenhans C, Eaton KA, Thevenot T, Suerbaum S
title=Switching of flagellar motility in "Helicobacter pylori" by reversible length variation of a short homopolymeric sequence repeat in fliP, a gene encoding a basal body protein
journal=Infect. Immun.
volume=68
issue=8
pages=4598–603
year=2000
month=August
pmid=10899861
pmc=98385
doi=
url=
] The characteristic sheathed flagellar filaments of helicobacters are composed of two copolymerized flagellins, FlaA and FlaB.cite book
isbn=1-904455-31-X
accessdate=2008-08-31
chapterurl=http://www.horizonpress.com/hpl2
author= Rust M, Schweinitzer T, Josenhans C
year=2008
chapter=Helicobacter Flagella, Motility and Chemotaxis
title = "Helicobacter pylori": Molecular Genetics and Cellular Biology (Yamaoka Y, ed.)
publisher = Caister Academic Press
]

Genome

"H. pylori" consists of a large diversity of strains, and the genomes of three have been completely sequenced.cite journal
author=Tomb JF, White O, Kerlavage AR, "et al"
title=The complete genome sequence of the gastric pathogen "Helicobacter pylori"
journal=Nature
volume=388
issue=6642
pages=539–47
year=1997
month=August
pmid=9252185
doi=10.1038/41483
url=
] [cite web
url=http://genolist.pasteur.fr/PyloriGene
title= Genome information for the "H. pylori" 26695 and J99 strains
publisher=Institut Pasteur
year=2002
format=
work=
accessdate=2008-09-01
] cite web
url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genome&cmd=Retrieve&dopt=Overview&list_uids=128
title=Helicobacter pylori 26695, complete genome
publisher=National Center for Biotechnology Information
format=
work=
accessdate=2008-09-01
] [cite web
url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genome&cmd=Retrieve&dopt=Overview&list_uids=139
title="Helicobacter pylori" J99, complete genome
publisher=National Center for Biotechnology Information
format=
work=
accessdate=2008-09-01
] cite journal
author=Oh JD, Kling-Bäckhed H, Giannakis M, "et al"
title=The complete genome sequence of a chronic atrophic gastritis "Helicobacter pylori" strain: evolution during disease progression
journal=Proc. Natl. Acad. Sci. U.S.A.
volume=103
issue=26
pages=9999–10004
year=2006
month=June
pmid=16788065
pmc=1480403
doi=10.1073/pnas.0603784103
url=
] The genome of the strain "26695" consists of about 1.7 million base pairs, with some 1,550 genes. The two sequenced strains show large genetic differences, with up to 6% of the nucleotides differing.

Study of the "H. pylori" genome is centered on attempts to understand pathogenesis, the ability of this organism to cause disease. Approximately 29% of the loci are 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.cite journal
author=Baldwin DN, Shepherd B, Kraemer P, "et al"
title=Identification of "Helicobacter pylori" genes that contribute to stomach colonization
journal=Infect. Immun.
volume=75
issue=2
pages=1005–16
year=2007
month=February
pmid=17101654
pmc=1828534
doi=10.1128/IAI.01176-06
url=
]

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 ulcers.cite journal
author=Broutet N, Marais A, Lamouliatte H, "et al"
title=cagA Status and eradication treatment outcome of anti-"Helicobacter pylori" triple therapies in patients with nonulcer dyspepsia
journal=J. Clin. Microbiol.
volume=39
issue=4
pages=1319–22
year=2001
month=April
pmid=11283049
pmc=87932
doi=10.1128/JCM.39.4.1319-1322.2001
url=http://jcm.asm.org/cgi/pmidlookup?view=long&pmid=11283049
issn=
] 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 that the island was acquired by horizontal transfer from another bacterial species.

Pathophysiology

To colonize the stomach "H. pylori" must survive the acidic pH of the lumen and burrow into the mucus to reach its niche, close to the stomach's epithelial cell layer. The bacterium has flagella and moves through the stomach lumen and drills into the mucoid lining of the stomach.cite journal
author=Ottemann KM, Lowenthal AC
title="Helicobacter pylori" uses motility for initial colonization and to attain robust infection
journal=Infect. Immun.
volume=70
issue=4
pages=1984–90
year=2002
month=April
pmid=11895962
pmc=127824
doi=
url=http://iai.asm.org/cgi/pmidlookup?view=long&pmid=11895962
] Many bacteria can be found deep in the mucus, which is continuously secreted by mucous cells and removed on the luminal side. To avoid being carried into the lumen, "H. pylori" senses the pH gradient within the mucus layer by chemotaxis and swims away from the acidic contents of the lumen towards the more neutral pH environment of the epithelial cell surface.cite journal
author=Schreiber S, Konradt M, Groll C, "et al"
title=The spatial orientation of "Helicobacter pylori" in the gastric mucus
journal=Proc. Natl. Acad. Sci. U.S.A.
volume=101
issue=14
pages=5024–9
year=2004
month=April
pmid=15044704
pmc=387367
doi=10.1073/pnas.0308386101
url=
] "H. pylori" is also found on the inner surface of the stomach epithelial cells and occasionally inside epithelial cells.cite journal
author=Petersen AM, Krogfelt KA
title="Helicobacter pylori": an invading microorganism? A review
journal=FEMS Immunol. Med. Microbiol.
volume=36
issue=3
pages=117–26
year=2003
month=May
pmid=12738380
doi=
url=
] It produces adhesins which bind to membrane-associated lipids and carbohydrates and help it adhere to epithelial cells. For example, the adhesin BabA binds to the Lewis b antigen displayed on the surface of stomach epithelial cells.cite journal
author=Ilver D, Arnqvist A, Ogren J, "et al"
title="Helicobacter pylori" adhesin binding fucosylated histo-blood group antigens revealed by retagging
journal=Science (journal)
volume=279
issue=5349
pages=373–7
year=1998
month=January
pmid=9430586
doi=
url=
] "H. pylori" produces large amounts of the enzyme urease, molecules of which are localized inside and outside of the bacterium. Urease breaks down 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 the enzyme. The ammonia that is produced is toxic to the epithelial cells, and, along with the other products of "H. pylori"—including protease, vacuolating cytotoxin A (VacA), and certain phospholipases—damages those cells. [cite journal
author=Smoot DT
title=How does "Helicobacter pylori" cause mucosal damage? Direct mechanisms
journal=Gastroenterology
volume=113
issue=6 Suppl
pages=S31–4; discussion S50
year=1997
month=December
pmid=9394757
doi=
url=
]

Colonization of the stomach by "H. pylori" results in chronic gastritis, an inflammation of the stomach lining. The severity of the inflammation is likely to underlie "H. pylori"-related diseases.cite journal
author=Shiotani A, Graham DY
title=Pathogenesis and therapy of gastric and duodenal ulcer disease
journal=Med. Clin. North Am.
volume=86
issue=6
pages=1447–66, viii
year=2002
month=November
pmid=12510460
doi=
url=
] Duodenal and stomach ulcers result when the consequences of inflammation allow the acid and pepsin in the stomach lumen to overwhelm the mechanisms that protect the stomach and duodenal mucosa from these caustic substances. The type of ulcer that develops depends on the location of chronic gastritis, which occurs at the site of "H. pylori" colonization.cite journal
author=Dixon MF
title=Patterns of inflammation linked to ulcer disease
journal=Baillieres Best Pract Res Clin Gastroenterol
volume=14
issue=1
pages=27–40
year=2000
month=February
pmid=10749087
doi=
url=
] The acidity within the stomach lumen affects the colonization pattern of "H. pylori" and therefore ultimately determines whether a duodenal or gastric ulcer will form. In people producing large amounts of acid, "H. pylori" colonizes the antrum of the stomach to avoid the acid-secreting parietal cells located in the corpus (main body) of the stomach. The inflammatory response to the bacteria induces G cells in the antrum to secrete the hormone gastrin, which travels through the bloodstream to the corpus.cite journal
author=Blaser MJ, Atherton JC
title="Helicobacter pylori" persistence: biology and disease
journal=J. Clin. Invest.
volume=113
issue=3
pages=321–33
year=2004
month=February
pmid=14755326
pmc=324548
doi=10.1172/JCI20925
url=
] Gastrin stimulates the parietal cells in the corpus to secrete even more acid into the stomach lumen. Chronically increased gastrin levels eventually cause the number of parietal cells to also increase, further escalating the amount of acid secreted.cite journal
author=Schubert ML, Peura DA
title=Control of gastric acid secretion in health and disease
journal=Gastroenterology
volume=134
issue=7
pages=1842–60
year=2008
month=June
pmid=18474247
doi=10.1053/j.gastro.2008.05.021
url=
] The increased acid load damages the duodenum, and ulceration may eventually result. In contrast, gastric ulcers are often associated with normal or reduced gastric acid production, suggesting that the mechanisms that protect the gastric mucosa are defective. In these patients "H. pylori" can also colonize the corpus of the stomach, where the acid-secreting parietal cells are located. However chronic inflammation induced by the bacteria causes further reduction of acid production and, eventually, atrophy of the stomach lining, which may lead to gastric ulcer and increases the risk for stomach cancer.

About 50-70% of "H. pylori" strains in Western countries carry the "cag" pathogenicity island ("cag" PAI).cite journal
author=Peek RM, Crabtree JE
title="Helicobacter" infection and gastric neoplasia
journal=J. Pathol.
volume=208
issue=2
pages=233–48
year=2006
month=January
pmid=16362989
doi=10.1002/path.1868
url=
] Western patients 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. Following attachment of "H. pylori" to stomach epithelial cells the type IV secretion system expressed by the "cag" PAI "injects" the inflammatory inducing agent peptidoglycan from their own cell wall into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic immune sensor Nod1, which then stimulates expression of cytokines that promote inflammation. [cite journal
author=Viala J, Chaput C, Boneca IG, "et al"
title=Nod1 responds to peptidoglycan delivered by the "Helicobacter pylori" "cag" pathogenicity island
journal=Nat. Immunol.
volume=5
issue=11
pages=1166–74
year=2004
month=November
pmid=15489856
doi=10.1038/ni1131
url=
]

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, and other cellular activities.cite journal
author=Backert S, Selbach M
title=Role of type IV secretion in "Helicobacter pylori" pathogenesis
journal=Cell. Microbiol.
volume=10
issue=8
pages=1573–81
year=2008
month=August
pmid=18410539
doi=10.1111/j.1462-5822.2008.01156.x
url=
] Once inside the cell the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase. Pathogenic strains of "H. pylori" have been shown to activate the epidermal growth factor receptor (EGFR), a membrane protein with a tyrosine kinase domain. Activation of the EGFR by "H. pylori" is associated with altered signal transduction and gene expression in host epithelial cells that may contribute to pathogenesis. It has also been suggested that a c-terminal region of the CagA protein (amino acids 873–1002) can regulate host cell gene transcription independent of protein tyrosine phosphorylation.

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" [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.
volume=18 Suppl 1
issue=
pages=82–9
year=2003
month=July
pmid=12925144
doi=
url=
] and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins such as adhesion proteins. It has been proposed that "H. pylori" induces inflammation and locally high levels of TNF-alpha and/or interleukin 6. According to the proposed perigenetic mechanism, inflammation-associated signaling molecules such as TNF-alpha can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes such as genes that code for cell adhesion proteins. [cite journal
author=Suganuma M, Yamaguchi K, Ono Y, "et al"
title=TNF-alpha-inducing protein, a carcinogenic factor secreted from "H. pylori", enters gastric cancer cells
journal=Int. J. Cancer
volume=123
issue=1
pages=117–22
year=2008
month=July
pmid=18412243
doi=10.1002/ijc.23484
url=
]

Diagnosis

Diagnosis of infection is usually made by checking for dyspeptic symptoms and by tests which can indicate "H. pylori" infection. 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). [cite journal
author=Stenström B, Mendis A, Marshall B
title=Helicobacter pylori - The latest in diagnosis and treatment
journal=Aust Fam Physician
volume=37
issue=8
pages=608–12
year=2008
month=August
pmid=18704207
doi=
url=
] 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. Some drugs can affect "H. pylori" urease activity and give false negatives with the urea-based tests.cite journal
author=Logan RP, Walker MM
title=ABC of the upper gastrointestinal tract: Epidemiology and diagnosis of Helicobacter pylori infection
journal=BMJ
volume=323
issue=7318
pages=920–2
year=2001
month=October
pmid=11668141
pmc=1121445
doi=
url=
]

Prevention

"H. pylori" is a major cause of diseases of the upper gastrointestinal tract. Eradication of the infection in individuals will improve symptoms including dyspepsia, gastritis and peptic ulcers, and may prevent gastric cancer. Rising antimicrobial resistance increases the need for a prevention strategy for the bacteria. [cite journal
author=Selgrad M, Malfertheiner P
title=New strategies for Helicobacter pylori eradication
journal=Curr Opin Pharmacol
volume=
issue=
pages=
year=2008
month=June
pmid=18555746
doi=10.1016/j.coph.2008.04.010
url=
] There have been extensive vaccine studies in mouse models, which have shown promising results. [cite journal
author=Hoffelner H, Rieder G, Haas R
title=Helicobacter pylori vaccine development: optimisation of strategies and importance of challenging strain and animal model
journal=Int. J. Med. Microbiol.
volume=298
issue=1–2
pages=151–9
year=2008
month=January
pmid=17714988
doi=10.1016/j.ijmm.2007.07.006
url=
] Researchers are studying different adjuvants, antigens, and routes of immunization to ascertain the most appropriate system of immune protection, with most of the research only recently moving from animal to human trials. [cite journal
author=Kabir S
title=The current status of Helicobacter pylori vaccines: a review
journal=Helicobacter
volume=12
issue=2
pages=89–102
year=2007
month=April
pmid=17309745
doi=10.1111/j.1523-5378.2007.00478.x
url=
]

An intramuscular vaccine against "H. pylori" infection is undergoing Phase I clinical trials and has shown an antibody response against the bacterium. Its clinical usefulness requires further study. [cite journal
author=Malfertheiner P, Schultze V, Rosenkranz B, "et al"
title=Safety and Immunogenicity of an Intramuscular Helicobacter pylori Vaccine in Noninfected Volunteers: A Phase I Study
journal=Gastroenterology
volume=
issue=
pages=
year=2008
month=May
pmid=18619971
doi=10.1053/j.gastro.2008.05.054
url=
]

Treatment

Once "H. pylori" is detected in patients 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 the antibiotics amoxicillin and clarithromycin, and a proton pump inhibitor such as omeprazole.cite journal
author=Mirbagheri SA, Hasibi M, Abouzari M, Rashidi A
title=Triple, standard quadruple and ampicillin-sulbactam-based quadruple therapies for H. pylori eradication: a comparative three-armed randomized clinical trial
journal=World J. Gastroenterol.
volume=12
issue=30
pages=4888–91
year=2006
month=August
pmid=16937475
doi=
url=http://www.wjgnet.com/1007-9327/12/4888.asp
accessdate=2008-09-02
] 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.cite journal
author=Malfertheiner P, Megraud F, O'Morain C, "et al"
title=Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report
journal=Gut
volume=56
issue=6
pages=772–81
year=2007
month=June
pmid=17170018
doi=10.1136/gut.2006.101634
url=
] 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.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
month=May
pmid=1971318
doi=
url=
] 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
month=August
pmid=1854110
doi=
url=
]

An increasing number of infected individuals are found to harbour 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. [cite journal
author=Stenström B, Mendis A, Marshall B
title=Helicobacter pylori - The latest in diagnosis and treatment
journal=Aust Fam Physician
volume=37
issue=8
pages=608–12
year=2008
month=August
pmid=18704207
doi=
url=
] [cite journal
author=Fischbach L, Evans EL
title=Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori
journal=Aliment. Pharmacol. Ther.
volume=26
issue=3
pages=343–57
year=2007
month=August
pmid=17635369
doi=10.1111/j.1365-2036.2007.03386.x
url=
] [cite journal
author=Graham DY, Shiotani A
title=New concepts of resistance in the treatment of Helicobacter pylori infections
journal=Nat Clin Pract Gastroenterol Hepatol
volume=5
issue=6
pages=321–31
year=2008
month=June
pmid=18446147
doi=10.1038/ncpgasthep1138
url=
] For the treatment of clarithromycin-resistant strains of "H. pylori" the use of levofloxacin as part of the therapy has been suggested. [cite journal
author=Perna F, Zullo A, Ricci C, Hassan C, Morini S, Vaira D
title=Levofloxacin-based triple therapy for Helicobacter pylori re-treatment: role of bacterial resistance
journal=Dig Liver Dis
volume=39
issue=11
pages=1001–5
year=2007
month=November
pmid=17889627
doi=10.1016/j.dld.2007.06.016
url=
] [cite journal
author=Hsu PI, Wu DC, Chen A, "et al"
title=Quadruple rescue therapy for Helicobacter pylori infection after two treatment failures
journal=Eur. J. Clin. Invest.
volume=38
issue=6
pages=404–9
year=2008
month=June
pmid=18435764
doi=10.1111/j.1365-2362.2008.01951.x
url=
]

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" will never experience clinical symptoms despite having chronic gastritis. Approximately 10-20% of those colonized by "H. pylori" will ultimately develop gastric and duodenal ulcers.cite journal
author=Kusters JG, van Vliet AH, Kuipers EJ
title=Pathogenesis of Helicobacter pylori infection
journal=Clin. Microbiol. Rev.
volume=19
issue=3
pages=449–90
year=2006
month=July
pmid=16847081
pmc=1539101
doi=10.1128/CMR.00054-05
url=
] "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.

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.cite journal
author=Goodman KJ, O'rourke K, Day RS, "et al"
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
month=December
pmid=16076858
doi=10.1093/ije/dyi152
url=
] cite journal
author=Goodman KJ, 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
month=March
pmid=11246592
doi=
url=
]

While "H. pylori" has been disappearing from the stomach of humans, the incidence of the related disorders acid reflux disease, Barrett's esophagus, and esophageal cancer have been rising dramatically. In 1996, Martin J. Blaser advanced the hypothesis that "H. pylori" has a beneficial effect: by regulating the acidity of the stomach contents, it lowers the impact of regurgitation of gastric acid into the esophagus. [cite journal
author=Blaser MJ, Atherton JC
title="Helicobacter pylori" persistence: biology and disease
journal=J. Clin. Invest.
volume=113
issue=3
pages=321–33
year=2004
month=February
pmid=14755326
pmc=324548
doi=10.1172/JCI20925
url=
] 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".cite journal
author=Graham DY, Yamaoka Y, Malaty HM
title=Contemplating the future without "Helicobacter pylori" and the dire consequences hypothesis
journal=Helicobacter
volume=12 Suppl 2
issue=
pages=64–8
year=2007
month=November
pmid=17991179
doi=10.1111/j.1523-5378.2007.00566.x
url=
] cite journal
author=Delaney B, McColl K
title=Review article: "Helicobacter pylori" and gastro-oesophageal reflux disease
journal=Aliment. Pharmacol. Ther.
volume=22 Suppl 1
issue=
pages=32–40
year=2005
month=August
pmid=16042657
doi=10.1111/j.1365-2036.2005.02607.x
url=
] Nevertheless, Blaser has refined his view to assert that "H. pylori" is a member of the normal flora of the stomach.cite journal
author=Blaser MJ
title=Who are we? Indigenous microbes and the ecology of human diseases
journal=EMBO reports
volume=7
issue=10
pages=956–60
year=2006
month=October
pmid=17016449
pmc=1618379
doi=10.1038/sj.embor.7400812
url=
] 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.cite journal
author=Blaser MJ, Chen Y, Reibman J
title=Does Helicobacter pylori protect against asthma and allergy?
journal=Gut
volume=57
issue=5
pages=561–7
year=2008
month=May
pmid=18194986
doi=10.1136/gut.2007.133462
url=
] His group has recently shown that "H. pylori" colonization is associated with a lower incidence of childhood asthma. [cite journal
author=Chen Y, Blaser MJ
title="Helicobacter pylori" colonization is inversely associated with childhood asthma
journal=J. Infect. Dis.
volume=198
issue=4
pages=553–60
year=2008
month=August
pmid=18598192
doi=10.1086/590158
url=
]

Epidemiology

At least half the world's population are infected by the bacterium, making it the most widespread infection in the world.cite journal
author=Pounder RE, Ng D
title=The prevalence of "Helicobacter pylori" infection in different countries
journal=Aliment. Pharmacol. Ther.
volume=9 Suppl 2
issue=
pages=33–9
year=1995
pmid=8547526
doi=
url=
] Actual infection rates vary from nation to nation; the Third World has much higher infection rates than the West (Western Europe, North America, Australasia), where rates are estimated to be around 25%. Infections are usually acquired in early childhood in all countries. However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions. 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. The higher prevalence among the elderly reflects higher infection rates when they were children rather than infection at later ages. Prevalence appears to be higher in African-American and Hispanic populations, although this is likely related to socioeconomic rather than racial factors. [cite journal
author=Smoak BL, Kelley PW, Taylor DN
title=Seroprevalence of "Helicobacter pylori" infections in a cohort of US Army recruits
journal=Am. J. Epidemiol.
volume=139
issue=5
pages=513–9
year=1994
month=March
pmid=8154475
doi=
url=
] [cite journal
author=Everhart JE, Kruszon-Moran D, Perez-Perez GI, Tralka TS, McQuillan G
title=Seroprevalence and ethnic differences in "Helicobacter pylori" infection among adults in the United States
journal=J. Infect. Dis.
volume=181
issue=4
pages=1359–63
year=2000
month=April
pmid=10762567
doi=
url=
] 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.cite journal
author=Malaty HM
title=Epidemiology of "Helicobacter pylori" infection
journal=Best Pract Res Clin Gastroenterol
volume=21
issue=2
pages=205–14
year=2007
pmid=17382273
doi=10.1016/j.bpg.2006.10.005
url=
] However, antibiotic resistance is appearing in "H. pylori"; there are already many metronidazole- and clarithromycin-resistant strains in most parts of the world. [cite journal
author=Mégraud F
title="H pylori" antibiotic resistance: prevalence, importance, and advances in testing
journal=Gut
volume=53
issue=9
pages=1374–84
year=2004
month=September
pmid=15306603
pmc=1774187
doi=10.1136/gut.2003.022111
url=
]

"H. pylori" is contagious, although the exact route of transmission is not known.cite journal
author=Mégraud F
title=Transmission of "Helicobacter pylori": faecal-oral versus oral-oral route
journal=Aliment. Pharmacol. Ther.
volume=9 Suppl 2
issue=
pages=85–91
year=1995
pmid=8547533
doi=
url=
] [cite journal
author=Cave DR
title=Transmission and epidemiology of "Helicobacter pylori"
journal=Am. J. Med.
volume=100
issue=5A
pages=12S–17S; discussion 17S–18S
year=1996
month=May
pmid=8644777
doi=
url=
] 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. Transmission occurs mainly within families in developed nations yet can also be acquired from the community in developing countries.cite journal
author=Delport W, van der Merwe SW
title=The transmission of "Helicobacter pylori": the effects of analysis method and study population on inference
journal=Best Pract Res Clin Gastroenterol
volume=21
issue=2
pages=215–36
year=2007
pmid=17382274
doi=10.1016/j.bpg.2006.10.001
url=
] "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.

History

German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture it and the results were eventually forgotten.cite journal
author=Blaser MJ
title=An endangered species in the stomach
journal=Sci. Am.
volume=292
issue=2
pages=38–45
year=2005
month=February
pmid=15715390
] The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893. [cite journal
author=Bizzozero G
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
] Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called "Vibrio rugula". He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. This work was included in the "Handbook of Gastric Diseases", but it had little impact as it was written in Polish. [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.
volume=54 Suppl 3
pages=23–41
year=2003
month=December
pmid=15075463
url=http://www.jpp.krakow.pl/journal/archive/1203_s3/pdf/23_1203_s3_article.pdf
accessdate=2008-08-25
format=PDF
] Several small studies conducted in the early 1900s demonstrated the presence of curved rods in the stomach of many patients with peptic ulcers and stomach cancer.cite journal
author=Egan BJ, O'Morain CA
title=A historical perspective of "Helicobacter" gastroduodenitis and its complications
journal=Best Pract Res Clin Gastroenterol
volume=21
issue=2
pages=335–46
year=2007
pmid=17382281
doi=10.1016/j.bpg.2006.12.002
url=
] However interest in the bacteria waned when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.cite journal
author=Palmer ED
title=Investigation of the gastric mucosa spirochetes of the human
journal=Gastroenterology
volume=27
issue=2
pages=218–20
year=1954
month=August
pmid=13183283
doi=
url=
]

Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s with the visualization of bacteria in the stomach of gastric ulcer patients.cite journal
author=Steer HW
title=Ultrastructure of cell migration throught the gastric epithelium and its relationship to bacteria
journal=J. Clin. Pathol.
volume=28
issue=8
pages=639–46
year=1975
month=August
pmid=1184762
pmc=475793
doi=
url=http://jcp.bmj.com/cgi/pmidlookup?view=long&pmid=1184762
] The bacterium had also been observed in 1979 by Australian pathologist Robin Warren, who did further research on it with Australian physician Barry Marshall beginning in 1981. After numerous 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 5 days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by infection by this bacterium and not by stress or spicy food as had been assumed before. [cite journal
author=Marshall BJ, Warren JR
title=Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration
journal=Lancet
volume=1
issue=8390
pages=1311–5
year=1984
month=June
pmid=6145023
]

Although there was some skepticism initially, within several years, numerous research groups verified the association of "H. pylori" with gastritis and to a lesser extent ulcers. [cite web
url=http://www.csicop.org/si/2004-11/bacteria.html
title=Bacteria, Ulcers, and Ostracism? "H. pylori" and the making of a myth
year=2004
author=Atwood IV KC
accessdate=2008-08-02
] To demonstrate that "H. pylori" caused gastritis and was not merely a bystander, Marshall drank a beaker of "H. pylori". He became ill several days later with nausea and vomiting. An endoscopy ten days after inoculation revealed signs of gastritis and the presence of "H. pylori". These results proved that "H. pylori" was the causative agent of gastritis. Marshall and Warren went on to show that 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.cite journal
author=Borody TJ, Cole P, Noonan S, "et al"
title=Recurrence of duodenal ulcer and "Campylobacter pylori" infection after eradication
journal=Med. J. Aust.
volume=151
issue=8
pages=431–5
year=1989
month=October
pmid=2687668
doi=
url=
] In 1994, the National Institutes of Health (USA) published an opinion stating that most recurrent duodenal and gastric ulcers were caused by "H. pylori" and recommended that antibiotics be included in the treatment regimen. [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
] Warren and Marshall were awarded the Nobel Prize in Medicine in 2005 for their work on "H. pylori". [cite web
url=http://nobelprize.org/medicine/laureates/2005/index.html
title=The Nobel Prize in Physiology or Medicine 2005
accessdate=2008-08-02
]

Recent research states that genetic diversity in "H. pylori" decreases with geographic distance from East Africa, the birthplace of modern humans. Using the genetic diversity data, the researchers have created simulations that indicate the bacteria seems 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, remaining associated with human hosts since that time. [cite journal
author=Linz B, Balloux F, Moodley Y, "et al"
title=An African origin for the intimate association between humans and "Helicobacter pylori"
journal=Nature
volume=445
issue=7130
pages=915–8
year=2007
month=February
pmid=17287725
pmc=1847463
doi=10.1038/nature05562
]

References

External links

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