Helicobacter pylori

From Academic Kids

Helicobacter pylori
Helicobacter pylori
Scientific classification
Kingdom:Bacteria
Phylum:Proteobacteria
Class:Epsilon Proteobacteria
Order:Campylobacterales
Family:Helicobacteraceae
Genus:Helicobacter
Species:H. pylori
Binomial name
Helicobacter pylori

Helicobacter pylori is a bacterium that infects the mucus lining of the human stomach. Many peptic ulcers and some types of gastritis are caused by H. pylori infection, although most humans who are infected will never develop symptoms. This bacterium lives in the human stomach exclusively and is the only known organism that can thrive in that highly acidic environment. It is helix-shaped (hence the name helicobacter) and can literally screw itself into the stomach lining to colonize.

Contents

History

In 1875, German scientists found spiral bacteria in the lining of the human stomach; the bacteria couldn't be grown in culture and the results were eventually forgotten.

The bacterium was rediscovered in 1982 by two Australian scientists Robin Warren and Barry Marshall, who isolated and cultured organisms from mucosal specimens from human stomachs. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by colonization with this bacterium, not by stress or spicy food as had been assumed before.

Some maintain that the medical community was slow to recognize the role of this bacterium in stomach ulcers and gastritis, believing that no bacterium could survive for long in the acidic environment of the stomach. After further studies were done, including one study in which Marshall drank a test tube of H. pylori, developed gastritis, and treated himself with antibiotics (thereby satisfying three out of the four Koch's postulates) the medical community began to come around. In 1994, the National Institutes of Health published an opinion stating that most recurrent gastric ulcers were caused by H. pylori, and recommended that antibiotics be included in the treatment regimen.

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

The bacterium was initially called Campylobacter pyloridis, then C. pylori (after a correction to the Latin grammar) and finally, after DNA sequencing showed that the bacterium didn't belong in the Campylobacter genus, it was placed in its own genus Helicobacter. The name pylori comes from the Latin word pylorus, which means gatekeeper, and refers to the circular opening leading from the stomach into the duodenum.

While H. pylori remains the only known species to inhabit the human stomach, some other species of the Helicobacter genus have now been identified in other mammals and some birds.

Structure of the bacterium

H. pylori is a spiral-shaped gram-negative bacterium , about 3 micrometres long with a diameter of about 0.5 micrometre. It has 4-6 flagella [1] (http://www.pathologyatlas.ro/Helicobacter%20pylori.html). It is microaerophilic, i.e. it requires oxygen but at lower levels than those contained in the atmosphere. It uses hydrogen methanogenesis as an energy source.

Under conditions of environmental stress, Helicobacter will convert from a spiral to a coccoid form. This coccoidal form of the organism has not been cultured, but has been found in the water supply in the US and is thought to be involved in the epidemiology of the bacterium. The coccoidal form has also been found to be able to adhere to gastric epithelial cells in vitro.

Missing image
Helicobacter_Pylori_Urease.png
Molecular model of H. pylori urease enzyme

With its flagella and its spiral shape, the bacterium drills through the mucus layer of the stomach, attaches to epithelial cells, and then can either be found suspended in the gastric mucosa or attached to one of the limited epithelial attachment sites. It excretes the enzyme urease, which converts urea into ammonia and bicarbonate. The release of ammonia is beneficial to the bacterium since it partially neutralizes the very acidic environment of the stomach (whose very purpose is to kill bacteria). Ammonia is, however, toxic to the epithelial cells, and with other products of H. pylori, including protease, catalase, and phospholipases, causes damage to surface epithelial cells.

A recent finding is that some strains of the bacteria have a particular mechanism for "injecting" the inflammatory agent peptidoglycan into the stomach cells.

Infection and diagnosis

Infection may be symptomatic or asymptomatic (without visible ill effects). It is estimated that up to 70% of infection is asymptomatic.

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

It is estimated that about 2/3 of the world population are infected by the bacterium. Actual infection rates vary from nation to nation - the West (Western Europe, North America, Australasia) having rates around 25% and the Third World much higher. In the latter it is common, probably due to poor sanitary conditions, to find infections in children. In the United States, infection is primarily in the older generations (about 50% for those over the age of 60 compared with 20% under 40 years) and the poorest. This is largely attributed to higher hygiene standards and more widespread use of antibiotics. However antibiotic resistance is appearing in H. pylori. There are already metronidazole resistant strains present in the UK population.

In the absence of antibiotic based treatments, H. pylori infection apparently persists for life; the human immune system is not able to eradicate it.

One can test for H. pylori infection with blood antibody or stool antigen tests, or with the carbon urea breath test (in which the patient drinks 14C or 13C labelled urea, which the bacterium metabolizes producing labelled carbon dioxide that can be detected in the breath), or endoscopy to provide a biopsy sample for testing for the presence of urease ('rapid urease test'), histology or microbial culture.

Treatment

Eradication therapy

In gastric ulcer patients where H. pylori is detected, normal procedure is eradication to allow the ulcer to heal. The standard first-line therapy is a one week triple-therapy of amoxicillin, clarithromycin and omeprazole – though sometimes a different proton pump inhibitor is substituted, or metronidazole is used in place of amoxicillin in those allergic to penicillin. Such a therapy has revolutionised the treatment of gastric ulcers and has made a cure to the disease possible, where previously symptom-control using antacids, H2-antagonists or proton pump inhibitors alone was the only option. Unfortunately, an increasing number of infected individuals are found to harbour bacteria resistant to first-line antibiotics. This results in initial treatment failure and requires additional rounds of antibiotic therapy. For resistant cases, a quadruple therapy may be used. Bismuth compounds are also effective in combination with the above drugs.

Gastric cancer connection

Gastric cancer (rare) and gastric lymphoma (MALT lymphoma) have been associated with H. pylori, and the bacterium has been categorized as a group I carcinogen by the International Agency for Research on Cancer (IARC). While the association is reasonably strong, it is not entirely clear that there is a causal relationship involved.

Two related mechanisms by which H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cell mutation. The other proposed mechanism has been called a "perigenetic pathway" (Tsuji et al 2003) 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.

Acid reflux and esophageal cancer

The infection rate with H. pylori has been decreasing in developing countries, presumably because of improved hygiene and increased antibiotics use. Accordingly, the incidence of gastric cancer in the U.S. has fallen by 80 percent from 1900 to 2000. However, gastroesophageal reflux disease (GORD or GERD depending on the use of British or American English, respectively) and cancer of the esophagus (BE: oesophagus have increased dramatically during the same period. In 1996, Martin Blaser put forward the theory that H. pylori might also have a beneficial effect: by regulating the acidity of the stomach contents, it lowers the impact of regurgitation of stomach acids into the esophagus. While some favorable evidence has been accumulated, as of 2005 the theory is not universally accepted.

Genome studies of different strains

Several strains are known, and the genomes of two have been completely sequenced. The Pylori Gene (http://genolist.pasteur.fr/PyloriGene/) website allows easy access to genome information for the H. pylori 26695 and H. pylori J99 strains. The genome consists of 1.7 million base pairs, with some 1550 genes. The two sequenced strains show large genetic differences; with up to 6% of the nucleotides differing.

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

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

Each human population has a characteristic distribution of H. pylori strains that typically infect members of that population. This allows researchers to use H. pylori to study human migration patterns. It could be established that H. pylori in Amazon Indians has East Asian rather than European origins, suggesting that it arrived with the original immigrants at least 11,000 years ago.

References

  • Marshall BJ. Unidentified curved bacillus on gastric epithelium in active chronic gastritis. Lancet 1983;1((8336):1273-1275. PMID 6134060.
  • Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach patients with gastritis and peptic ulceration. Lancet 1984;1(8390):1311-1315. PMID 6145023.
  • Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement Online 1994 Jan 7-9.12(1):1-23. Cited 2004 Dec 21. Fulltext (http://consensus.nih.gov/cons/094/094_statement.htm).
  • Helicobacter pylori and peptic ulcer. Centers for Disease Control and Prevention. Cited 2004 Dec 21. Fulltext (http://www.cdc.gov/ulcer/).
  • Blaser MJ. An Endangered Species in the Stomach. Scientific American 2005;292(2):38-45. partial text (http://www.sciam.com/article.cfm?articleID=00024948-2764-11E8-A28583414B7F0000&ref=sciam&chanID=sa006). PMID 15715390.
  • Logan RPH, Walker MM. Clinical review: ABC of the upper gastrointestinal tract. Epidemiology and diagnosis of Helicobacter pylori infection. BMJ 2001;323:920-922. Full text (http://bmj.bmjjournals.com/cgi/content/full/323/7318/920). PMID 11668141.
  • Tsuji S, Kawai N, Tsujii M, Kawano S, Hori M. Review article: inflammation-related promotion of gastrointestinal carcinogenesis - a perigenetic pathway. Aliment Pharmacol Ther 2003;18(Suppl 1):82-9. PMID 12925144.
  • Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunol 2004;5:1166-74. Fulltext (http://dx.doi.org/10.1038/ni1131). PMID 15489856.

External links

  • The Helicobacter Foundation (http://www.helico.com/) provides information on Helicobacter pylori and its effects - founded by Dr. Barry J. Marshall, one of the discoverers of H. Pylori
  • European Helicobacter Study Group (http://www.helicobacter.org/) sponsors annual international workshop, yearbook, and clinical guidelines
  • Atwood KC. Bacteria, Ulcers, and Ostracism?: H. Pylori and the Making of a Myth. Skeptical Inquirer November 2004. Fulltext (http://www.csicop.org/si/2004-11/bacteria.html) Claims that medicines 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".
  • Pylori Gene (http://genolist.pasteur.fr/PyloriGene/), giving the genome sequences of various strains
  • Microscopic image of Helicobacter pylori (http://www.pathologyatlas.ro/Helicobacter%20pylori.html)be:Helicobacter pylori

da:Helicobacter pylori de:Helicobacter pylori es:Helicobacter pylori fr:Helicobacter pylori nl:Helicobacter pylori zh:幽門螺旋桿菌

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