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Helicobacter pylori
Scientific classification
Kingdom: Bacteria Phylum: Proteobacteria Class: Epsilon Proteobacteria Order: Campylobacterales Family: Helicobacteraceae Genus: Helicobacter Species: H. pylori
Binomial name
Helicobacter pylori ICD-9 code: 041.86

Helicobacter pylori (pronounced /ˌhɛlɪkəˈbæktɚ paɪˈlɔəraɪ/) 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 peptic ulcers and stomach cancer. However, most who are infected do not show any symptoms of disease.

More people are infected with H. pylori than any other species of bacteria; 50% or more of the world's population harbour it. It is more prevalent in developing countries. The route of transmission is unknown, although people become infected in childhood. H. pylori's helix shape (from which the generic name is derived) is thought to have evolved to penetrate and favor its motility in the mucus gel layer.^[1][2]

Etymology

The bacterium was initially named Campylobacter pyloridis, then C. pylori (after a correction to the Latin grammar). In 1989, after DNA sequencing and other data showed that the bacterium did not belong in the genus Campylobacter, it was placed in its own genus, Helicobacter. The generic name derived from the Ancient Greek hělix/έλιξ "spiral" or "coil".^[3] 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.^[3]

History

See also: Timeline of peptic ulcer disease and Helicobacter pylori

German scientists found helix-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture it and the results were eventually forgotten.^[4] The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893.^[5] 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 helix 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.^[6]

The bacterium was rediscovered in 1979 by Australian pathologist Robin Warren, who did further research on it with Australian physician Barry Marshall beginning in 1981; they isolated the organisms from mucosal material from human stomachs and were the first to successfully culture them. 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.^[7]

The medical community was slow to recognize the role of this bacterium in stomach ulcers and gastritis, believing that no microorganism could survive for long in the acidic environment of the stomach.^[8] 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 of 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 the antibacterial agent 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.^[9] Evidence has been accumulating to suggest that duodenal ulcers are also associated with H. pylori infection.^[10][11] Warren and Marshall were awarded the Nobel Prize in Medicine in 2005 for their work on H. pylori.^[12]

While H. pylori remains the most medically important bacterial inhabitant of the human stomach, other species of the genus Helicobacter have been identified in other mammals and some birds, and some of these can infect humans.^[13] Helicobacter species have also been found to infect the livers of certain mammals and to cause liver disease.^[14]

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.^[15]

Microbiology

H. pylori colonized on the surface of regenerative epithelium (image from Warthin-Starry's silver stain)

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.^[16] It tests positive for oxidase, catalase, and urease. It is capable of forming biofilms^[17] and conversion from helical to coccoid form,^[18] both likely to favor its survival and be factors in the epidemiology of the bacterium. The coccoid form has been found to be able to adhere to gastric epithelial cells in vitro. ^[19] This form of the organism has not been cultured, but has been found in the water supply in the US. ^[2]

H. pylori possesses five major outer membrane protein (OMP) families.^[20] 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.^[20] The outer membrane also contains cholesterol glucosides, which is found in few other bacteria.^[20] The characteristic sheathed flagellar filaments of helicobacters are composed of two copolymerized flagellins, FlaA and FlaB. Flagellar motility is essential for Helicobacter species to colonize the gastric mucus.^[21]

Genome

EM photograph of H. pylori

Several strains are known, and the genomes of two have been completely sequenced.^[22][23] The genome of the strain "26695" consists of about 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.^{citation needed}

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.^{citation needed}

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.^{citation needed} 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.^[22]

Pathogenesis

Molecular model of H. pylori urease enzyme

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. However most infected people will never experience clinical symptoms despite having chronic gastritis. 10-20% of those colonized by H. pylori will ultimately develop peptic ulcers.^[20] 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.^[20]

H. pylori weakens the protective mucous coating of the stomach and duodenum by damaging the epithelial cells, allowing acid to damage and inflame the sensitive tissue beneath. Its helical shape allows the bacterium to move through the mucous lining easily. 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. Known areas include the inside of the mucus gel layer (with a preference for the superficial area); above epithelial cells; and inside vacuoles formed by H. pylori within epithelial cells. It produces adhesins which bind to membrane-associated lipids and carbohydrates and help it adhere to epithelial cells. An example of this is the Lewis b antigen. It produces large amounts of urease enzymes 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 the enzyme. 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 phospholipases—damages those cells.^{citation needed}

Some strains of the bacterium have a particular mechanism for "injecting" the inflammatory inducing agents peptidoglycan from their own cell wall into epithelial stomach cells. This factor may play a role in allowing certain strains to invade host tissue.^[24]

The CagA protein is transported into human cells where it may disrupt the normal functioning of the cytoskeleton. 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.

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"^[25] 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.^{citation needed}

Statistically, an inverse relationship between H. pylori and both Barrett esophagus and esophageal adenocarcinoma (but not squamous cell carcinoma) has been shown.^[26] While some favorable evidence has been accumulated, the theory is not universally accepted.^[27]

Diagnosis

Diagnosis of infection is usually made by checking for dyspeptic symptoms and then doing 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). 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.^[28]

Immunohistochemical staining of H. pylori from a gastric biopsy.

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.^[29] The Sydney gastroenterologist Thomas Borody invented the first triple therapy in 1987.^[30] 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.^[31] 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.^[32][33]

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. 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.^{citation needed}

It is widely believed that in the absence of treatment, H. pylori infection—once established in its gastric niche—persists for life.^[2] 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.^[34][35]

Epidemiology

At least half the world's population are infected by the bacterium, making it the most widespread infection in the world.^[36] 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%.^[36] Infections are usually acquired in early childhood in all countries.^[20] However the infection rate of children in developing nations is higher than in industrialized nations probably due to poor sanitary conditions children. 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.^[36] The higher prevalence among the elderly reflects higher infection rates when they were children rather than infection at later ages.^[20] Prevalence appears to be higher in African American and Hispanic populations, although this is likely related to socioeconomic rather than racial factors.^[37][38] 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.^[39] However, antibiotic resistance is appearing in H. pylori; there are already many metronidazole resistant strains in Europe, the United States, and developing countries.^[40]

H. pylori is contagious, although the exact route of transmission is not known.^{[41] [42]} Transmission occurs mainly within families in developed nations yet can also be acquired from the community in developing countries.^[43] Many researchers think that it is transmitted orally by means of fecal matter through the ingestion of waste tainted food or water, so a hygienic environment could help decrease the risk of H. pylori infection. The bacteria have been isolated from feces,^[41] saliva and dental plaque of infected patients, which suggests oral-oral or fecal-oral as possible transmission routes. There is experimental evidence, however, to show that Heliobacter species are not, in fact transmitted via the fecal-oral route, but rather through oral-oral contact.^[2]

Prognosis

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.^[4][44] While some favorable evidence has been accumulated, as of 2005 the theory is not universally accepted.^{citation needed}

References

External links

Wikispecies has information related to:

Helicobacter pylori

Wikimedia Commons has media related to:

Helicobacter pylori

• "The Helicobacter Foundation". Retrieved on 2008-08-02.
• "European Helicobacter Study Group". Retrieved on 2008-08-02.