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More than 50% of the world's population harbor ''H. pylori'' in their upper [[gastrointestinal tract]]. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries. Anal sex seems to have a beneficial effect in preventing infection, so ladies...you know what you must do. ''H. pylori'''s helix shape (from which the [[genus|generic]] name is derived) is thought to have evolved to penetrate the [[mucus|mucoid]] lining of the stomach.<ref name= YamaokaY>{{cite book
More than 50% of the world's population harbor ''H. pylori'' in their upper [[gastrointestinal tract]]. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries. ''H. pylori'''s helix shape (from which the [[genus|generic]] name is derived) is thought to have evolved to penetrate the [[mucus|mucoid]] lining of the stomach.<ref name= YamaokaY>{{cite book
|author=Yamaoka, Yoshio
|author=Yamaoka, Yoshio
|title=Helicobacter pylori: Molecular Genetics and Cellular Biology
|title=Helicobacter pylori: Molecular Genetics and Cellular Biology

Revision as of 12:32, 6 March 2012

Helicobacter pylori

Helicobacter pylori (/ˌhɛlɨkɵˈbæktər paɪˈlɔraɪ/; H. pylori), previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were not previously believed to have a microbial cause. It is also linked to the development of duodenal ulcers and stomach cancer. However, over 80 percent of individuals infected with the bacterium are asymptomatic and it has been postulated that it may play an important role in the natural stomach ecology.[1]

More than 50% of the world's population harbor H. pylori in their upper gastrointestinal tract. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries. 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.[2][3]

Signs and symptoms

Over 80% of people infected with H. pylori show no symptoms.[4] Acute infection may appear as an acute gastritis with abdominal pain (stomach ache) or nausea.[5] Where this develops into chronic gastritis, the symptoms, if present, are often those of non-ulcer dyspepsia: stomach pains, nausea, bloating, belching and sometimes vomiting.[6][7]

Individuals infected with H. pylori have a 10 to 20% lifetime risk of developing peptic ulcers and a 1 to 2% risk of acquiring stomach cancer.[8] Inflammation of the pyloric antrum is more likely to lead to duodenal ulcers, while inflammation of the corpus (body of the stomach) is more likely to lead to gastric ulcers and gastric carcinoma.[9]

Microbiology

Helicobacter pylori
Scientific classification
Domain:
Bacteria
Phylum:
Proteobacteria
Class:
Epsilonproteobacteria
Order:
Campylobacterales
Family:
Helicobacteraceae
Genus:
Helicobacter
Species:
H. pylori
Binomial name
Helicobacter pylori
(Marshall et al. 1985) Goodwin et al., 1989
Scanning electron micrograph of H. pylori

H. pylori is a helix-shaped (classified as a curved rod, not spirochaete), Gram-negative bacterium, about 3 micrometres long with a diameter of about 0.5 micrometres. It is microaerophilic; that is, it requires oxygen. It contains a hydrogenase which can be used to obtain energy by oxidizing molecular hydrogen (H2) produced by intestinal bacteria.[10] It produces oxidase, catalase, and urease. It is capable of forming biofilms[11] and can convert from spiral to a possibly viable but nonculturable coccoid form,[12] both likely to favor its survival and be factors in the epidemiology of the bacterium.

H. pylori possesses five major outer membrane protein (OMP) families.[13] 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.[13] The outer membrane also contains cholesterol glucosides, which are found in few other bacteria.[13] H. pylori has four to six lophotrichous flagella; all gastric and enterohepatic Helicobacter species are highly motile due to flagella.[14] The characteristic sheathed flagellar filaments of Helicobacter are composed of two copolymerized flagellins, FlaA and FlaB.[15]

Genome

H. pylori consists of a large diversity of strains, and the genomes of three have been completely sequenced.[16][17][18][19][20] 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.[18]

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. Two of 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.[21]

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.[22] 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 the island was acquired by horizontal transfer from another bacterial species.[16]

Pathophysiology

Molecular model of H. pylori urease enzyme

To colonize the stomach, H. pylori must survive the acidic pH of the lumen and use its flagella to burrow into the mucus to reach its niche, close to the stomach's epithelial cell layer.[23] Many bacteria can be found deep in the mucus, which is continuously secreted by mucus-secreting 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.[24] H. pylori is also found on the inner surface of the stomach epithelial cells and occasionally inside epithelial cells.[25] 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.[26] 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. The ammonia is converted to ammonium by accepting a proton (H+), which neutralizes gastric acid. The survival of H. pylori in the acidic stomach is dependent on urease. The ammonia produced is toxic to the epithelial cells, and, along with the other products of H. pylori—including proteases, vacuolating cytotoxin A (VacA), and certain phospholipases—, damages those cells.[27]

Inflammatory processes of H. pylori infections are also mediated by highly disulfide-bridged proteins. Helicobacter cysteine-rich proteins (Hcp), particularly HcpA (hp0211), triggers an immune response through the differentiation of human myeloid Thp1 monocytes into macrophages. In analogy to eucaryotic cytokines, they interfer with host cell functions and change the morphology of monocytes, inducing the expression of the surface marker protein CD11b, phagocytic activity, as well as cell adherence, which are indicative of monocyte differentiation into macrophages.[28]

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.[29] 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.[30] 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.[13] 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.[31] 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.[32] 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 the mechanisms that protect the gastric mucosa are defective.[32] 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.[33]

About 50-70% of H. pylori strains in Western countries carry the cag pathogenicity island (cag PAI).[34] 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.[13] Following attachment of H. pylori to stomach epithelial cells, the type IV secretion system expressed by the cag PAI "injects" the inflammation-inducing agent, peptidoglycan, from their own cell wall into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic pattern recognition receptor (immune sensor) Nod1, which then stimulates expression of cytokines that promote inflammation.[35]

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, cell polarity, and other cellular activities.[36] Once inside the cell, the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase (TK). CagA then allosterically activates protein tyrosine phosphatase/protooncogene Shp2.[37] 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.[21][22] There is a great deal of diversity between strains of H. pylori, and the strain with which one is infected is predictive of the outcome.

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",[38] and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as adhesion proteins. H. pylori has been proposed to induce inflammation and locally high levels of TNF-α and/or interleukin 6 (IL-6). According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF-α, 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.[39]

Diagnosis

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

Colonization with H. pylori is not a disease in and of itself but a condition associated with a number of disorders of the upper gastrointestinal tract.[13] Testing for H. pylori is recommended if there is peptic ulcer disease, low grade gastric MALT lymphoma, after endoscopic resection of early gastric cancer, if there are first degree relatives with gastric cancer, and in certain cases of dyspepsia,[40] not routinely.[13] Several ways of testing exist. 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).[40] 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. There is also a urine ELISA test with a 96% sensitivity and 79% specificity. None of the test methods are 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.[41]

Prevention

H. pylori is a major cause of certain diseases of the upper gastrointestinal tract. Rising antibiotic resistance increases the need to search for new therapeutic strategies; this might include prevention in form of vaccination.[42] Extensive vaccine studies in mouse models have shown promising results.[43] Researchers are studying different adjuvants, antigens, and routes of immunization to ascertain the most appropriate system of immune protection; however, most of the research only recently moved from animal to human trials.[44] A number of foods may be useful to prevent colonization with H. pylori including: green tea, red wine, broccoli sprouts, garlic, probiotics and flavonoids.[45]

Vaccines

Vaccines against H. pylori could be used as prophylactic vaccines to prevent the infection or as therapeutic vaccines to cure the infection, to improve the eradication success of standard regimens or to reduce the bacterial density in the gastric mucosa and the risk for emergence of antibiotic resistant strains. In recent years, many attempts, using various H. pylori antigens such as urease, CagA, HP-NAP, HspA or combinations, many adjuvants and different routes of immunisation have been made to create vaccines against H. pylori infection. Although some attempts are promising, no effective and safe vaccine against H. pylori is currently available for humans. New directions for immunisation with the use of DNA, living vectors, microspheres etc. are currently under evaluation. The vaccination plan and the groups who should receive vaccination are still to be determined, but the vaccination will be useful, especially in developing countries.[4] 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.[46]

Treatment

Further information: Helicobacter pylori eradication protocols

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 proton pump inhibitors such as omeprazole, lansoprazole and the antibiotics clarithromycin and amoxicillin.[47] 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.[48] 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.[49][50]

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, such as bismuth subsalicylate.[40][51][52] For the treatment of clarithromycin-resistant strains of H. pylori, the use of levofloxacin as part of the therapy has been suggested.[53][54]

An article in the American Journal of Clinical Nutrition found evidence that "ingesting lactic acid bacteria exerts a suppressive effect on Helicobacter pylori infection in both animals and humans," noting that "supplementing with Lactobacillus- and Bifidobacterium-containing yogurt (AB-yogurt) was shown to improve the rates of eradication of H. pylori in humans."[55]

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.[13] 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.[13]

In the absence of treatment, H. pylori infection—once established in its gastric niche—is widely believed to persist for life.[3] 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.[56][57]

The incidence of acid reflux disease, Barrett's esophagus, and esophageal cancer have been rising dramatically.[58] In 1996, Martin J. Blaser advanced the hypothesis that H. pylori has a beneficial effect: by regulating the acidity of the stomach contents.[31][58] 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.[59][60] Nevertheless, Blaser has refined his view to assert that H. pylori is a member of the normal flora of the stomach.[61] 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.[61][62] His group has recently shown that H. pylori colonization is associated with a lower incidence of childhood asthma.[63]

Epidemiology

At least half the world's population are infected by the bacterium, making it the most widespread infection in the world.[64] Actual infection rates vary from nation to nation; the developing world has much higher infection rates than the West (Western Europe, North America, Australasia), where rates are estimated to be around 25%.[64] Infections are usually acquired in early childhood in all countries.[13] 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.[64] The higher prevalence among the elderly reflects higher infection rates when they were children rather than infection at later ages.[13] Prevalence appears to be higher in African-American and Hispanic populations, most likely due to socioeconomic factors.[65][66] 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.[67] However, antibiotic resistance is appearing in H. pylori; there are already many metronidazole- and clarithromycin-resistant strains in most parts of the world.[68]

H. pylori is contagious, although the exact route of transmission is not known.[69][70] Person-to-person transmission by either the oral-oral or fecal-oral route is most likely.[3] Consistent with these transmission routes, the bacteria have been isolated from feces, saliva and dental plaque of some infected people.[3] Transmission occurs mainly within families in developed nations yet can also be acquired from the community in developing countries.[71] 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.[3]

Evolution

Helicobacter pylori migrated out of Africa along with its human host circa 60,000 years ago.[72] Its subsequent evolution created seven prototypes - Europe (isolated from Europe, the Middle East, India and Iran), NE Africa (from Northeast Africa), Africa1 (from countries in Western Africa and South Africa), Africa2 (from South Africa), Asia2 (from Northern India and among isolates from Bangladesh, Thailand and Malaysia), Sahul (from Australian Aboriginals and Papua New Guineans) and East Asia with the subpopulations E Asia (from East Asians), Maori (from Taiwanese Aboriginals, Melanesians and Polynesians) and Amerind (Native Americans). The precursors of these prototypes have been named ancestral Europe1, ancestral Europe2, ancestral East Asia, ancestral Africa1, ancestral Africa2 and ancestral Sahul. These ancestral prototypes appear to have originated in Africa, Central and East Asia. European and African strains were introduced into the Americas along with its colonisation - both thousands of years ago and more recently - and the slave trade.

History

See also: Timeline of peptic ulcer disease and Helicobacter pylori

Helicobacter pylori was first discovered in the stomachs of patients with gastritis and stomach ulcers in 1982 by Dr. Barry Marshall and Dr. Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium can live in the human stomach, as the stomach produced extensive amounts of acid of a strength similar to the acid found in a car battery. Marshall and Warren rewrote the textbooks with reference to what causes gastritis and gastric ulcers. In recognition of their discovery, they were awarded the 2005 Nobel Prize in Physiology or Medicine.[73] 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.[58] The Italian researcher Giulio Bizzozero described similarly-shaped bacteria living in the acidic environment of the stomach of dogs in 1893.[74] 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.[75] Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomach of many patients with peptic ulcers and stomach cancer.[76] Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.[77]

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.[78] 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.[79]

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.[80] To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy ten days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent of gastritis. Marshall and Warren went on to demonstrate 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.[81] In 1994, the National Institutes of Health (USA) published an opinion stating most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen.[82]

The bacterium was initially named Campylobacter pyloridis, then renamed C. pylori (pylori being the genitive of pylorus) to correct a Latin grammar error. When 16S ribosomal RNA 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".[83] 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.[83]

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 seem 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, and it has remained associated with human hosts since that time.[84]

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