Helicobacter pylori
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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 are infected and will never develop symptoms. The bacterium is helix shaped (hence the name helicobacter) and can literally screw itself into the stomach lining to colonize it.
History
The bacterium was first described in 1982 by two Australian scientists Robin Warren and Barry Marshall, who isolated and cultured organisms from human mucosal specimens. 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 (meaning gatekeeper), and refers to the circular opening leading from the stomach into the duodenum. In their 1982 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 the medical community had long assumed.
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. Finally, after further studies were done, including one study in which Marshall drank a test tube of H. pylori, developed ulcers, and treated himself with antibiotics (thereby satsifying three out of the four Koch's postulates for disease) 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.
Today, many stomach ulcers are treated with antibiotics effective against H. pylori. 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 bacteria, about 3 micrometers long with a diameter of about 0.5 micrometers. It has 4-6 flagella. It is microaerophilic, i.e. it requires oxygen but at lower levels than those contained in the atmosphere.
With its flagella and its spiral shape, the bacterium drills through the mucus layer of the stomach and attaches to epithelial cells. It contains the enzyme urease which converts urea into ammonia and bicarbonate. The ammonia is useful 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. A molecular model of the H. pylori urease enzyme is shown to the right.
Infection and diagnosis
About 2/3 of the world population is infected by the bacterium. Under poor sanitary conditions, one commonly finds infected children; in the U.S., older people (about 50% of those over the age of 60, 20% of those under the age of 40), and poor people are more likely to be infected. The infection apparently persists for life; the immune system cannot fend off the organism. The bacteria have been isolated from feces, saliva and dental plaque of infected patients, which suggests possible transmission routes. One can test for H. pylori infection with blood antibody tests, breath tests (where the patient drinks 14C or 13C labeled urea, which the bacterium metabolizes to carbon dioxide that can be detected in the breath), or endoscopy.
Eradication therapy
In gastric ulcer patients where H. pylori is present, the fist-line therapy is the eradication of the organism causing the ulcer. 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 hypersensitive 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 or H2-antagonists was the only option.
Gastric cancer connection
Gastric cancer (rare) has 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).
Two related mechanisms by which H. pylori can 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" [1] 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 in inflammation and locally high levels of TNF-alpha. 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.
Genome studies of different strains
Several strains are known, and the genomes of two have been completely sequenced. The Pylori Gene website allows easy access to genome information for the H. pylori 26695 and H. pylori J99 strains. There are 62 genes in the "pathogenesis" category of this database. Both of these 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.
Study of the H. pylori genome is centered on attempts to understand the ability of this organism to cause disease. 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 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.