Helicobacter pylori

History

See also: Timeline of peptic ulcer disease and Helicobacter pylori

In 1875, German scientists found helical shaped bacteria in the lining of the human stomach. The bacteria could not be grown in culture and the results were eventually forgotten.^[2]

In 1893, the Italian researcher Giulio Bizzozero described helical shaped bacteria living in the acidic environment of the stomach of dogs.^[3]

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 helical shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogeny of gastric diseases. This work was included in the "Handbook of Gastric Diseases" but it did not have much impact as it was written in Polish.^[4]

The bacterium was rediscovered in 1979 by Australian pathologist Robin Warren, who did further research on it with Barry Marshall beginning in 1981; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them.^[5] In their original paper,^[6] 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 antibiotics be included in the treatment regimen.^[8] Evidence has been accumulating to suggest that duodenal ulcers are also associated with H. pylori infection.^[9][10] In 2005, Warren and Marshall were awarded the Nobel Prize in Medicine for their work on H. pylori.^[11]

Before the appreciation of the bacterium's role, stomach ulcers were typically treated with medicines that neutralize 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 named Campylobacter pyloridis, then C. pylori (after a correction to the Latin grammar) and in 1989, after DNA sequencing and other data showed that the bacterium did not belong in the Campylobacter genus, it was placed in its own genus, Helicobacter. The name pylōri means "of the pylorus" or pyloric valve (the circular opening leading from the stomach into the duodenum), from the Greek word πυλωρός, which means gatekeeper.

While H. pylori remains the most medically important bacterial inhabitant of the human stomach, other species of the Helicobacter genus have been identified in other mammals and some birds, and some of these can infect humans.^[12] Helicobacter species have also been found to infect the livers of certain mammals and to cause liver disease.^[13]

Structure

H. pylori is a helical shaped Gram-negative bacterium, about 3 micrometres long with a diameter of about 0.5 micrometre. It has 4–6 flagella. It is microaerophilic, i.e. it requires biofilms^[15] and conversion from helical to coccoid form^[16], both likely to favor its survival and be factors in the epidemiology of the bacterium. The coccoid form of the organism has not been cultured, but has been found in the water supply in the US. This form has also been found to be able to adhere to gastric epithelial cells in vitro.

 

Colonization

With its flagella, the bacterium moves through the stomach lumen and drills into the mucus catalase, and phospholipases, causes damage to those cells.

Some strains of the bacteria have a particular mechanism for "injecting" the inflammatory inducing agents peptidoglycan from their own cell wall into epithelial stomach cells. (See below for "cagA pathogenicity island" in the section Genome studies of different strains) This factor may play a role in allowing certain strains to invade host tissue.^[17]

Causes of infection

H. Pylori is bacterial/viral but it is believed to be transmitted orally so it might be contagious. Many researchers think that H. pylori is transmitted orally by means of fecal matter through the ingestion of waste tainted food or water. A clean and hygienic environment can help decrease the risk of H. Pylori infection.

Diagnosis of infection

 

Diagnosis of infection is usually made by checking for dyspeptic symptoms and then doing tests which can suggest H. pylori infection. One can test noninvasively for H. pylori infection with a blood 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 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.

Infection may be symptomatic or asymptomatic (without perceptible ill effects). It is estimated that up to 70% of infection is asymptomatic and that about 2/3 of the world population are infected by the bacterium, making it the most widespread infection in the world. Actual infection rates vary from nation to nation - the West (Western Europe, North America, Australasia) having rates around 25% and much higher in the Third World. 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 widespread use of antibiotics. However, metronidazole resistant strains in Europe, the United States, and developing countries.

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

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.^[19][20]

Treatment of infection

  In peptic ulcer patients where infection is detected, the normal procedure is eradicating H. pylori to allow the ulcer to heal. The standard first-line therapy is a one week triple therapy. The Sydney gastroenterolgist Thomas Borody invented the first triple therapy in 1987.^[21] Today, the standard triple therapy is proton pump inhibitors alone was the only option.^[24][25]

A meta-analysis of randomized controlled trials suggests that supplementation with probiotics can improve eradication rates and reduce adverse events.^[26]

Unfortunately, an increasing number of infected individuals are found to harbour levofloxacin as part of the therapy has been suggested.

Some studies show that consumption of broccoli sprouts can be effective at inhibiting H. pylori growth^[27] with sulforaphane being at least one of the active agents^[28].

Some studies show that mastic gum can destroy H. pylori in vitro, but studies done in vivo have shown it to be ineffective.^[29]

A study done on Mongolian gerbils indicates that polysaccharide found in green tea is significantly effective in preventing adhesion of H. pylori to human cultures of epithelial cells.^[31]

As explained below, some authors suggest that some strains of H. pylori may be protective against certain diseases of the esophagus and cardia. Therefore, a more cautious approach than complete eradication may be necessary in some cases.

Helicobacter and cancer

While the incidence of H. pylori infection in humans is decreasing in developing countries,^{[citation needed]} presumably because of improving sanitation and increasing use of antibiotics, in the United States the incidence of gastric cancer has decreased by 80 percent from 1900 to 2000. This apparent correlation is consistent with an epidemiological link between H. pylori and cancer. Specifically, both gastric cancer and gastric MALT lymphoma (lymphoma of the mucosa-associated lymphoid tissue) 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). Despite these associations, a direct causal relationship has not been demonstrated. Nonetheless, among bacteria suspected to cause cancer, H. pylori is the leading contender.

Two related mechanisms by which H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of 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

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.^[2] 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 base pairs, with some 1550 genes. The two sequenced strains show large genetic differences, with up to 6% of the nucleosides 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 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.^{[citation needed]}

See also

• Gastritis
• Peptic ulcer
• Stomach

Notes

References

• Helicobacter pylori and peptic ulcer. Centers for Disease Control and Prevention. Retrieved on 2004-12-21.
• Logan, Robert P H; Walker, Marjorie M (20 October 2001). "Clinical review: ABC of the upper gastrointestinal tract. Epidemiology and diagnosis of Helicobacter pylori infection". BMJ 323: 920–922. PMID 11668141.

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