Helicobacter pylori: Past… Present… Future

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Helicobacter pylori is a small, spiral-shaped, highly motile gram negative bacterium that is related to Campylobacter and colonises non-acid secreting musoca of the stomach and upper intestinal tract [1]. It is urease, catalase, and oxidase positive. Originally called Campylobacter pyloridis and then corrected to Campylobacter pylori, the bacteria were renamed again due to taxonomic data as Helicobacter pylori in a new genus, Helicobacter.

Infection with H.pylori is very common, with approximately 50% of the world’s population infected [2]. Once present, infection will often become chronic and persistent and evidence shows strong correlation between its presence and gastrointestinal diseases like gastritis, peptic ulcer disease, gastric carcinoma and MALT lymphoma [3].

History

H. pylori was discovered by Marshall and Warren in 1982 {4] resulting in what was at the time, a divergence from the archetypal understanding of gastric disease. It was commonly thought that stress and diet were the only causes of peptic ulcers however the work of Marshall and Warren identified and isolated Campylobacter-like organisms (CLO) in ulcer biopsies. This discovery was met with much scepticism and resulted in an infamous example of tenacity and scientific endeavour. In 1985 Marshall performed self-inoculation by CLOs and exhibited symptomatic gastritis, which he subsequently treated successfully with metronidazole and bismuth salts, thereby proving their ability to cause gastritis [5]. Their work on H. pylori and the resulting paradigm-shift in the understanding of gastric disease led to them being awarded the Nobel Prize for Medicine in 2005.
PATHOLOGY
H. pylori is considered a type I carcinogen and is the most common cause of infection-related cancers, representing 5.5% of the global cancer burden [6].
While in most cases infection with the bacteria is asymptomatic, long-term carriage significantly increases the risk of developing diseases. Studies have reported approximately 10% develop peptic ulcer disease, 1 to 3% develop gastric adenocarcinoma, and <0.1% develop mucosa-associated lymphoid tissue (MALT) lymphoma [7]. The pathogenicity of H. pylori and subsequent risk of cancer is dependent on both the bacterial and host genotypes as well as environmental exposures [8].
Two loci play a part in determining the virulence of H. pylori; the cag pathogenicity island (cag PAI) and vacA. The cag PAI encodes the CagA protein, often used to broadly differentiate between strains, which is tyrosine phosphorylated inside the host cell resulting in increased cellular migration and has been linked to oncogenesis [9]. As well as encoding for CagA, cag PAI also delivers H. pylori peptidoglycan to the host cells triggering an intracellular signaling cascade, which culminates in the production of type I interferon (IFN), an important group of proteins involved in regulation of the immune system [10]. The toxin VacA encoded by the vacA locus, also has a role to play in modulation of the immune system and inflammatory response.
While the relative virulence of H. pylori can be identified by analysis of the bacterial genotype, there are a number of host factors that affect the development of H. pylori-induced carcinogenesis including gastric inflammation and a reduction in acid secretion [11].
Interestingly, it has also been postulated there is a synergistic relationship between high salt diets and H. pylori infection on gastric inflammation and damage. The link has been studied in gerbils [12] however the mechanisms of action are not fully understood. Some hypotheses point to a link between salt and its effect on gastric mucosa and epithelium allowing carcinogens to pass into gastric tissue and facilitating malignant transformation, while other studies link salt to increased inflammation and upregulation in cytokines such as interferon. One more recent study observed a potential correlation between high gastric salt concentration and modulation of gene expression in H. pylori [13].