Helicobacter pylori is the first formally recognized bacterial
carcinogen and is one of the most successful human pathogens, as over half of
the world's population is colonized with this gram-negative bacterium. Unless
treated, colonization usually persists lifelong.After an incubation period of a
few days, H. pylori causes, in some
persons, a mild gastritis which may last for about two weeks. The infection may
be transient in some, but in most, it persists for years or decades. Such
colonization is usually asymptomatic, though chronic superficial gastritis may
be demonstrable histologically. The bacteria are present only in the overlying
mucus and do not invade the mucosa. Gastric antrum is the commonest site of colonization,
though any part of the stomach may be involved. The infection is strictly
confined to the gastric mucosa, in the stomach, as well as in areas of gastric
metaplasia and heteropia in the duodenum.
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. 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. H. pylori is also found on the inner surface of
the stomach epithelial
cells and occasionally inside epithelial cells. It produces adhesins which bind to membrane-associated lipids and carbohydrates which helps it adhere to the epithelial cells.
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. Unlike other bacterial ureases, which are found only in the cytoplasm, H. pylori urease is located and also enzymatically
active on the cell surface. Cytoplasmic
urease adsorbs onto the surface of intact bacteria after the protein is
released from the cytoplasm by spontaneous autolysis of a subpopulation of the
bacterium. A recent crystal structure study demonstrated that the H. pylori urease enzyme has a unique
supramolecular structure that may be important for survival in acidic
conditions. The H. pylori urease
has a 3-fold symmetry, spherical assembly of about 12 catalytic sites, containing
only α and β subunits in contrast to trimers of α, β, γ subunits in other
bacterial ureases. 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.
The cagA (cytotoxin-associated gene A)
gene is the most extensively studied of the H. pylori genes.
Early studies indicated that the CagA protein was a marker for more severe
disease because it was more frequently associated with strains isolated from
patients with peptic ulcer and gastric cancer. It is almost always associated
with increased inflammation and more severe disease. However, it’s almost
universal presence in strains in developing countries irrespective of disease
presentation indicates that other factors (bacterial, host, and environmental)
must also be important for development of peptic ulcer or gastric malignancy.
Variability in the 3′ region of the cagA gene may confer greater risk for gastric cancer
and an enhanced susceptibility to pH, but direct evidence for this is still
needed. Alternatively, it may reflect the geographical clustering of the
infection.
The VacA
protein influences cellular processes via different routes, thus assisting in
chronic colonization of the gastric mucosa by H. pylori. Surface-bound VacA may be directly delivered
to the cell membrane whereas, secreted VacA may either bind to a cell membrane
receptor and initiate a proinflammatory response, or can be taken up directly
by the cell and be trafficked to the mitochondria and induce apoptosis. It can
be taken up by pinocytosis and induce vacuolization, or form a membrane
channel, resulting in leakage of nutrients to the extracellular space, or pass
through the tight junctions and inhibit T-cell activation and proliferation.
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", 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. Presence of H. pylori infection
triggers a excessive inflammatory and immune response in the host. IL-6 and
IL-8 appear early in the cascade of inflammatory molecules. H. pylori products also stimulate IL-10, IL-12
and interferon (IFN)-γ in a Th1 type of gastric immune response.
