Mechanism of mucosal damage
The bacterium resides predominantly in the supraepithelial mucus, and only 20% of the population binds to mucous cells. Pathogenesis starts with the action of the type IV bacterial secretion system: the microbe injects a protein into the host cell — the product of the cagA gene. Inside the epithelial cell, this protein is phosphorylated and triggers the synthesis of IL-8.
Interleukin-8 acts as a potent chemoattractant for neutrophils. They massively migrate into the mucous membrane and die during phagocytosis ("respiratory burst"). The release of lysosomal hydrolases and proteases destroys the protective barrier, while lipid peroxidation damages the epithelium. Additional damage is caused by the VacA toxin, which induces cell vacuolization, alters the cytoskeleton, and triggers apoptosis.
Immune response and the "African enigma"
Breaching the epithelial barrier provides antigens with a pathway into the lamina propria of the mucosa. Macrophages present antigens and release IL-1. The further course of events depends on the polarization of the immune response:
- Th1 response (cellular): accompanied by aggressive inflammation and severe tissue damage.
- Th2 response (humoral): stimulates antibody production with minimal mucosal alteration.
It is the genetically fixed predominance of the Th2 response that explains the "African enigma": despite the total infection rate of the African population, peptic ulcer disease is extremely rare among them. To avoid elimination, the bacterium is also able to block the maturation of microsomes in macrophages, suppressing antigen presentation and the Th1 response.
Two disease scenarios: ulcer or cancer
The outcome of the infection largely depends on the age at which infection occurred.
- Ulcer phenotype (infection in adolescents). The bacterium colonizes the antrum. Inflammation reduces somatostatin production and increases gastrin levels. Persistent hyperchlorhydria develops. Excess acid enters the duodenum, causing protective gastric metaplasia there. Helicobacter pylori colonizes these areas, provoking duodenitis and duodenal ulcer formation.
- Cancer phenotype (infection in early childhood). Against the background of excess salt and a deficiency of vitamins C and E, pangastritis develops. Acid secretion initially increases, but then drops due to the depletion of the parietal cell pool. Atrophy of the gastric body mucosa, achylia, and intestinal metaplasia develop. The result is hyposecretion and a high risk of gastric cancer.
How glandular atrophy develops
Glandular atrophy is the result of regeneration failure. Due to continuous damage to the surface-foveolar epithelium by the VacA toxin, cells of the generative zone begin to differentiate massively into surface cells to compensate for their loss. No resources remain to replenish the glandular epithelium, and the glands atrophy.
Concurrently, due to the destruction of parietal cells (from infection or an autoimmune reaction), hydrochloric acid production decreases. An increase in pH in the gastric lumen activates the CDX-2 transcription factor. It changes gastric differentiation to intestinal — this is how intestinal metaplasia arises, which accompanies atrophy.
Briefly: answers to topical questions
Which virulence factors of Helicobacter pylori cause damage to the gastric mucosa?
Damage to the gastric mucosa is associated with the following Helicobacter pylori virulence factors:
- Pathogenicity island cag PAI, whose marker is the cagA gene: encodes the type IV secretion system; the bacterium introduces the CagA protein into the host cell, which triggers signaling pathways, leads to cytoskeletal changes, disruption of intercellular contacts, altered proliferation and apoptosis, as well as the release of IL-8.
- VacA — vacuolating cytotoxin A: causes vacuolization of epithelial cells, cytoskeletal changes, induction of apoptosis, and inhibition of proliferation.
- Mucinases — enzymes that cause mucin degradation and mucus liquefaction.
- Urease — hydrolyzes urea into ammonia and carbon dioxide, neutralizes acid around the bacterium; the source also indicates that the neutralization process produces ammonium hydrochloride, which destroys the epithelium.
By means of which enzyme does Helicobacter pylori neutralize hydrochloric acid and survive in the stomach?
Helicobacter pylori neutralizes hydrochloric acid and survives in the aggressive environment of the stomach due to the enzyme urease.
- Urease — an enzyme that hydrolyzes urea into ammonia and carbon dioxide.
As a result of this enzyme's action, an "alkaline cloud" (neutral environment) is created around the bacterium, which ensures acid neutralization and allows the microorganism to colonize the mucous membrane.
What diagnostic methods are used to detect Helicobacter pylori in clinical practice?
To detect Helicobacter pylori in clinical practice, invasive and non-invasive diagnostic methods are used.
- Invasive methods (require biopsy during EGD):
- Rapid urease test (CLO test).
- Histological detection (stains with Giemsa, Gram, toluidine blue, Warthin–Starry silver staining).
- Microbiological (culture) examination of gastric wall biopsy specimens.
- Molecular biological examination of gastric mucosa biopsy specimens.
- Non-invasive methods:
- 13C-urea breath test.
- Determination of H. pylori antigen in stool (including rapid immunochromatographic assay).
- Molecular biological examination of feces.
- Determination of antibodies to H. pylori in blood (serological method).
For memorizing phenotypes: Ulcer — Urgent secretion (hyperchlorhydria, adolescents). Cancer — Cdestruction of glands (hyposecretion, early childhood) [Note: keep original meaning mapping].
Class and exam questions
How does Helicobacter pylori obtain nutrition while residing in mucus?
The bacterium purposefully disrupts the contacts of the surface-foveolar epithelium. This provides it with access to nutrients directly from the host tissues.
Why does the bacterium colonize the intestine in peptic ulcer disease if it is specific only to the stomach?
Due to acid hypersecretion in the duodenum, protective gastric metaplasia occurs. The bacterium colonizes precisely these "gastric" islands in an atypical location.
What histological criterion confirms HP-associated gastritis?
The diagnosis is established upon detecting even a mild degree of bacterial colonization in at least one specimen. Indirect signs include neutrophil infiltration and the appearance of lymphoid follicles.
What else to study on this topic
- Molecular structure and functions of the type IV bacterial secretion system
- Role of the VacA cytotoxin in inducing epithelial cell apoptosis
- Mechanisms of autoimmune parietal cell damage
- Histological stains for detecting the bacterium (Giemsa, Warthin–Starry)
- Effect of the cdx2 gene on cellular differentiation and development of metaplasia
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