Pathophysiology of Helicobacter pylori Infection
Initial Colonization and Survival Mechanisms
H. pylori is a spiral-shaped, flagellated, microaerophilic Gram-negative bacterium that has evolved specialized mechanisms to survive and persist in the hostile acidic environment of the human stomach. 1, 2
Key Colonization Factors
Urease enzyme is critical for initial survival, converting urea to ammonia and carbon dioxide, which creates a protective alkaline microenvironment around the bacterium that neutralizes gastric acid. 1, 3
Flagella provide motility that allows the bacterium to swim through the viscous mucus layer and reach the gastric epithelial surface, preventing elimination by mucus turnover and gastric peristalsis. 1, 4
The bacterium preferentially colonizes the gastric antrum where the pH is higher (more hospitable), though bacterial density varies throughout the stomach depending on acid secretion patterns. 5
Delta-glutamyltranspeptidase contributes to colonization by mechanisms that are still being elucidated but appear important for establishing infection. 1
Adherence to Gastric Epithelium
While most H. pylori cells remain motile in the mucus layer, a critical subset adheres directly to gastric epithelial cells, which is essential for disease pathogenesis. 4
Adherence prevents bacterial elimination by mucus turnover and gastric peristalsis, allowing persistent colonization throughout the individual's lifetime unless treated. 4
H. pylori possesses an extraordinarily large set of outer membrane proteins (adhesins) that bind to specific receptor structures on gastric epithelial cells, with bacteria exhibiting better adherence properties colonizing at higher densities. 4
Intimate attachment facilitates efficient delivery of virulence proteins directly into gastric epithelial cells, most notably the CagA oncoprotein. 4, 6
Virulence Factors and Inflammatory Response
CagA Pathogenicity Island
The cag pathogenicity island (PAI) encodes multiple proteins including CagA, a 120-140 kDa immunodominant oncoprotein present in approximately 70% of H. pylori strains infecting European populations. 7
CagA is injected into gastric epithelial cells where it initiates a signal transduction cascade, resulting in interleukin-8 production and an intense inflammatory response. 1, 6
Presence of cagA is associated with increased risk for peptic ulcer disease, atrophic gastritis, and gastric cancer development. 7
Vacuolating Cytotoxin (VacA)
VacA is a major virulence factor that damages host epithelial cells and contributes to persistent colonization by manipulating host immune responses. 1, 6
VacA, along with lipopolysaccharide and urease, allows H. pylori to persist for decades while invoking chronic inflammation. 1
Immune Evasion and Chronic Inflammation
H. pylori induces a chronic active gastritis in all infected individuals, though this remains asymptomatic in the majority. 2
The bacterium triggers a Th-1 cytokine response and proinflammatory cytokine production that exacerbates inflammation but paradoxically fails to eliminate the organism. 1, 2
Host antibodies and Th-1 responses do not clear the infection, presenting major challenges for vaccine development and explaining why the infection persists throughout life. 1
Pattern of Gastritis and Acid Secretion
The anatomical distribution of gastritis determines clinical outcomes by altering gastric acid secretion. 5
Antral-predominant gastritis leads to increased acid production, predisposing to duodenal ulcers by increasing acid delivery to the duodenum. 5
Corpus-predominant (body) gastritis causes decreased acid production due to destruction of parietal cells, and substantially increases gastric cancer risk. 5
Hypochlorhydria from atrophic corpus gastritis allows overgrowth of non-H. pylori organisms that produce carcinogenic metabolites, and reduces luminal ascorbic acid (an antioxidant that scavenges carcinogenic N-nitrosamines). 5
Carcinogenic Cascade
H. pylori drives a stepwise progression from chronic inflammation to malignancy over decades. 5
The cascade proceeds: chronic active gastritis → atrophic gastritis → intestinal metaplasia → gastric adenocarcinoma, with each step representing increasing cancer risk. 5
Products of inducible nitric oxide synthase (iNOS) and cyclooxygenase may perturb the balance between gastric epithelial cell apoptosis (leading to ulcer formation) and proliferation (leading to cancer). 1
H. pylori is causally linked to 71-95% of all gastric cancers, making it the most important proven risk factor for non-cardiac gastric adenocarcinoma. 5
Intestinal metaplasia represents a point of no return and is generally considered irreversible even after H. pylori eradication, though gastric atrophy may be partially reversible in the corpus. 5
Genetic Diversity and Strain Variation
H. pylori is the most genetically diverse bacterial species known, with a panmictic population structure that contributes to varying disease severity produced by different strains. 1
Bacterial virulence factors (CagA and VacA genotypes) interact with host genetics and environmental factors to determine whether infection remains asymptomatic or progresses to severe disease. 5, 2
Metabolic Adaptations
H. pylori is microaerophilic with oxygen-sensitive enzymes in central metabolic pathways, explaining its requirement for low oxygen tension. 3
The bacterium has an incomplete citric acid cycle and several incomplete biosynthetic pathways, resulting in complex nutritional requirements. 3
The respiratory chain is remarkably simple with a single terminal oxidase and fumarate reductase as the only anaerobic reductase, using NADPH as the preferred electron donor rather than NADH. 3
Clinical Implications
Understanding H. pylori pathophysiology explains why eradication before development of preneoplastic conditions (atrophy and intestinal metaplasia) is most effective in reducing gastric cancer risk. 5 Once intestinal metaplasia develops, the carcinogenic process may continue even after bacterial eradication, though eradication still halts further progression of gastritis. 5