Pathogenesis of Helicobacter pylori

H. pylori on gastric epithelial cells (false-coloured SEM). Source: Yamada's Textbook of Gastroenterology, 7th ed.

1. The Organism

2. How H. pylori Survives in the Stomach

3. Colonization and Adhesion

• BabA (blood-antigen binding protein A): binds fucosylated Lewis b antigen on gastric epithelial cells.
• SabA: binds sialyl Lewis X receptors, particularly upregulated in inflamed mucosa.

4. Virulence Factors: The Key Players

A. CagA and the Cag Pathogenicity Island (cag PAI)

• Injected into the host cell cytoplasm via the T4SS
• Tyrosine-phosphorylated by Src and Abl kinases inside the host cell
• Phospho-CagA activates the tyrosine phosphatase SHP-2, triggering morphological transformations resembling growth factor stimulation
• Non-phosphorylated CagA interacts with E-cadherin, c-Met receptor, and activates β-catenin → disrupts cell-cell junctions, causes loss of cell polarity, and drives mitogenic responses
• Increases spermine oxidase (SMO) production → oxidative DNA damage → selects for apoptosis-resistant cells → carcinogenesis
• Targets tumor suppressor p53 to dysregulate apoptosis
• Activates NF-κB → IL-8 and proinflammatory gene expression → neutrophil recruitment

• PG activates NOD1 → RIP2 → TRAF6 → TAK1 → NF-κB → IL-8
• HBP activates ALPK1 → TIFA oligomerization → NF-κB → IL-8

Intracellular signaling pathways activated by H. pylori's cag secretion system. Source: Yamada's Textbook of Gastroenterology, 7th ed.

B. VacA (Vacuolating Cytotoxin A)

• Secreted protein that enters host cells and forms channels in lysosomal and endosomal membranes, generating multiple large cytoplasmic vacuoles
• Induces apoptosis in epithelial cells
• Disrupts the balance between cell death and proliferation
• Acts as an activator of IL-8-mediated acute inflammation
• VacA i1 strains (inner region allele 1) strongly associate with cagA positivity and gastric cancer risk
• Also delivered to host cells by the T4SS

C. Other Virulence Factors

5. The Inflammatory Response

1. Acute phase: Bacterial adherence triggers IL-8 release from epithelial cells → recruits neutrophils → "active gastritis"
2. Chronic phase: Sequential recruitment of T and B lymphocytes, plasma cells, and macrophages
3. Cytokine cascade: Enhanced expression of TNF-α, IL-1β, IL-6, IL-8, and IL-12
4. Immune evasion: Despite this response, H. pylori is not cleared - it down-regulates the Th1/Th17 response and evades phagocytic killing

6. How Gastritis Leads to Disease

Pathogenesis of H. pylori gastritis and its diverging disease outcomes. Source: Robbins Pathologic Basis of Disease.

Antral-Predominant Gastritis → Peptic Ulcer Disease (PUD)

• Antral gastritis → local inflammation → inhibits D cells (which normally produce somatostatin) → loss of inhibition on G cells → hypergastrinemia
• Excess gastrin stimulates parietal cells in the corpus → increased acid secretion (hyperchlorhydria)
• High acid load damages the duodenal bulb → gastric metaplasia of duodenal epithelium → H. pylori colonizes the metaplastic patches → duodenitis → duodenal ulcer (DU)
• NSAIDs synergize by disrupting the prostaglandin-mediated mucosal defence
• Lifetime risk of PUD in infected individuals: ~10-20%

Pangastritis / Corpus-Predominant Gastritis → Atrophy → Gastric Cancer

• Long-standing infection extends to the gastric body and fundus
• Atrophic gastritis with loss of parietal cells → hypochlorhydria (paradoxically reduces ulcer risk)
• Intestinal metaplasia (mucous cells replaced by intestinal-type cells)
• Progression: chronic gastritis → atrophy → intestinal metaplasia → dysplasia → gastric adenocarcinoma (Correa cascade)
• H. pylori is classified as a Group 1 (definite) carcinogen by the IARC
• CagA-positive strains are more strongly linked to cancer

Gastric MALToma (Mucosa-Associated Lymphoid Tissue)

• Normally the stomach has no lymphoid tissue
• Chronic H. pylori infection induces polyclonal B-cell proliferation in the gastric mucosa (acquired MALT)
• Ongoing antigenic stimulation may lead to acquisition of driver mutations → monoclonal gastric B-cell MALT lymphoma
• Early-stage MALToma may regress with H. pylori eradication alone

7. Host Genetic Factors

• IL-1β and IL-1RN polymorphisms: increased IL-1β expression → stronger acid suppression → more favorable environment for corpus colonization → greater atrophy risk
• TNF-α polymorphisms: increased TNF production → enhanced mucosal damage
• IL-10 polymorphisms: decreased IL-10 (anti-inflammatory) → more aggressive inflammation
• These polymorphisms help explain why only ~10-20% of infected individuals develop PUD and <1% develop gastric cancer

8. Summary Flowchart

H. pylori ingested (childhood, fecal-oral)
         ↓
Urease + flagella → survives gastric acid, penetrates mucus
         ↓
Adhesins (BabA, SabA) → colonizes gastric epithelium
         ↓
T4SS injects CagA, PG, HBP → NF-κB → IL-8 → neutrophils
VacA → vacuolation, apoptosis
         ↓
Chronic active gastritis
    /              \
Antral             Corpus + Antrum
(hyperchlorhydria) (atrophy, hypochlorhydria)
    ↓                      ↓
DU / GU            Intestinal metaplasia
                          ↓
                   Dysplasia → Adenocarcinoma
                   MALToma

• Yamada's Textbook of Gastroenterology, 7th ed., Ch. 49 & 51
• Robbins & Cotran Pathologic Basis of Disease (Robbins), Ch. 17
• Jawetz, Melnick & Adelberg's Medical Microbiology, 28th ed.
• Sherris & Ryan's Medical Microbiology, 8th ed.
• Maingot's Abdominal Operations