H.pylori gastritis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Yamuna Kondapally, M.B.B.S[3]
Overview
Helicobacter pylori colonization produces gastritis in essentially all infected individuals. Without eradication, chronic–active gastritis persists for life. In a minority of patients it progresses over decades along the Correa cascade: non-atrophic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → intestinal-type gastric adenocarcinoma.[1][2][3] Several factors determine the outcome of infection:
- Bacterial virulence, mainly the cag pathogenicity island (cag PAI) with CagA, ADP-heptose, and the VacA genotype.
- The host immune response, which is vigorous but ineffective.
- The gastric microenvironment, including the gastric microbiota.[1][4]
The anatomic distribution of gastritis predicts the dominant complication:
- Antral-predominant gastritis leads to duodenal ulcer.
- Corpus-predominant or multifocal atrophic gastritis leads to gastric ulcer and gastric cancer.[2][5]
Persistent antigenic stimulation induces mucosa-associated lymphoid tissue (MALT), from which gastric MALT lymphoma can arise.[1]
Pathophysiology
Colonization and establishment of infection
H. pylori is a spiral, flagellated, microaerophilic gram-negative bacterium adapted to the gastric niche. Each colonization step is mechanistically linked to disease:[1]
- Urease-mediated acid buffering: hydrolysis of urea generates ammonia, which neutralizes acid around the organism and allows survival and movement through the mucus layer. Ammonia and its metabolites are also directly cytotoxic to the epithelium.[1]
- Flagellar motility: allows the organism to penetrate the mucus gel and reach the near-neutral epithelial surface.[1]
- Adhesins: BabA (binds Lewis b), SabA (binds sialyl-Lewis x), AlpA/B, OipA, and HopZ anchor the bacterium to epithelial cells and intercellular junctions. This anchoring allows sustained delivery of effector molecules.[1][6]
- Gland-base tropism: most organisms attach to short-lived surface pit cells. A subset migrates to the gland base and contacts long-lived stem and progenitor cells, where pro-inflammatory and pro-proliferative signaling begins.[4][7]
Virulence factors driving mucosal injury
How severe the gastritis becomes depends more on strain virulence than on the mere presence of the organism.[1][8]
| Factor | Mechanism | Clinical relevance |
|---|---|---|
| cag PAI / CagA | The cag PAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells. Phosphorylated CagA has several downstream effects:
These effects may persist after the bacterium is gone (the "hit-and-run" model). |
CagA-positive strains carry a higher risk of severe gastritis, atrophy, peptic ulcer, and gastric cancer. They are associated with faster progression of atrophic gastritis. East Asian–type CagA (EPIYA-D motif) is more virulent than Western-type CagA.[1][4][5][9][10] |
| ADP-heptose | CagA-independent metabolite translocated through the T4SS. It activates the ALPK1–TIFA–NF-κB axis. | Now recognized as a major driver of initial mucosal inflammation and IL-8 production.[4][7] |
| VacA | Present in virtually all strains, with genotype-dependent activity (s1/i1/m1 is most pathogenic). It forms membrane pores, induces vacuolation and mitochondrial apoptosis, impairs autophagy, and suppresses T- and B-lymphocyte function. | Contributes to epithelial injury, immune evasion, and persistence. More virulent vacA genotypes are associated with more severe gastroduodenal disease.[1][8][5] |
| Survival factors (catalase, superoxide dismutase, arginase) | Scavenge reactive oxygen and nitrogen species, confer acid tolerance, and blunt host bactericidal activity. | Support lifelong persistence despite an active immune response.[11] |
Acute infection
- Acute infection is usually subclinical and is rarely identified clinically.[12]
- It is characterized by neutrophilic gastritis and transient hypochlorhydria.[12]
- Spontaneous clearance is uncommon. In most cases the infection persists and evolves into chronic–active gastritis, which is the clinically relevant lesion.[1]
Chronic–active gastritis and the host immune response
Colonization triggers a pro-inflammatory epithelial response. This response recruits two cell populations:
- Neutrophils, which form the "active" component.
- Mononuclear cells (lymphocytes and plasma cells), which form the "chronic" component.
The result is chronic–active gastritis, which typically remains asymptomatic for decades.[1]
Key mechanisms of the chronic–active phase:
- Pathway convergence on NF-κB: TLRs, NOD1 and other pattern-recognition receptors, and the ADP-heptose/ALPK1 pathway all activate NF-κB.[1][13]
- Cytokine and T-cell profile: NF-κB activation sustains production of IL-1β, IL-6, IL-8, and TNF-α. The adaptive response is predominantly Th1/Th17 polarized.[1][13]
- Failure to clear the organism: VacA-mediated lymphocyte suppression, tolerogenic dendritic-cell signaling, and regulatory T cell activity allow the bacterium to persist despite a vigorous response. This futile chronic inflammation is the central driver of downstream mucosal injury.[1][14]
- Lymphoid follicles and MALT: normal antral mucosa contains essentially no organized lymphoid tissue. Persistent antigenic stimulation induces lymphoid follicles, a consistent feature of chronic infection. These follicles form acquired MALT, the substrate for gastric marginal-zone (MALT) B-cell lymphoma.[1][15]
Topographic phenotype and acid secretion
| Feature | Antral-predominant gastritis | Corpus-predominant / multifocal atrophic gastritis |
|---|---|---|
| Parietal cell mass | Preserved | Reduced (oxyntic atrophy) |
| Acid output | Normal or increased | Reduced (hypochlorhydria or achlorhydria) |
| Dominant complication | Duodenal ulcer | Gastric ulcer, atrophy, intestinal metaplasia, gastric adenocarcinoma |
Progression to atrophy, metaplasia, and neoplasia
Atrophic gastritis
- Chronic inflammation with excess epithelial apoptosis causes loss of acid-secreting parietal cells and chief cells. Compensatory hyperproliferation and altered differentiation follow.[16][17]
- The prevalence and severity of atrophy increase with the duration of infection.[17]
- Molecular drivers of progression from chronic atrophic gastritis toward cancer include NF-κB activation and IL-8 release.[17]
- Co-factors that further increase cancer risk include Epstein–Barr virus co-infection and cellular senescence.[17]
Pyloric metaplasia (SPEM) and intestinal metaplasia
- Pyloric metaplasia is the first metaplastic response of injured oxyntic mucosa. It consists of spasmolytic polypeptide-expressing metaplasia (SPEM), derived from transdifferentiated chief cells, together with foveolar and mucous neck cell hyperplasia.[18]
- Persistence: metaplasia usually resolves once the injury heals. It can persist when inflammation continues or the injury is severe and chronic.[18]
- Progression to intestinal metaplasia: persistent pyloric metaplasia can progress to intestinal metaplasia (IM). IM glands with mixed gastric and intestinal lineages carry the highest risk of progressing to dysplasia and cancer.[18]
- Extent and topography: how widespread and where the atrophic-metaplastic change is located determines cancer risk.[2][17]
- Bile reflux: bile reflux is an additional injurious factor that may promote intestinal-type epithelial replacement.[19]
Genotoxic, epigenetic, and stem-cell mechanisms
- Direct genotoxicity: T4SS-competent H. pylori induces DNA double-strand breaks. In hosts with deficient homologous recombination repair, this creates "multi-hit" carcinogenesis.[14][3]
- Oxidative stress: inflammation-driven oxidative stress and DNA damage contribute to genomic instability.[3]
- Epigenetic silencing: aberrant hypermethylation of tumor-suppressor promoters contributes to progression.[3]
- Stem-cell niche remodeling: infection increases stromal R-spondin 3 and suppresses epithelial bone morphogenetic protein (BMP) signaling. Stromal IL-1β signaling, acting through prostaglandin E2, activates epithelial YAP. This drives gland hyperplasia and reprograms the epithelium toward a fetal-like regenerative state.[7][4]
Gastric microbiota and declining H. pylori density
- As atrophy and achlorhydria develop, H. pylori density falls.[1][4]
- Intestinalized epithelium is not colonized by the organism, which further reduces its density.[1][4]
- A dysbiotic non-Helicobacter gastric microbiota then expands and may itself contribute to neoplastic progression.[1][4]
- Clinical consequence: failure to demonstrate H. pylori in an atrophic or metaplastic stomach does not exclude it as the cause.[1]
Histopathology
Chronic–active gastritis (neutrophils plus lymphocytes and plasma cells) on histology is highly characteristic of active H. pylori infection.[1] The updated Sydney System grades the following features:[20]
| Feature | Definition | Grading |
|---|---|---|
| Chronic inflammation | Increased lymphocytes and plasma cells in the lamina propria | Mild, moderate, or severe increase in density |
| Activity | Neutrophilic infiltrate of the lamina propria, pits, or surface epithelium | Mild: less than one-third of pits/surface infiltrated Moderate: one-third to two-thirds Severe: more than two-thirds |
| Atrophy | Loss of specialized glands from the antrum or corpus | Mild, moderate, or severe loss |
| H. pylori density | Organisms on the surface epithelium | Mild: scattered organisms covering less than one-third of the surface Moderate: intermediate numbers Severe: large clusters or a continuous layer over more than two-thirds of the surface |
| Intestinal metaplasia | Intestinal-type replacement of the gastric epithelium | Mild: less than one-third of mucosa involved Moderate: one-third to two-thirds Severe: more than two-thirds |
- Stage-based staging: OLGA (atrophy) and OLGIM (intestinal metaplasia) staging supplement the Sydney System. They stratify cancer risk by the stage and topography of atrophic-metaplastic change.[1]
- Detailed staging and surveillance belong in the classification and diagnostic microchapters.
Clinical implications of the pathophysiology
- Eradication timing: H. pylori gastritis is progressive unless treated. Eradication halts progression of the cascade, with the greatest benefit when performed before atrophy or intestinal metaplasia develops.[1][2]
- Residual risk after eradication: patients with established atrophy or intestinal metaplasia remain at increased cancer risk after eradication.[2][17]
- Strain versus presence: strain virulence, host genetics, and environment (for example, high salt intake and EBV co-infection) determine outcome, not colonization alone. Only a small minority of infected individuals (approximately 1–3%) develop gastric cancer.[2][17]
Areas of uncertainty
- Relative risk of metaplasia types: whether intestinal metaplasia confers greater cancer risk than pyloric metaplasia or atrophy alone remains debated.[18]
- Reversibility: atrophy may partially regress after eradication. Established intestinal metaplasia is generally considered of limited reversibility.[2][19]
- Predicting progression: no validated bacterial biomarker reliably identifies which infected individuals will progress. Eradication decisions therefore cannot yet be individualized by CagA or VacA genotype.[1]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek R, Schulz C, Smith SI, Suerbaum S (2023). "Helicobacter pylori infection". Nat Rev Dis Primers. 9 (1): 19. doi:10.1038/s41572-023-00431-8. PMID 37081005 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Sundar R, Nakayama I, Markar SR, Shitara K, van Laarhoven HWM; et al. (2025). "Gastric cancer". Lancet. 405 (10494): 2087–2102. doi:10.1016/S0140-6736(25)00052-2.
- ↑ 3.0 3.1 3.2 3.3 Duan Y, Xu Y, Dou Y, Xu D (2025). "Helicobacter pylori and gastric cancer: mechanisms and new perspectives". J Hematol Oncol. 18 (1): 10. doi:10.1186/s13045-024-01654-2.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Wizenty J, Sigal M (2025). "Helicobacter pylori, microbiota and gastric cancer — principles of microorganism-driven carcinogenesis". Nat Rev Gastroenterol Hepatol. 22 (5): 296–313. doi:10.1038/s41575-025-01042-2.
- ↑ 5.0 5.1 5.2 5.3 De Falco M, Lucariello A, Iaquinto S; et al. (2015). "Molecular mechanisms of Helicobacter pylori pathogenesis". J Cell Physiol. 230 (8): 1702–7. doi:10.1002/jcp.24933.
- ↑ Bhattacharjee A, Sahoo OS, Sarkar A; et al. (2024). "Infiltration to infection: key virulence players of Helicobacter pylori pathogenicity". Infection. 52 (2): 345–384. doi:10.1007/s15010-023-02159-9.
- ↑ 7.0 7.1 7.2 Beccaceci G, Müllerke S, Berger H; et al. (2026). "Helicobacter pylori triggers gastric mucosal remodeling toward a fetal-like transcriptional program via stromal IL-1β signaling". Nat Commun. 17 (1): 9510. doi:10.1038/s41467-026-77520-1. PMC 13546300 Check
|pmc=value (help). - ↑ 8.0 8.1 Wattanawongdon W, Simawaranon Bartpho T, Tongtawee T (2023). "Relationship between Helicobacter pylori virulence genes and gastroduodenal disease". J Int Med Res. 51 (3): 3000605231161465. doi:10.1177/03000605231161465.
- ↑ Xue Z, Li W, Ding H; et al. (2024). "Virulence gene polymorphisms in Shandong Helicobacter pylori strains and their relevance to gastric cancer". PLoS One. 19 (9): e0309844. doi:10.1371/journal.pone.0309844.
- ↑ Liu W, Tian J, Hui W; et al. (2021). "A retrospective study assessing the acceleration effect of type I Helicobacter pylori infection on the progress of atrophic gastritis". Sci Rep. 11 (1): 4143. doi:10.1038/s41598-021-83647-6.
- ↑ Marzhoseyni Z, Mousavi MJ, Ghotloo S (2024). "Helicobacter pylori antigens as immunomodulators of immune system". Helicobacter. 29 (1): e13058. doi:10.1111/hel.13058.
- ↑ 12.0 12.1 Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rathbone BJ; et al. (1991). "Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations". Gut. 32 (11): 1415–8. PMC 1379180. PMID 1752479.
- ↑ 13.0 13.1 Zhou J, Li J, Chen J, Lan X, Ai Y; et al. (2025). "Decoding inflammatory mediators in the Correa's cascade: from chronic gastritis to carcinogenesis and targeted therapies". Int Immunopharmacol. 162: 115191. doi:10.1016/j.intimp.2025.115191.
- ↑ 14.0 14.1 Müller A, He J (2023). "A double whammy on gastric cancer risk". N Engl J Med. 388 (13): 1225–1229. doi:10.1056/NEJMe2215503.
- ↑ Genta RM, Hamner HW, Graham DY (1993). "Gastric lymphoid follicles in Helicobacter pylori infection: frequency, distribution, and response to triple therapy". Hum Pathol. 24 (6): 577–83. PMID 8505036.
- ↑ Bessède E, Dubus P, Mégraud F, Varon C (2015). "Helicobacter pylori infection and stem cells at the origin of gastric cancer". Oncogene. 34 (20): 2547–55. doi:10.1038/onc.2014.187.
- ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 Zhang Z, Chen S, Li S, Zheng Y, Mai L, Zhang X (2025). "Association of Helicobacter pylori related chronic atrophic gastritis and gastric cancer risk: a literature review". Front Med (Lausanne). 12: 1504749. doi:10.3389/fmed.2025.1504749. PMC 11882515 Check
|pmc=value (help). - ↑ 18.0 18.1 18.2 18.3 Cornish SK, Choi E, Mills JC, Goldenring JR (2026). "The origins and progression of pyloric metaplasia following gastric mucosal injury". Physiol Rev. 106 (4): 2441–2471. doi:10.1152/physrev.00042.2025.
- ↑ 19.0 19.1 Walker MM (2003). "Is intestinal metaplasia of the stomach reversible?". Gut. 52 (1): 1–4. PMC 1773527. PMID 12477745.
- ↑ Dixon MF, Genta RM, Yardley JH, Correa P (1996). "Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994". Am J Surg Pathol. 20 (10): 1161–81. PMID 8827022.