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] Aravind Reddy Kothagadi M.B.B.S[3]

Overview

Most clinically important gastritis arises from three mechanisms: Helicobacter pylori–associated gastritis, autoimmune gastritis (AIG), and reactive (chemical) gastropathy. H. pylori is the most common cause worldwide and the main driver of the inflammation-to-cancer sequence. AIG is T cell–mediated destruction of corpus parietal cells, producing atrophy confined to the corpus. Reactive gastropathy is non-immune epithelial injury from NSAIDs, bile reflux, and alcohol, usually with little true inflammation. Clinical outcome depends mainly on where the inflammation sits in the stomach and how it changes gastric acid secretion, not simply on whether the organism is present.[1] Chronic inflammation involving the corpus drives the Correa cascade: atrophy, then intestinal metaplasia, then dysplasia, then intestinal-type gastric adenocarcinoma. Histologic staging of this cascade with OLGA/OLGIM identifies patients at high cancer risk.[2][3]

Pathophysiology

Helicobacter pylori–associated gastritis

Colonization and topographic phenotypes

  • H. pylori crosses the mucus layer using flagellar motility and local alkalinization generated by urease.
  • It then adheres to epithelial cells through adhesins (BabA, SabA, OipA) that bind Lewis blood-group antigens.[1]
  • Almost everyone with persistent colonization develops chronic gastritis. The topographic pattern determines the phenotype and its consequences:[4][1]
Topographic phenotypes of chronic H. pylori gastritis
Phenotype Approximate frequency Acid secretion Mechanism Clinical consequence
Mild non-atrophic pangastritis Most infected persons Normal Low-grade inflammation without atrophy Usually asymptomatic; no major sequelae
Antral-predominant gastritis ~10–15% Increased Corpus is relatively spared, so parietal-cell mass is preserved. Antral inflammation impairs inhibitory control by somatostatin-secreting D cells, raising gastrin and acid output. Duodenal ulcer phenotype
Corpus-predominant / multifocal atrophic gastritis ~1% Decreased (hypochlorhydria or achlorhydria) Inflammation of the oxyntic corpus leads to oxyntic atrophy. Low pepsinogen I and a low pepsinogen I/II ratio are physiologic markers. Gastric ulcer and gastric cancer phenotype
  • Acute infection causes transient hypochlorhydria, which helps the organism colonize.
  • Chronic infection then diverges into one of two patterns:[5][6]
    • the acid-hypersecretory antral pattern, or
    • the acid-hyposecretory corpus pattern, driven partly by IL-1β suppression of the parietal-cell proton pump.

Virulence factors

  • cag pathogenicity island and CagA
    • cag-positive strains assemble a type IV secretion system (T4SS) that injects CagA into epithelial cells.
    • Phosphorylated CagA activates SHP2–ERK signaling and also activates AKT and WNT signaling.
    • CagA inhibits PAR1b, which disrupts cell polarity and tight junctions. It also promotes genomic instability and epithelial–mesenchymal transition.
    • Downstream mutations can become self-sustaining. CagA can therefore act by a "hit-and-run" mechanism, in which malignant transformation no longer requires the organism.[7]
    • cag-positive strains cause more severe gastritis, atrophy, ulceration, and distal cancer.[7]
  • VacA
    • VacA is present in nearly all strains. Its pathogenicity depends on genotype; s1/i1/m1 alleles are the most virulent.
    • It forms membrane pores, induces vacuolation and apoptosis, supplies nutrients to the bacteria, and promotes immune evasion.[8][9]
  • ADP-heptose and peptidoglycan
    • These CagA-independent molecules are translocated through the T4SS.
    • They activate ALPK1–TIFA–NF-κB signaling, a major pathway for initial mucosal inflammation and IL-8–driven neutrophil recruitment.[7][1]

Immune response and chronicity

Autoimmune gastritis

  • AIG is a chronic, non–self-limiting, T cell–mediated disorder.
  • It is restricted to the oxyntic (corpus/fundus) mucosa and spares the antrum, the mirror image of antral-predominant H. pylori gastritis.[10]
  • Autoantigen
    • The target is the parietal-cell H⁺/K⁺-ATPase (the gastric proton pump).
    • Autoreactive CD4⁺ Th1 cells recognize the proton pump through MHC class II.
    • Parietal cells die by apoptosis through Fas–FasL and perforin–granzyme mechanisms.[11][10]
  • Autoantibodies
    • Anti-parietal cell antibodies (PCA) and intrinsic factor antibodies (IFA) are serologic hallmarks, but their accuracy is suboptimal.
    • PCA has a high false-positive rate, and IFA has low sensitivity.
    • Diagnosis therefore rests on histologic corpus-restricted atrophy together with endoscopy and serology, not on antibodies alone.[12][13]
  • Functional consequences
  • Natural history

Reactive (chemical) gastropathy

  • Reactive gastropathy is a non-immune injury pattern. It is now among the most common histologic gastric diagnoses, especially where H. pylori prevalence is low.[16]
  • Causes include:[17]
  • NSAIDs and aspirin
    • Cyclooxygenase inhibition depletes mucosal prostaglandins. This reduces mucus and bicarbonate secretion and mucosal blood flow.
    • COX-independent proinflammatory effects also contribute.
    • Luminal acid worsens the injury, which is the mechanistic rationale for acid suppression.[17]
  • Bile reflux
    • Bile salts solubilize the mucus layer and disrupt epithelial membranes, allowing acid to back-diffuse into the mucosa.[18]
  • Alcohol
    • Alcohol dissolves the mucus layer, increases mucosal permeability, and induces oxidative stress.

Histologic correlates of the three mechanisms

Feature H. pylori gastritis Autoimmune gastritis Reactive gastropathy
Distribution Antrum-predominant, pangastritis, or multifocal Corpus/fundus only; antrum spared Typically antrum
Inflammation Chronic lymphoplasmacytic infiltrate with neutrophilic activity; lymphoid follicles Lymphoplasmacytic infiltrate targeting oxyntic glands; progressive oxyntic atrophy Scant acute and chronic inflammatory cells
Epithelial changes Atrophy and metaplasia with chronicity Pyloric and intestinal metaplasia; ECL-cell hyperplasia Foveolar hyperplasia with corkscrew pits, mucin depletion, lamina propria smooth-muscle fibers, capillary congestion
Supporting references [1] [10] [16][18]
  • A dense surface eosinophilic band is typical of NSAID injury.[18]

The Correa cascade and precancerous progression

  • Chronic inflammation involving the corpus drives a stepwise histologic sequence:[2][19]
    1. non-atrophic gastritis
    2. atrophic gastritis
    3. intestinal metaplasia
    4. dysplasia
    5. intestinal-type adenocarcinoma
  • H. pylori is the dominant initiator, with about 75% attributable risk; it is a WHO class 1 carcinogen. AIG drives an analogous pathway restricted to the corpus.[2][19]
  • Atrophy and its subtypes
    • Atrophy is loss of native glands.
    • The glands are replaced by fibrosis (non-metaplastic atrophy), pseudopyloric/pyloric metaplasia, or intestinal metaplasia.
    • Intestinal metaplasia is therefore a subtype of atrophy, not a separate lesion.[20]
  • Pyloric metaplasia and SPEM
    • Spasmolytic polypeptide-expressing metaplasia (SPEM; TFF2⁺/GIF⁺) arises when corpus chief cells are reprogrammed after oxyntic injury.
    • It can precede intestinal metaplasia or develop alongside it.
    • Single-cell data now describe region-specific, partly non-linear trajectories layered on the classic tissue-level cascade.[21][7][22]
  • Intestinal metaplasia subtype
    • Incomplete intestinal metaplasia carries a higher cancer risk than the complete type.[23]
  • Molecular changes
    • Chromosomal instability, copy-number alterations, telomere shortening, and DNA methylation accumulate across the cascade.
    • Intestinal metaplasia is often described as a relative "point of no return" that signals elevated risk.[24]
  • Gastric microbiota
    • In the achlorhydric corpus, the gastric microbiota becomes dysbiotic and genotoxic. It can perpetuate carcinogenesis even after H. pylori is lost.[1][7]
  • Progression rates
    • Non-dysplastic intestinal metaplasia progresses to cancer at a pooled rate of about 12.4 per 10,000 person-years.[19]
    • Only about 1–3% of infected people ultimately develop gastric cancer.[2]

Histologic grading and staging: updated Sydney System, OLGA, and OLGIM

  • Updated Sydney System
    • It grades chronic inflammation, activity (neutrophils), atrophy, intestinal metaplasia, and H. pylori density as mild, moderate, or severe.[25]
    • It uses a defined 5-biopsy protocol: antrum ×2, corpus ×2, and incisura ×1.
    • Antral and corpus specimens go in separate jars so that atrophy can be localized.[26]
  • OLGA and OLGIM
    • OLGA (atrophy) and OLGIM (intestinal metaplasia) combine severity and topography into stages 0–IV.
    • Stages III–IV mark high cancer risk. International guidelines endorse these stages for risk stratification.[3][20]
System What it scores Strengths Limitations
Updated Sydney System Inflammation, activity, atrophy, intestinal metaplasia, H. pylori density; each graded mild/moderate/severe Standardized, topographic biopsy protocol; provides the grading that OLGA/OLGIM are built on Descriptive; does not by itself produce a cancer-risk stage
OLGA Atrophy of all subtypes (non-metaplastic, pyloric, intestinal) in antrum and corpus, combined into stages 0–IV Captures all atrophy, so OLGA stage is always at least the OLGIM stage; stages III–IV are high risk Higher interobserver variability
OLGIM Intestinal metaplasia only, in antrum and corpus, combined into stages 0–IV Lower interobserver variability; strongly elevated cancer risk at stages III–IV; measurable risk even at stage II May be less sensitive than OLGA
  • Support for the table above:[27][3]
  • Routine OLGA/OLGIM reporting remains limited in US practice.[26][28]

Clinical implications of mechanism

  • Topography predicts phenotype.
    • Antral-predominant gastritis means high acid and a tendency to duodenal ulcer.
    • Corpus-predominant atrophic gastritis means low acid and a tendency to gastric ulcer and cancer.[4]
  • Pepsinogen as a marker. Low pepsinogen I and a low pepsinogen I/II ratio signal corpus atrophy.[4]
  • Corpus-restricted atrophy with antral sparing should prompt evaluation for AIG.
    • Antral atrophy in a presumed AIG case suggests concurrent H. pylori infection.[10]
    • Corpus atrophy plus hypergastrinemia plus B12/iron deficiency suggests AIG and the risk of type 1 gastric NET.[10]
  • Reactive gastropathy is an injury pattern, not an infection. Foveolar hyperplasia with scant inflammation should prompt review of NSAIDs/aspirin, other culprit drugs, bile reflux, and alcohol.[16]
  • Timing of eradication. H. pylori eradication interrupts the cascade most effectively before atrophy or metaplasia develop. Once extensive metaplasia or dysbiosis is established, residual risk persists.[1][19]

Common pitfalls

  • Labeling endoscopic erythema "gastritis" without histology; much of it is reactive gastropathy.[16]
  • Ruling out AIG on negative PCA/IFA alone. Histology showing corpus atrophy is the anchor.[12]
  • Pooling antrum and corpus biopsies in one jar, which prevents topographic atrophy assessment and OLGA/OLGIM staging.[26]

Areas of uncertainty

  • It is debated whether intestinal metaplasia confers substantially more risk than pyloric metaplasia or atrophy alone. It is also unclear whether metaplasia without H. pylori is truly precancerous.[21]
  • Single-cell and lineage data are reframing the linear Correa cascade as a regionally stratified, partly parallel process. Diffuse-type cancer may bypass intestinal metaplasia altogether.[29][22]
  • A role for H. pylori in initiating AIG through molecular mimicry remains unproven.[10]
  • It is unsettled whether OLGA or OLGIM is the better predictor, and whether OLGIM stage II warrants surveillance.[28][27]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 Malfertheiner P, Camargo MC, El-Omar E; et al. (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. ↑ 2.0 2.1 2.2 2.3 Sundar R, Nakayama I, Markar SR, Shitara K, van Laarhoven HWM; et al. (2025). "Gastric cancer". Lancet. doi:10.1016/S0140-6736(25)00052-2.
  3. ↑ 3.0 3.1 3.2 Rugge M, Sugano K, Scarpignato C; et al. (2019). "Gastric cancer prevention targeted on risk assessment: Gastritis OLGA staging". Helicobacter. 24 (2): e12571. doi:10.1111/hel.12571. PMID 30773732.
  4. ↑ 4.0 4.1 4.2 Amieva MR, El-Omar EM (2008). "Host-bacterial interactions in Helicobacter pylori infection". Gastroenterology. 134 (1): 306–23. doi:10.1053/j.gastro.2007.11.009. PMID 18166359.
  5. ↑ Yao X, Smolka AJ (2019). "Gastric parietal cell physiology and Helicobacter pylori-induced disease". Gastroenterology. 156 (8): 2158–2173. doi:10.1053/j.gastro.2019.02.036. PMID 30831083.
  6. ↑ Waldum HL, Kleveland PM, Sørdal ØF (2016). "Helicobacter pylori and gastric acid: an intimate and reciprocal relationship". Therap Adv Gastroenterol. 9 (6): 836–844. doi:10.1177/1756283X16663395. PMID 27803738.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Wizenty J, Sigal M (2025). "Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis". Nat Rev Gastroenterol Hepatol. 22 (5): 296–313.
  8. ↑ Song et al. [VacA genotypes and pathogenicity]. Eur J Clin Microbiol Infect Dis. 2026.
  9. ↑ De Falco M, et al. [Helicobacter pylori pathogenesis / VacA]. J Cell Physiol. 2015.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 Lenti MV, Rugge M, Lahner E; et al. (2020). "Autoimmune gastritis". Nat Rev Dis Primers. 6 (1): 56. doi:10.1038/s41572-020-0187-8. PMID 32647173 Check |pmid= value (help).
  11. ↑ 11.0 11.1 Toh BH (2017). "Pathophysiology and laboratory diagnosis of pernicious anemia". Immunol Res. 65 (1): 326–330. doi:10.1007/s12026-016-8841-7. PMID 27538411.
  12. ↑ 12.0 12.1 Lenti MV, Miceli E, Vanoli A, Di Sabatino A. Autoimmune gastritis: emerging insights and clinical management. Nat Rev Gastroenterol Hepatol. 2026.
  13. ↑ Kishikawa H, Nakamura K, Ojiro K; et al. (2022). "Relevance of pepsinogen, gastrin, and endoscopic atrophy in the diagnosis of autoimmune gastritis". Sci Rep. 12 (1). doi:10.1038/s41598-022-07947-1.
  14. ↑ Green R, Allen LH, Bjørke-Monsen AL; et al. (2017). "Vitamin B12 deficiency". Nat Rev Dis Primers. 3: 17040. doi:10.1038/nrdp.2017.40. PMID 28660890.
  15. ↑ Bergamaschi G, Di Sabatino A, Corazza GR (2018). "Pathogenesis, diagnosis and treatment of anaemia in immune-mediated gastrointestinal disorders". Br J Haematol. 182 (3): 319–329.
  16. ↑ 16.0 16.1 16.2 16.3 El-Zimaity H, Riddell RH (2021). "Beyond Helicobacter: dealing with other variants of gastritis—an algorithmic approach". Histopathology. 78 (1).
  17. ↑ 17.0 17.1 Washington MK, Peek RM. Gastritis and gastropathy. In: Yamada's Textbook of Gastroenterology. 7th ed. Wiley-Blackwell; 2022.
  18. ↑ 18.0 18.1 18.2 Srivastava A, Lauwers GY (2007). "Pathology of non-infective gastritis". Histopathology. 50 (1): 15–29. doi:10.1111/j.1365-2559.2006.02553.x. PMID 17204018.
  19. ↑ 19.0 19.1 19.2 19.3 Gawron AJ, Shah SC, Altayar O; et al. (2020). "AGA Technical Review on Gastric Intestinal Metaplasia—Natural History and Clinical Outcomes". Gastroenterology. 158 (3): 705–731. doi:10.1053/j.gastro.2019.12.001. PMID 31816300.
  20. ↑ 20.0 20.1 Matysiak-Budnik T, Camargo MC, Piazuelo MB, Leja M (2020). "Recent guidelines on the management of patients with gastric atrophy: common points and controversies". Dig Dis Sci. 65 (7): 1899–1903.
  21. ↑ 21.0 21.1 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.
  22. ↑ 22.0 22.1 Zhang et al. [Single-cell/lineage trajectories in gastric precancerous progression]. Pharmacol Res. 2026.
  23. ↑ Shah SC, Gawron AJ, Mustafa RA, Piazuelo MB (2020). "Histologic subtyping of gastric intestinal metaplasia: overview and considerations for clinical practice". Gastroenterology. 158 (3): 745–750. doi:10.1053/j.gastro.2019.12.004. PMID 31887261.
  24. ↑ Yeoh KG, Tan P (2022). "Mapping the genomic diaspora of gastric cancer". Nat Rev Cancer. 22 (2): 71–84. doi:10.1038/s41568-021-00412-7. PMID 34702982 Check |pmid= value (help).
  25. ↑ 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. doi:10.1097/00000478-199610000-00001. PMID 8827022.
  26. ↑ 26.0 26.1 26.2 Shah SC, Piazuelo MB, Kuipers EJ, Li D (2021). "AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: Expert Review". Gastroenterology. 161 (4): 1325–1332.e7. doi:10.1053/j.gastro.2021.06.078. PMID 34454714 Check |pmid= value (help).
  27. ↑ 27.0 27.1 Benites-Goñi H, Cabrera-Hinojosa D, Latorre G; et al. (2024). "OLGA and OLGIM staging systems on the risk assessment of gastric cancer: a systematic review and meta-analysis of prospective cohorts". Therap Adv Gastroenterol. PMID 40104323 Check |pmid= value (help).
  28. ↑ 28.0 28.1 Huang RJ, Laszkowska M, In H, Hwang JH, Epplein M (2023). "Controlling gastric cancer in a world of heterogeneous risk". Gastroenterology. 164 (5): 736–751. doi:10.1053/j.gastro.2023.01.018. PMID 36706842 Check |pmid= value (help).
  29. ↑ Chen et al. [Gastric carcinogenesis pathways]. Cancer Metastasis Rev. 2026.

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