H. pylori infection elicits a complex gastric immune reaction marked by accumulation of adaptive and innate immune cells—comprising T and B lymphocytes, neutrophils, plasma cells, and macrophages—together with variable injury to the surface epithelium (Fig. 1) [1]. Direct invasion of H. pylori into the gastric mucosa is rarely observed in vivo; therefore, alternative mechanisms underlying the induction of inflammation have been proposed. Among the proposed pathways, soluble factors released by the bacteria play a significant role in initiating mucosal inflammation. Notably, urease has been identified in the lamina propria, where the H. pylori urease complex facilitates chemotaxis of neutrophils and monocytes and enhances activation of mononuclear immune cells [2]. Additionally, low-molecular-weight compounds and H. pylori porins exert chemotactic effects [3,4]. In experimental settings, soluble components derived from H. pylori intensify endothelial cell–neutrophil interactions and facilitate leukocyte adhesion through integrin-dependent engagement of CD11b/CD18 and CD11a/CD18 with intercellular adhesion molecule-1 [5].

In addition to soluble bacterial factors, H. pylori can provoke gastric inflammation through direct interactions with epithelial cells, thereby amplifying cytokine production. In individuals with infection, the gastric epithelium exhibits augmented manifestation of proinflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin-1β, interleukin-2, interleukin-6, and interleukin-8 [6-10]. This conceptual framework aligns with earlier observations showing that epithelial engagement by Salmonella typhimurium initiates chemokine-driven signaling cascades guiding polymorphonuclear leukocytes toward the epithelial surface. Among these mediators, interleukin-8 functions as a potent neutrophil activator and is produced predominantly by gastric epithelial cells in vivo [11-13].

Autoimmune gastritis represents a slowly evolving inflammatory condition in which immune-driven injury selectively targets gastric parietal cells, leading to their progressive depletion and replacement by atrophic and metaplastic epitheliumc [14,15]. The disease process is orchestrated through coordinated actions of autoantibodies directed against the parietal cell H+/K+-ATPase and antigen-specific T lymphocytes, resulting in declining acid secretion and eventual achlorhydria. In parallel, antibodies against intrinsic factor compromise cobalamin absorption [14].

Multiple observations support the involvement of immunemediated mechanisms in a subset of individuals with H. pylori– associated gastritis. These include prominent infiltration of T and/or B lymphocytes surrounding gastric glands and extending into the epithelial layer of the corpus mucosa [16], a preferential burden of atrophic and inflammatory changes within the oxyntic region [17,18], augmented apoptotic activity in oxyntic glands, and functional alterations characterized by reduced acid secretion accompanied by hypergastrinemia [19]. Additional support for a causal link between gastric autoimmunity and H. pylori infection comes from reports indicating that bacterial eradication stabilizes or partially reverses early, pre-atrophic stages of autoimmune gastritis [20-22].

Despite growing insights, the biological mechanisms underlying autoimmune gastritis remain unclear. Currently, the disease is most appropriately conceptualized as arising from a multifactorial immune landscape, in which genetic susceptibility, environmental exposures, and hormonal influences intersect with selective and broad immune dysregulation to drive autoimmune pathology [23,24].

Gastrointestinal toxicity linked with nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin largely reflects suppression of cyclooxygenase activity, a key enzymatic pathway that governs prostaglandin synthesis from arachidonic acid [25]. The inhibition of the inducible cyclooxygenase-2 isoform underlies the desired antipyretic, anti-inflammatory, analgesic, and antipyretic effects of these agents. However, the systemic blockade of the constitutive cyclooxygenase-1 isoform reduces prostaglandin availability and consequently impairs mucosal protective mechanisms [25].

Reduced prostaglandin synthesis compromises gastric mucosal defense by lowering intrinsic resistance [26] and diminishing mucosal perfusion, an effect partly mediated by NSAID- and aspirin-induced suppression of nitric oxide synthesis through blockade of nitric oxide synthase [27]. Concurrently, decreased prostaglandin availability shifts arachidonic acid metabolism toward the lipoxygenase pathway, enhancing the generation of leukotrienes—particularly leukotriene B4—as well as other proinflammatory mediators such as complement component C5 and TNF-α, thereby exacerbating mucosal inflammation and ischemic injury [28,29].

NSAIDs exert local epithelial toxicity through direct interactions with membrane phospholipids and disruption of mitochondrial oxidative phosphorylation, resulting in structural injury to cell membranes, including breakdown of the phos-pholipid barrier and tight junction integrity. These changes increase transcellular permeability. In parallel, systemic cyclooxygenase inhibition compromises microvascular perfusion, while luminal injurious factors further intensify mucosal damage, collectively promoting inflammation, erosive injury, and ulcer formation [30].

Immune checkpoint inhibitors have recently appeared as a cause of gastritis driven by immune imbalance rather than direct chemical toxicity or acid-mediated injury. Although the exact pathogenic pathways remain unclear, these agents broadly amplify T-cell activation and expansion, interfere with the homeostasis of regulatory T cells, and may enhance humoral autoimmune responses, collectively resulting in immune-related adverse events [31]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors are associated with an increase in circulating Th17 populations and depletion of regulatory T cells, thereby predisposing to immune toxicity [32-34]. In contrast, programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) inhibitors disrupt the differentiation of regulatory T cells from Th1 precursors, attenuating immunosuppressive control and augmenting effector T-cell activity [35,36]. The resulting immune disequilibrium promotes excessive activation of CD8+ and CD4+ T lymphocytes, culminating in immune-mediated injury to otherwise normal gastric mucosa [37]. Furthermore, blockade of PD-1/PD-L1 and CTLA-4 pathways enhances the production of proinflammatory cytokines, including TNF, interferon-γ, and interleukin-17, which further reinforce T-cell stimulation and proliferation, and subsequent mucosal inflammation [31].

Cytomegalovirus (CMV) typically remains latent in lymphocytes but reactivates during immunosuppression [38]. It is believed to cause gastric injury through vasculitis of endothelial cells, which leads to vessel occlusion and ischemic mucosal damage, resulting in ulcers even in immunocompetent patients [39].

Epstein–Barr virus induces chronic inflammation during its viral reactivation cycle by recruiting high levels of immune cell infiltration [40]. This persistent response triggers tissue damage, significantly increasing the risk of atrophic gastritis, a key precursor in the progression toward gastric cancer.

Collagenous gastritis is defined by subepithelial collagen bands >10 μm with lamina propria inflammation. Eosinophilic gastritis shows dense eosinophilic infiltration (>30/HPF) in the absence of secondary causes. Systemic disease–related gastritis includes graft-versus-host disease (glandular apoptosis), CMV infection, sarcoidosis, and amyloidosis.

Technological progress in endoscopic imaging has enabled high-resolution visualization of gastric mucosal architecture, substantially expanding its diagnostic utility. Endoscopy now serves as a cornerstone for evaluating gastritis, identifying H. pylori infection, and stratifying the risk of gastric cancer. To harmonize the interpretation of endoscopic gastric findings, the Kyoto classification was suggested in 2013.41 This framework standardizes endoscopic assessment of mucosal features associated with gastric carcinogenesis. The classification encompasses 19 findings, including diffuse erythema, patchy erythematous changes, map-like redness, spotty redness, and linear erythematous streaks; structural abnormalities such as mucosal nodularity, atrophy, intestinal metaplasia, and hypertrophic or tortuous folds; vascular patterns including a regular arrangement of collecting venules; epithelial and surface features such as mucosal edema, erosive lesions, adherent mucus, and hematin; and focal lesions including foveolar hyperplastic polyps, fundic gland polyps, xanthomas, multiple flat white elevated lesions, and raised erosions (Fig. 2). In the Kyoto classification framework, diffuse mucosal redness—regardless of whether collecting venules are preserved—is primarily used to reflect H. pylori infection status. In contrast, structural features such as mucosal atrophy, nodularity, hypertrophic folds, and intestinal metaplasia are weighted as features of gastric cancer risk [42,43].

The diagnosis of gastritis needs histopathological confirmation of inflammatory cell infiltration within the gastric mucosa, which may involve the lamina propria, glandular lumina, or the epithelial surface. In certain conditions, most notably Crohn’s disease–associated gastritis, inflammatory infiltrates can extend beyond the mucosa into the submucosa [44]. Lymphoid aggregates or epithelioid granulomas may be encountered. Detailed evaluation of the inflammatory cell composition, their anatomical distribution across oxyntic and mucosecretory regions, and the characteristics and localization of accompanying epithelial alterations, such as mucosal atrophy, provides critical information regarding the underlying cause of gastritis [44].

In addition to the inflammatory infiltration, structural changes of the epithelial compartment are frequently observed, among which mucosal atrophy is of particular clinical importance. The presence of atrophy serves as the defining feature distinguishing non-atrophic from atrophic gastritis, which typically reflects prolonged, unresolved inflammatory injury. Therefore, accurate assessment of mucosal atrophy is a clinical priority, given its established association with an increased risk of gastric cancer [44].

Glandular atrophy can arise from multiple injurious influences, which may act simultaneously, leading to direct cytotoxic damage, such as that induced by H. pylori, or immunemediated injury, as observed in autoimmune gastritis. These processes affect the native glandular compartments, including oxyntic glands of the corpus and fundus and mucin-secreting glands of the antrum. Irrespective of the underlying pathogenic pathway or anatomical distribution, atrophy is defined by the disappearance of normal, resident glandular structures [45,46].

The Updated Sydney System integrates topography, morphology, and etiology to generate standardized and clinically relevant diagnoses of gastritis. It recommends systematic biopsies from the antrum, corpus, and incisura, with grading of H. pylori density, neutrophilic activity, chronic inflammation, glandular atrophy, and intestinal metaplasia using a visual analogue scale. Routine hematoxylin and eosin staining is supplemented by special stains such as modified Giemsa or Warthin– Starry for H. pylori, immunohistochemistry when needed, and Alcian blue/periodic acid–Schiff stain for intestinal metaplasia [47].

The Operative Link for Gastritis Assessment and Operative Link on Gastric Intestinal Metaplasia are histology-based staging systems derived from the Updated Sydney System, which stratifies gastric cancer risk according to the extent and topography of atrophy and intestinal metaplasia. Patients with stage III/IV show a significantly increased risk of gastric cancer and warrant closer endoscopic surveillance [48].

Serologic evaluation complements endoscopy and histology in gastritis. Autoimmune gastritis is supported by parietal cell and intrinsic factor antibodies. Serum gastrin and pepsinogen I/II levels (and ratio) help detect corpus atrophy non-invasively and correlate well with histologic findings [49].

H. pylori infection is the most significant established determinant of gastric cancer risk and was described as a Group 1 carcinogen in 1994 [50]. Globally, approximately two million cases of infection-related cancer occur each year, with gastric cancer related to H. pylori infection accounting for approximately one-third of this total [51]. The protective effect of H. pylori eradication was confirmed by a 2014 meta-analysis of prospective randomized controlled trials performed in asymp-tomatic adult populations [52]. Across the pooled studies, gastric cancer developed in 51 of 3294 patients who received eradication therapy (1.6%), whereas 76 of 3203 participants in the comparison group (2.4%) were diagnosed with gastric cancer, corresponding to a relative risk of 0.66 (95% confidence interval [CI], 0.46–0.95).

Despite recommendations advocating H. pylori eradication as a strategy to reduce the risk of gastric cancer, evidence from population-based settings remains limited. To address this gap, recent large-scale investigations in Japan pooled data from four cohort studies comprising 48530 men and women aged 40–74 years [53]. During the period from 2010 to 2018, a total of 649 incident cases of gastric cancer were documented. Participants who tested positive for H. pylori and/or pepsinogen markers and did not receive eradication therapy exhibited a markedly elevated cancer risk compared with those negative for both markers (hazard ratio [HR], 5.89; 95% CI, 4.41–7.87). In contrast, participants who had undergone eradication before study entry showed a transient increase in risk shortly after treatment (baseline to <1 year: HR, 1.74; 95% CI, 1.18–2.57), followed by a progressive decline over time (1 year to <6 years: HR, 0.81; 95% CI, 0.59–1.11; ≥6 years: HR, 0.44; 95% CI, 0.28– 0.68). These findings indicate that H. pylori eradication is associated with a sustained reduction in the long-term risk of gastric cancer.

Even after successful eradication of H. pylori, individuals with histologically confirmed intestinal metaplasia and residual gastric mucosal atrophy remain at heightened risk of gastric malignancy. In a retrospective cohort of 2737 patients monitored with annual endoscopic surveillance following eradication therapy, the incidence of diffuse-type gastric cancer rose progressively over time, with the most considerable increase observed among those presenting with mild to moderate atrophic changes at baseline [54]. Post-eradication surveillance revealed an annual gastric cancer incidence rate of 0.35% within the study cohort.

Based on these findings, extended endoscopic surveillance for more than a decade is advised, with a particular emphasis on older individuals [54-59].

Surveillance strategies should be individualized, with follow-up intervals determined by risk stratification that incorporates the severity and distribution of gastric atrophy (antral versus corpus involvement), as well as patient-specific factors including age, family history of gastric cancer, and coexisting medical conditions [60].