Gastric microenvironment and gastric cancer: Interplay of acid, microbiota, and inflammation

Abstract

Gastric cancer arises within a complex and dynamic microenvironment shaped by gastric acid secretion, microbial communities, and chronic inflammation. While Helicobacter pylori (H. pylori) remains the primary etiological factor, recent studies have highlighted the contribution of non-H. pylori microbiota and their interactions with host factors in the progression of gastric carcinogenesis. This review explores the bidirectional interplay among hypochlorhydria, microbial dysbiosis, and mucosal immune responses, emphasizing how this triad drives the transition from chronic gastritis to metaplasia and malignancy. We detail the ecological and functional properties of key gastric microbial taxa, examine the regulatory roles of acid and parietal cells, and discuss inflammation-mediated epithelial remodeling. In addition, we summarize advances in multi-omics technologies - including 16S rRNA sequencing, metagenomics, spatial transcriptomics, and single-cell RNA-seq-that are uncovering new dimensions of host-microbe interactions in the gastric niche. Collectively, these findings expand the classical Correa cascade into a more integrative ecosystem-based model of gastric cancer pathogenesis. While most studies remain preclinical or observational, the emerging insights provide a foundation for future investigations into risk stratification and gastric ecosystem-modulating strategies with potential relevance for prevention, early detection, and adjunctive intervention.

Key Words: Gastric microenvironment; Gastric acid; Parietal cells; Helicobacter pylori; Gastric microbiota

Core Tip: Gastric microenvironment is shaped by gastric acid secretion, microbiota composition, and mucosal inflammation, which collectively drive the progression from gastritis to metaplasia and gastric cancer. Their bidirectional interactions create a self-reinforcing cycle of hypochlorhydria, microbial dysbiosis, and chronic inflammation. This comprehensive review provides an integrated perspective on these processes, offering updated insights into pathogenic mechanisms, risk stratification, and potential preventive or therapeutic strategies.

INTRODUCTION

Gastric cancer remains a significant global health burden, ranking among the leading causes of cancer-related mortality worldwide[1,2]. Its prognosis is frequently poor, as early-stage disease is typically asymptomatic, and a substantial proportion of patients are diagnosed only after the disease has progressed to advanced stages[3]. Over the past few decades, considerable advances have been made in elucidating the molecular subtypes, risk factors, and pathogenic pathways of gastric cancer[4]. Large-scale genomic studies, including those conducted by The Cancer Genome Atlas, have identified several molecular subtypes, such as microsatellite instability-high, Epstein-Barr virus-associated, genomically stable, and chromosomal instability groups[5,6]. These classifications highlight the biological heterogeneity of gastric cancer and suggest that distinct subtypes may arise from different etiologic and environmental factors.

Intestinal-type gastric cancer has long been regarded as the prototypical example of inflammation-driven, mutation-accumulating carcinogenesis. The classical model outlines a multistep progression from chronic gastritis to atrophy, intestinal metaplasia (IM), dysplasia, and ultimately carcinoma[7,8]. This cascade was strongly substantiated by the identification of Helicobacter pylori (H. pylori) as a class I carcinogen, which initiates chronic inflammation and alters the mucosal environment in ways that promote malignant transformation[9,10]. However, despite its pivotal role, H. pylori alone does not fully explain the complexity and heterogeneity observed among patients with gastric cancer. Growing evidence suggests that additional factors-including gastric acid secretion, non-H. pylori microbial communities, mucosal immunity, host genetic susceptibility, and epithelial repair mechanisms-interact synergistically to drive tumorigenesis[11,12].

Among these factors, the gastric microenvironment has emerged as a conceptual framework that unifies three key physiological axes, as shown in Figure 1: (1) Gastric acid secretion and parietal cell homeostasis; (2) Composition and function of the gastric microbiota; and (3) Inflammation and epithelial remodeling.

Figure 1 Illustration of dysbiosis of the gastric microenvironment. This schematic figure depicts the altered gastric microenvironment under dysbiotic conditions, highlighting changes in gastric acidity, microbial composition, epithelial integrity, and inflammatory status that are associated with gastric carcinogenesis.

Historically, these components were regarded as distinct processes: Gastric acid was primarily considered a defensive barrier; bacteria, aside from H. pylori, were viewed as largely irrelevant; and inflammation was seen mainly as a consequence of infection. However, recent insights-particularly those arising from multi-omics sequencing, lineage-tracing animal models, and high-resolution imaging-indicate that these elements are profoundly interconnected[13,14]. Altered acid secretion reshapes the gastric microbial landscape; changes in microbial communities modulate mucosal immune responses; chronic inflammation drives epithelial reprogramming; and epithelial injury, in turn, influences both acid secretion and microbial colonization[14,15]. Collectively, these interactions constitute a self-reinforcing network that governs the trajectory of gastric mucosal homeostasis and disease progression[16].

The identification of lesions such as spasmolytic polypeptide-expressing metaplasia (SPEM), the discovery of previously underrecognized bacterial contributors such as Streptococcus anginosus (S. anginosus), and the growing awareness of parietal cell niche disruption have prompted a reevaluation of Correa’s classical model[17,18]. Rather than a strictly linear sequence, gastric carcinogenesis is increasingly viewed as a dynamic, nonlinear process shaped by continuous bidirectional interactions between the mucosal epithelium and its surrounding microenvironment[19]. Moreover, the transition from H. pylori-dominated microbial communities to more diverse polymicrobial ecosystems during atrophy supports a broader ecological perspective, suggesting that gastric cancer may represent the culmination of sustained microenvironmental dysregulation rather than the outcome of a single-pathogen-driven pathway.

Given these emerging insights, a comprehensive review of the gastric microenvironment is both timely and necessary. This article synthesizes evidence accumulated over the past three decades, with particular emphasis on: (1) The physiological and pathological roles of gastric acid secretion; (2) The expanding understanding of the gastric microbiota beyond H. pylori; and (3) The central role of inflammation in epithelial remodeling and carcinogenesis. By integrating these three axes, this review aims to present an updated conceptual model for the development of intestinal-type gastric cancer and to identify opportunities for future research and clinical translation.

GASTRIC ACID SECRETION AND THE PARIETAL CELL NICHE

Gastric acid secretion represents a fundamental physiological function of the stomach, essential for digestion, nutrient absorption, and microbial defense[20]. The regulation of gastric acidity is highly complex and precisely coordinated by neural, hormonal, and paracrine pathways that converge on parietal cells, which are primarily located in the gastric corpus[21,22]. Historically, gastric acid has been viewed chiefly as a bactericidal agent, offering protection against ingested pathogens and limiting microbial overgrowth in the upper gastrointestinal tract[23]. However, accumulating evidence now indicates that gastric acid secretion is closely associated with mucosal homeostasis, epithelial lineage dynamics, immune surveillance, and microbial ecology[24]. These findings have led to a reconsideration of the traditional paradigm, which regarded acid secretion solely as a defensive mechanism[25] (Figure 2).

Figure 2 Illustration of the coordinated control of parietal cell acid secretion by gastrin, somatostatin, and histamine. Gastrin stimulates enterochromaffin-like cells via CCK-2 receptors to release histamine, which activates parietal cells through H₂ receptors. Somatostatin from delta cells exerts inhibitory effects through SSTR2 on gastrin cells, ECL cells, and parietal cells, maintaining feedback regulation of gastric acid output.

Physiological regulation of gastric acid secretion

Parietal cells secrete hydrochloric acid via the H⁺/K⁺ ATPase proton pump located on their apical canalicular membranes. Acid secretion is stimulated by the synergistic actions of acetylcholine, gastrin, and histamine, each activating distinct but converging signaling pathways. Gastrin, produced by G cells in the antral mucosa, promotes not only acid secretion but also epithelial proliferation and differentiation in the corpus[21]. Histamine, released by enterochromaffin-like cells, enhances H⁺/K⁺ ATPase activity through H₂ receptor signaling. Somatostatin, an inhibitory hormone secreted by Delta cells, regulates this system through negative feedback, suppressing excessive acid secretion.

Under physiological conditions, the acid-secreting apparatus maintains a delicate balance that ensures microbial control while preserving mucosal integrity[26]. The mucus-bicarbonate barrier, produced by surface mucous cells, establishes a pH gradient that protects the epithelium from luminal acidity. Trefoil factors, secreted by mucous neck cells, further reinforce this barrier by stabilizing the mucosal surface in response to injury or stress[27]. These mechanisms highlight the critical role of coordinated interactions among parietal cells, mucous cells, endocrine cells, and the underlying stromal environment.

Parietal cell as a central ecological regulator

Beyond their role in acid production, parietal cells are increasingly recognized as key regulators of the gastric gland microenvironment. They provide trophic support to multiple epithelial lineages, particularly chief cells and isthmal stem/progenitor cells. Studies have shown that parietal cells secrete a variety of signaling molecules-including sonic hedgehog (Shh), EGF-family ligands, and Wnt-modulatory factors-that sustain glandular differentiation patterns and promote mucosal homeostasis[27]. Beyond their acid-secreting function, parietal cells also regulate the immune microenvironment. Engevik et al[20] demonstrated that Shh secreted by parietal cells acts as a chemoattractant for macrophages during epithelial repair; mice lacking myeloid Shh signaling exhibited impaired mucosal regeneration and reduced immune cell recruitment[3]. This finding supports a broader ecological role for parietal cells in coordinating immune-epithelial crosstalk within the gastric niche[28].

This functional centrality has led to the conceptualization of a parietal cell niche, wherein the presence and viability of parietal cells influence the behavior of neighboring epithelial populations. Loss of parietal cells disrupts this niche, resulting not only in impaired acid secretion but also in marked alterations in epithelial regeneration, mucosal immune signaling, and susceptibility to metaplasia[29]. These findings offer a mechanistic basis for the observed association between acid loss, parietal cell atrophy, and increased gastric cancer risk.

Parietal cell loss and its systemic consequences

Parietal cell atrophy is a hallmark of chronic gastritis and constitutes an early and critical step in the progression toward intestinal-type gastric cancer[30,31]. Whether triggered by chronic H. pylori infection, autoimmune gastritis, chemical injury, or sustained inflammation, the loss of parietal cells initiates a cascade of pathological events that extend well beyond diminished acid secretion. The consequences of parietal cell atrophy include.

Altered epithelial differentiation and gland remodeling: Parietal cell loss compromises the architectural and functional integrity of gastric glands. The reduction in parietal cell-derived signaling contributes to: (1) Hyperproliferation of isthmal stem/progenitor cells; (2) Chief cell de-differentiation or reprogramming under stress; (3) Expansion of mucous neck cell lineages; (4) Formation of SPEM; and (5) SPEM is widely recognized as a reparative lineage that arises in response to glandular injury. However, under conditions of chronic inflammation, persistent SPEM may progress to IM, thereby creating a cellular environment conducive to dysplastic transformation.

Microbial shifts driven by hypoacidity: Reduced acid secretion profoundly alters the gastric ecosystem. A hypoacidic environment permits colonization by oral, intestinal, and opportunistic bacteria that are normally suppressed by gastric acidity[32,33]. These newly established microbial populations may generate nitrosating agents, reactive oxygen species, and other metabolites that exacerbate mucosal injury and inflammation. As such, acid loss serves as a gateway event, facilitating the shift from H. pylori-dominated colonization to a polymicrobial community with significant carcinogenic potential.

Increased susceptibility to immune-mediated inflammation: This chronic inflammatory response accelerates glandular destruction, impairs epithelial renewal pathways, and promotes cytokine-driven epithelial reprogramming. Pro-inflammatory mediators such as interleukin (IL)-1β, interferon (IFN)-γ, and tumor necrosis factor-α (TNF-α) play key roles in amplifying this inflammatory environment and driving metaplastic transitions.

Rethinking acid secretion: Direct vs indirect mechanisms

Historically, there has been debate over whether gastric acid contributes to carcinogenesis through direct mucosal injury or indirectly via microbial and inflammatory pathways. Accumulating evidence now favors the latter: Acid secretion primarily influences gastric cancer risk by shaping the gastric microenvironment, including microbial composition, the inflammatory landscape, and epithelial regenerative dynamics[12]. Thus, parietal cell atrophy-and the resulting microenvironmental dysregulation-are increasingly recognized as a central driver of gastric carcinogenesis, with acid loss functioning as both a marker and a mediator of broader ecological disruption[34].

GASTRIC MICROBIOTA BEYOND H. PYLORI

For nearly a century, the stomach was widely considered a sterile environment due to its highly acidic lumen. This assumption was fundamentally challenged by the discovery of H. pylori, which demonstrated not only that bacteria could persist in the gastric environment, but also that microbial colonization could directly induce chronic inflammation and promote carcinogenesis[35,36]. For many years, research in gastric microbiology focused almost exclusively on H. pylori, reinforcing its role as the principal pathogen in gastric disease. However, the advent of high-throughput sequencing technologies, broad-spectrum culture methods, and multi-omics approaches has revealed that the gastric microbiota is significantly more diverse and dynamically regulated than previously understood[37,38]. Importantly, these microbial communities are not merely passive inhabitants; they actively influence mucosal immunity, epithelial cell turnover, and carcinogenic processes, particularly in the context of chronic mucosal injury and altered gastric acid secretion.

Recent studies have revealed that non-H. pylori bacteria can actively drive gastric tumorigenesis via multiple mechanisms, including chronic inflammation, genotoxic metabolite production, and immune evasion. Transplantation of gastric microbiota from patients with IM or cancer into germ-free mice led to rapid development of parietal cell loss and low-grade dysplasia, supporting a causal role for dysbiotic communities[39]. Specific oral bacteria such as S. anginosus and Fusobacterium nucleatum have demonstrated direct oncogenic potential in mouse models, inducing atrophy, IM, and dysplasia through inflammatory and proliferative pathways[40,41]. Human cohort and meta-analysis studies consistently identify enrichment of oral taxa-including Streptococcus, Fusobacterium, and Veillonella-in gastric cancer tissues, especially in H. pylori-negative patients[42]. Mechanistic investigations show that bacterial surface proteins (e.g., TMPC of S. anginosus) and metabolites can activate MAPK, nuclear factor kappa-B, and DNA damage pathways, while also promoting immune suppression via regulatory macrophage polarization[41]. Collectively, these findings support a paradigm in which polymicrobial dysbiosis-beyond H. pylori-acts as a critical ecological force in the stepwise progression of gastric carcinogenesis (Table 1).

Table 1 Commonly enriched taxa in atrophic stomachs.

Bacterial taxa	Classification
Streptococcus	Oral commensal
Veillonella	Oral commensal
Prevotella	Oral/intestinal
Lactobacillus	Acid-tolerant
Actinomyces	Oral commensal
Rothia	Oral commensal
Haemophilus	Oral/respiratory
Enterococcus	Intestinal
Escherichia/Shigella	Intestinal/pathogenic

Ecological shift and hypoacidity-driven dysbiosis

In early-stage H. pylori infection, the organism dominates the gastric niche through specialized acid-resistance mechanisms, niche formation within the mucus layer, and robust ecological exclusion of competing bacteria[43,44]. However, as chronic gastritis advances and parietal cell function declines, acid secretion diminishes, and the mucosal architecture becomes increasingly disrupted. This transition represents a critical ecological shift in which H. pylori begins to lose its competitive dominance, and the gastric environment becomes progressively more permissive to colonization by oral commensals, intestinal bacteria, and opportunistic pathogens. Such ecological expansion is a hallmark of gastric atrophy and IM and carries significant implications for cancer risk. Meta-analyses of gastric biopsies demonstrate that individuals with chronic atrophic gastritis or IM exhibit markedly increased microbial diversity compared with those with H. pylori-positive gastritis or healthy controls[45].

Gastric hypoacidity-whether resulting from H. pylori-associated atrophy, autoimmune gastritis, long-term proton pump inhibitor (PPI) use, or intrinsic parietal cell dysfunction-fosters microbial overgrowth through multiple interconnected mechanisms[46,47]. First, reduced bactericidal activity permits the survival and colonization of pH-sensitive commensals and pathogens, as gastric acid serves as the primary barrier to microbial entry[48]. Second, the loss of parietal cells disrupts glandular architecture and modifies mucus composition, thereby generating novel ecological niches for microbial adhesion and proliferation. Finally, hypoacidity impairs antigen presentation, modulates macrophage activity, and alters T-cell recruitment, collectively establishing an immune environment that favors microbial persistence. Together, these changes drive a multidimensional ecological transformation in which the stomach increasingly acquires characteristics of the upper intestinal tract, both microbiologically and physiologically[49].

Dynamic interactions and the polymicrobial network

Although H. pylori plays a dominant role in early disease, it engages in dynamic, context-dependent interactions with other bacterial species throughout the course of gastric pathology[37]. During early infection, H. pylori suppresses the growth of competing bacteria by modifying the acid microenvironment, producing bacteriocin-like factors, occupying protective niches within the deep mucus layer, and manipulating host immune responses. However, as acid secretion declines with the onset of atrophy and metaplasia, H. pylori progressively loses its ecological advantage. This shift permits colonization by bacteria originating from the oral cavity and the intestine, resulting in increased microbial diversity within the gastric environment[50]. Although H. pylori may persist at low abundance, it continues to influence inflammatory processes. Specific taxa may even promote H. pylori persistence by supplying metabolic substrates, degrading elements of the mucus barrier, or enhancing localized inflammation. In late-stage disease-particularly in the context of IM and dysplasia-H. pylori is often present at low levels or absent, yet carcinogenesis proceeds. This strongly suggests that non-H. pylori bacteria may serve as the primary drivers of inflammation and that microbial metabolites continue to induce epithelial stress. These observations support the emerging concept of a “polymicrobial carcinogenic network” that supplants the traditional single-pathogen paradigm. This evolving perspective is reinforced by advances in technology that have enabled unprecedented insights into the gastric microbiome. Techniques such as 16S rRNA sequencing provide broad taxonomic profiling, while metagenomic sequencing allows the identification of functional pathways[51]. Metabolomics has revealed bacterial metabolites implicated in mucosal injury, spatial transcriptomics has mapped host-microbe interactions at glandular resolution, and single-cell sequencing has identified epithelial responses to microbial stress[52-54]. Collectively, these approaches demonstrate that gastric microbial communities are spatially organized, metabolically active, and closely integrated within the mucosal microenvironment. These findings confirm that gastric cancer, particularly in its later stages, is not exclusively driven by H. pylori.

INFLAMMATION-DRIVEN EPITHELIAL REMODELING

Chronic inflammation is one of the most decisive forces shaping the gastric epithelium and initiating the cascade toward carcinogenesis[55]. In the stomach, where the mucosa is continuously exposed to mechanical stress, dietary components, and a diverse array of microbial stimuli, epithelial homeostasis depends on a precisely regulated balance between injury and repair[56]. When inflammation becomes persistent-as seen in long-standing H. pylori infection, microbial dysbiosis, parietal cell atrophy, autoimmune gastritis, or chemically induced mucosal injury-this balance breaks down[57]. The epithelial lining is subsequently subjected to continuous cycles of damage and regeneration, generating a biological context particularly conducive to metaplastic transformation and malignant progression[58]. The gastric response to inflammatory injury is therefore not merely a transient repair mechanism but a prolonged process of cellular reprogramming, during which epithelial identity, lineage allocation, and proliferative dynamics are fundamentally altered[59] (Figure 3).

Figure 3 Helicobacter pylori-induced epithelial injury triggers the release and clearance of cell debris by macrophages, activating innate immune signaling and antigen presentation. Dendritic cells and macrophages promote CD4+ T-cell activation through co-stimulatory pathways, driving Th1 and Th17 differentiation. The resulting cytokines (e.g., interferon-γ, tumor necrosis factor-α, interleukin-17) amplify chronic inflammation and contribute to remodeling of the epithelial phenotype. B cells activated through T-cell help differentiate into plasma cells and secrete IgA to support mucosal protection. Together, these interactions link local tissue damage with chronic inflammation and downstream epithelial changes. H. pylori: Helicobacter pylori; IL: Interleukin; IFN: Interferon; TNF-α: Tumor necrosis factor-α.

Among the various triggers of gastric inflammation, H. pylori remains the most extensively characterized and potent. Its virulence factors, particularly CagA and VacA, exert profound effects on epithelial signaling[60]. CagA is translocated directly into host cells, where it disrupts pathways that regulate cell polarity, adhesion, and proliferation, leading to aberrant activation of oncogenic signals such as SHP2-ERK and β-catenin[61]. VacA impairs mitochondrial function, suppresses T-cell responses, and compromises epithelial barrier integrity. Collectively, these effects establish a persistent inflammatory microenvironment characterized by the continuous infiltration of neutrophils, macrophages, and T cells, which release reactive oxygen and nitrogen species that cause DNA damage.

A key consequence of this inflammatory milieu is the disruption of parietal cell function, leading to the collapse of the glandular niche. Cytokines such as IL-1β, TNF-α, and IFN-γ strongly inhibit acid secretion and promote parietal cell apoptosis[62]. As parietal cells are lost, the gastric epithelium is deprived not only of its ability to maintain luminal acidity but also of the molecular signals necessary to sustain normal lineage differentiation. This destabilization of the glandular ecosystem places a significant regenerative burden on the mucosa, compelling chief cells and progenitor populations to engage alternative differentiation pathways. Over time, SPEM often progresses to IM, driven by transcriptional reprogramming events such as CDX2 activation, epigenetic modifications, and sustained exposure to inflammatory cytokines[63].

The transition from normal epithelium to metaplasia is accompanied by extensive remodeling of the stromal compartment. Macrophages accumulate in large numbers and adopt context-dependent phenotypes: M1 macrophages exacerbate tissue injury through oxidative bursts and the release of pro-inflammatory cytokines, whereas M2 macrophages facilitate tissue remodeling, angiogenesis, and the expansion of metaplastic lineages[64-66]. Fibroblasts activated by chronic inflammation differentiate into cancer-associated fibroblasts, which secrete growth factors and remodel the extracellular matrix to support epithelial proliferation and invasion. T cells, particularly Th1-polarized subsets, produce IFN-γ and other cytokines that contribute to ongoing parietal cell loss, while regulatory T cells expand and suppress immune surveillance, enabling the persistence and clonal expansion of mutated epithelial cells. The cumulative effect is a stromal environment that no longer restrains aberrant epithelial growth but instead actively supports it[67].

Chronic inflammation also accelerates the accumulation of genetic and epigenetic alterations within the epithelial compartment. Reactive oxygen and nitrogen species produced by infiltrating immune cells induce sustained DNA damage, overwhelming repair mechanisms and promoting mutations in key tumor suppressor genes, such as TP53, ARID1A, and CDH1[68-70]. In addition, chronic injury increases stem cell turnover, expanding the population of cells vulnerable to mutation and facilitating the selective clonal expansion of lineages with survival advantages in the inflamed microenvironment. Epigenetic reprogramming - via DNA methylation, histone modification, and chromatin remodeling - further reinforces metaplastic identity, rendering the progression toward dysplasia increasingly irreversible. Over time, the gastric epithelium transitions from a state characterized by dynamic injury and repair to one dominated by a progressively expanding field of genetically altered, inflammation-adapted epithelial clones.

In this context, inflammation functions not merely as a downstream consequence of gastric injury but as a central integrator of the gastric microenvironment. It amplifies the effects of acid dysregulation, accelerates the consequences of microbial dysbiosis, drives epithelial reprogramming, and reshapes the stromal architecture to support neoplastic development[71]. The cumulative outcome is an organ-wide ecological transformation, in which the previously well-regulated gastric mucosa evolves into a chronically injured, metabolically stressed, and genetically unstable landscape primed for malignant progression[72].

INTERACTIONS AMONG GASTRIC ACID, MICROBIOTA, AND INFLAMMATION: AN INTEGRATED MICROENVIRONMENTAL MODEL

Chronic gastritis - most often initiated by prolonged H. pylori infection - destroys acid-secreting parietal cells, raising gastric pH and enabling colonization by non-Helicobacter microbes[73]. This achlorhydric environment permits normally suppressed organisms (including oral and intestinal commensals) to flourish. In particular, nitrate-reducing bacteria convert dietary nitrites into N-nitrosamines (potent mutagens), and lactate-producing microbes generate high levels of lactate and acetaldehyde; these metabolites (and other reactive oxygen/nitrogen species) can directly damage DNA and fuel tumor metabolism[74]. Collectively, such microbial factors provoke epithelial injury and cell death, releasing pro-inflammatory signals. The gastric mucosa becomes infiltrated by immune cells (neutrophils, macrophages) and overexpresses cytokines and enzymes (e.g., IL-6, TNF-α, COX-2), creating an oxidatively stressed, pro-inflammatory microenvironment. Sustained inflammation then sets up a vicious cycle of DNA damage and regeneration, establishing a chronic gastritis[75].

For example, once parietal cells are lost, acid output collapses and the stomach lumen becomes neutral or alkaline. Bacterial counts then surge to millions per milliliter (versus virtually none in a healthy stomach), and available substrates (urea, nitrates, sugars) favor fermentative and nitrate-reducing species. Cytokines and oxidative stress from ongoing gastritis further impair any remaining parietal cells, reinforcing hypochlorhydria and loss of the acid barrier[76]. Over time, this self-amplifying cycle creates a procarcinogenic niche: The inflamed, high-pH mucosa experiences ongoing inflammatory and metabolic stress[77]. Additional organisms (e.g., Candida and oral bacteria like Fusobacterium and Porphyromonas) exploit this niche to amplify mucosal injury[78]. In practice, the gastric flora shifts toward species associated with chronic inflammation and nitrosation[79]. These microbes in turn drive chronic gastritis, which further suppresses acid secretion[80]. Over time, this feedback loop promotes epithelial transformation toward gastric carcinoma[81]. The model explains both H. pylori-dependent and -independent carcinogenesis[82], as diverse bacteria can contribute once the acid barrier is lost. In many ways, H. pylori’s role is to trigger the cascade: Patients with autoimmune gastritis or long-term acid suppression show similar dysbiosis and elevated cancer risk. Thus, gastric carcinogenesis follows the chain: Hypochlorhydria → dysbiotic microbiota → chronic inflammation → epithelial transformation. Ultimately, converging microbial and immune insults destroy the gastric microenvironment and drive malignant conversion[83,84].

CLINICAL IMPLICATIONS AND TRANSLATIONAL PERSPECTIVES OF THE GASTRIC MICROENVIRONMENT

PPIs, non-steroidal anti-inflammatory drugs (NSAIDs), and antibiotic therapies all have clinically relevant effects on the gastric microenvironment that influence gastric cancer risk. Long-term PPI use reduces gastric acidity and alters the gastric microbiome, and multiple epidemiological studies have linked chronic PPI therapy to a modest increase in gastric cancer risk (typically on the order of 1.5-2-fold)[31]. This association appears to persist even after H. pylori eradication, suggesting that profound acid suppression and resultant bacterial overgrowth (e.g., increased colonization by oral flora such as Streptococcus spp.) may promote carcinogenesis via hypergastrinemia and N-nitrosamine formation. In contrast, NSAID use-particularly aspirin-has been associated with lower gastric cancer incidence, presumably by mitigating chronic inflammatory drive; meta-analyses report roughly a 20% risk reduction in long-term NSAID users[85]. Antibiotic-based eradication of H. pylori is a cornerstone of gastric cancer prevention: Randomized trials and meta-analyses confirm that curing H. pylori infection significantly decreases subsequent gastric cancer incidence[86]. Population-level data have not borne out initial concerns that widespread H. pylori eradication might increase esophageal adenocarcinoma rates; notably, no rise in esophageal cancer has been observed post-eradication in large cohort studies. However, gastric cancers still occur in the absence of H. pylori, and recent evidence implicates other gastric microbes in carcinogenesis. For example, even after successful H. pylori clearance, patients with gastric dysbiosis (enrichment of non-H. pylori bacteria such as Fusobacterium and Neisseria) show elevated gastric cancer incidence[42]. These findings raise the question of whether assessing the gastric microbiota beyond H. pylori could inform risk stratification in the future. Indeed, emerging research suggests that microbiome-based diagnostics (e.g., microbial DNA profiling of gastric, saliva, or stool samples) can distinguish gastric cancer or high-risk precursors with notable accuracy. Nonetheless, such approaches remain investigational; there are currently no established guidelines for screening or surveillance of non-H. pylori gastric microbiota, and further validation of microbial biomarkers is required before clinical adoption.

CONCLUSION

The development of gastric cancer is increasingly recognized not as the result of a single pathogenic event but as the outcome of a prolonged ecological shift within the gastric microenvironment. Acid secretion, microbial composition, and inflammatory responses constitute a dynamic and interdependent network that determines whether the stomach maintains physiological homeostasis or progresses toward metaplasia and malignant transformation. Disruption of gastric acidity-whether induced by H. pylori infection, parietal cell atrophy, autoimmune processes, or environmental exposures-creates a permissive niche that facilitates microbial expansion and diversification.

These altered microbial communities, in turn, generate metabolic products and inflammatory signals that exacerbate epithelial stress and promote chronic mucosal injury. Sustained inflammation progressively destabilizes epithelial identity, driving lineage reprogramming, metaplastic transitions, increased cellular turnover, and the accumulation of genetic and epigenetic alterations that anchor the trajectory toward dysplasia. Recent discoveries, including the carcinogenic roles of non-H. pylori bacteria, further highlight that gastric carcinogenesis is shaped by broader microbial ecosystems rather than by a single pathogen. Taken together, these insights support a view of gastric cancer as a progressive collapse of gastric ecological equilibrium-an extended process in which acid loss, microbial dysbiosis, and chronic inflammation reinforce one another and collectively reshape epithelial evolution. Recognizing gastric cancer as a microenvironment-driven disease provides a unifying conceptual framework that integrates past observations and opens new avenues for understanding, detecting, and ultimately intervening in the earliest stages of carcinogenesis.