Herbal Medicine and the Gastrointestinal Microbiota in Gastric Precancerous Lesions and Gastric Cancer: Mechanistic Evidence and Translational Challenges

Abstract

Gastric cancer (GC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Increasing evidence indicates that microbial alterations associated with GC extend beyond Helicobacter pylori (H. pylori) infection and involve coordinated ecological changes across the oral cavity, gastric mucosa, gastric fluid, and intestine. These compartment-specific microbial communities exhibit distinct compositional and functional characteristics throughout the progression from chronic gastritis and precancerous lesions of gastric cancer (PLGC) to established GC, suggesting that gastrointestinal microbial dysbiosis contributes to disease development through interactions involving mucosal barrier function, inflammation, immune regulation, and microbial metabolism. Traditional Chinese medicine (TCM) has been widely used in the prevention and treatment of GC and PLGC. Recent experimental and clinical studies suggest that certain herbal formulas and natural compounds may influence gastrointestinal microbial composition, microbial metabolites, host immune responses, and epithelial barrier function while also exhibiting anti- H. pylori, anti-inflammatory, and anti-tumor activities. This review summarizes current evidence regarding compartment-specific alterations of the oral, gastric mucosal, gastric fluid, and intestinal microbiota during gastric carcinogenesis, emphasizing the ecological heterogeneity of these microbial niches and the methodological considerations required for their interpretation. We further summarize experimental evidence demonstrating that TCM formulas and bioactive constituents regulate gastrointestinal microbiota, microbial metabolism, programmed cell death, and inflammatory signaling in models of H. pylori infection, PLGC, and GC. In addition, available randomized clinical studies investigating microbiota-related effects of TCM formulas in patients with PLGC or GC are critically reviewed.

Introduction

Gastric cancer (GC) remains one of the leading causes of cancer incidence and mortality worldwide. Characterized by an insidious onset, rapid progression, and a high propensity for distant metastasis, GC is associated with poor overall survival and continues to pose a major public health challenge in China and globally.¹ Gastric carcinogenesis is generally recognized as a multistep process that progresses from chronic gastritis through a series of precancerous lesions of gastric cancer (PLGC), including gastric atrophy, intestinal metaplasia, and dysplasia, ultimately culminating in invasive carcinoma. This continuous “inflammation–precancerous lesion–carcinogenesis” cascade provides a critical therapeutic window for early prevention and intervention. Therefore, developing effective strategies to prevent and treat GC and its precancerous lesions is of considerable clinical importance.

Recent studies have suggested that traditional Chinese medicine (TCM) may influence gastric disease progression through multiple bioactive constituents acting on diverse molecular targets. A growing body of evidence suggests that TCM exerts promising therapeutic effects in upper gastrointestinal malignancies.² Following oral administration, TCM directly interacts with the gastrointestinal microenvironment and establishes complex bidirectional interactions with the gastrointestinal microbiota. In addition to alleviating common gastrointestinal symptoms, such as belching, acid reflux, abdominal distension, abdominal pain, and dyspepsia, TCM can reshape microbial community composition, regulate microbiota-derived metabolites, modulate host immune responses, and maintain mucosal barrier integrity, thereby influencing both the initiation and progression of GC and PLGC.³

The gastrointestinal microbiota has emerged as a pivotal regulator connecting host metabolism, immunity, inflammation, and epithelial homeostasis, and is now recognized as a key contributor to the development of GC and PLGC.⁴ Microbial dysbiosis may promote gastric carcinogenesis through multiple mechanisms, including disruption of the gastric mucosal barrier, persistent activation of inflammatory signaling, immune dysregulation, and the production of carcinogenic metabolites. Although several recent reviews have summarized the associations among gastrointestinal microbiota, gastric cancer, precancerous gastric lesions, and TCM interventions,^5–8 most have focused on descriptive changes in microbial composition or general therapeutic effects. A comprehensive overview integrating microbiota remodeling with microbial metabolism, immune regulation, programmed cell death, and mucosal barrier restoration, particularly in the context of specific TCM formulas and active constituents, remains lacking.

Accordingly, this review comprehensively summarizes current evidence regarding the role of TCM in modulating the gastrointestinal microbiota during the development of GC and PLGC. We highlight the regulatory effects of TCM on the oral, gastric, and intestinal microbiota, together with microbiota-associated metabolic reprogramming, immune modulation, mucosal barrier repair, and programmed cell death. Furthermore, we discuss evidence from both preclinical and clinical studies to illustrate the therapeutic potential of microbiota-targeted TCM interventions for the prevention and treatment of GC and PLGC, with the aim of providing updated mechanistic insights and future directions for translational research.

Literature Search Strategy

Relevant studies were identified through systematic searches of the PubMed, Web of Science, Embase, and CNKI databases from inception to June 2026. The search strategy combined Medical Subject Headings and free-text terms, including “gastric cancer,” “precancerous lesions of gastric cancer,” “gastric precancerous lesions,” “gut microbiota,” “gastric microbiota,” “oral microbiota,” “traditional Chinese medicine,” “Chinese herbal medicine,” “herbal formula,” and the names of representative herbal formulas and active compounds. Original studies involving human subjects, animal models, and cell-based experiments, together with relevant multi-omics studies published in English or Chinese, were included. Additional eligible articles were identified by manually screening the reference lists of retrieved publications. As this is a narrative review, no predefined systematic review protocol, risk-of-bias assessment, or quantitative quality evaluation was performed.

Compartment-Specific Alterations of the Gastrointestinal Microbiota in Gastric Cancer

The stomach has long been considered a relatively hostile microbial habitat because of its highly acidic environment, which limits microbial survival and colonization. However, following the discovery of Helicobacter pylori (H. pylori) and the advent of high-throughput sequencing and multi-omics technologies, it has become evident that the stomach harbors a low-biomass yet diverse microbial ecosystem. Compared with the intestinal microbiota, the gastric microbiota is more susceptible to local environmental factors, including gastric acidity, H. pylori infection status, medication exposure, and anatomical sampling sites. Consequently, comprehensive characterization of the gastric microbiome remains challenging because of its considerable biological complexity and marked inter-individual variability.

In healthy individuals, the gastric microbiota is primarily composed of the phyla Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, Fusobacteria, and Gemmatimonadetes, encompassing more than 100 bacterial genera, including Streptococcus, Lactobacillus, Rothia, Neisseria, Veillonella, Haemophilus, and Prevotella.⁹ Importantly, the gastric microbiota displays pronounced spatial heterogeneity. Microbial richness is generally higher in the gastric corpus than in the antrum, whereas microbial diversity is greater in gastric fluid than in the mucosal layer.¹⁰ Moreover, gastric mucosa-associated communities are enriched in Firmicutes and Proteobacteria, whereas gastric fluid contains relatively higher proportions of Actinobacteria and Bacteroidetes, underscoring the substantial influence of sampling compartments on microbial profiling⁶ (Figure 1).

Figure 1.

Compartment-specific Microbiota Dysbiosis and the Oral–Gut Axis in Gastric Carcinogenesis.

Oral Microbiota

Microbial alterations associated with gastric carcinogenesis are not confined to the stomach but involve multiple microbial compartments throughout the gastrointestinal tract. As the upstream microbial ecosystem of the digestive tract, the oral cavity harbors a highly diverse microbial community whose composition may influence downstream gastric microbial profiles through oral–gastric microbial transmission. Current evidence suggests that interactions between oral microorganisms, gastric microbial communities, and host mucosal responses may occur during different stages of gastric carcinogenesis, although the underlying mechanisms remain incompletely understood.

Population-based studies using 16S rRNA sequencing have demonstrated that the oral microbiota exhibits a community structure distinct from those of the gastric antrum and corpus, indicating that the oral cavity represents an independent microbial ecosystem rather than simply a reservoir of gastric microorganisms. Oral microbial composition is also influenced by several host factors, among which H. pylori infection appears to be an important determinant. In healthy individuals, the oral microbiota is predominantly composed of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria, with Streptococcus, Prevotella, Fusobacterium, Haemophilus, and Neisseria representing the dominant genera. During the progression of gastric precancerous lesions, stage-dependent alterations in oral microbial composition have been reported. Patients with intestinal metaplasia (IM) exhibit increased relative abundances of Streptococcus, Haemophilus, Prevotella, and Veillonella, whereas low-grade dysplasia (LGD) is associated with enrichment of Peptostreptococcus. These observations indicate that alterations in the oral microbiota are associated with early stages of GC, although their causal contribution to disease progression remains to be established.¹¹

Several studies have also explored whether oral-derived microorganisms contribute to the gastric microbial community. An integrated analysis of tongue coating and gastric juice samples identified 21 discriminatory bacterial taxa that differentiated patients with gastritis from healthy controls. Among these, Campylobacter concisus abundance was positively associated with the severity of PLGC and was detected in both tongue coating and gastric juice samples, suggesting potential cross-compartment microbial transmission.¹² Similarly, paired analyses of tongue coating and gastric mucosal samples demonstrated that H. pylori infection increased the proportion of shared microbial taxa between the oral cavity and gastric mucosa, consistent with the possibility that H. pylori-associated ecological alterations facilitate the presence of oral-derived bacteria within the stomach.¹³ In addition, several bacterial taxa commonly detected in the oral cavity remain enriched in gastric tumor tissues during disease progression.¹¹ However, because gastric biopsy and gastric fluid samples represent low-biomass specimens that are susceptible to contamination from the oral cavity, endoscopic procedures, and laboratory reagents, these findings should be interpreted cautiously. Detection of oral-associated taxa does not necessarily indicate stable gastric colonization and should be considered together with sampling procedures, biopsy location, gastric pH, and H. pylori infection status.

Beyond taxonomic composition, functional alterations in the oral microbiota have also been associated with gastric cancer. A salivary microbiome study involving 293 individuals with superficial gastritis, atrophic gastritis, and gastric cancer reported enrichment of potentially pro-inflammatory genera, including Corynebacterium and Streptococcus, together with depletion of nitrate- and nitrite-reducing commensals such as Haemophilus, Neisseria, Parvimonas, Peptostreptococcus, Porphyromonas, and Prevotella in patients with GC.¹⁴ Because Haemophilus and Neisseria participate in oral nitrate–nitrite metabolism, reduced abundance of these genera may decrease nitrite clearance and potentially favor the accumulation of N-nitroso compounds. Functional prediction analyses further identified enrichment of inflammatory pathways and branched-chain amino acid (BCAA) biosynthesis, including isoleucine and valine metabolism, in the oral microbiota of patients with gastric cancer. These findings suggest that changes in oral microbial function may accompany GC; however, whether these alterations actively contribute to tumor development or primarily reflect disease-associated ecological changes remains unclear.

Because saliva and tongue coating can be collected non-invasively, oral microbial profiles have also been investigated as potential biomarkers for gastric cancer detection. A random forest model based on salivary microbiota distinguished patients with GC from those with gastritis with an area under the receiver operating characteristic curve of 0.91, with Streptococcus and several additional taxa contributing to model performance.¹⁴ Likewise, tongue coating microbiota has shown potential for identifying individuals at increased risk of PLGC and GC.^15,16 Nevertheless, these findings require external validation across independent populations before they can be translated into clinical practice.

Despite increasing interest in the oral microbiota, current evidence remains largely derived from cross-sectional observational studies and therefore cannot establish temporal or causal relationships between oral microbial alterations and GC. Moreover, oral microbial composition is influenced by multiple confounding factors, including dietary habits, oral hygiene, periodontal disease, medication use, and sampling methodology, which may limit the reproducibility of reported microbial biomarkers. Future studies should incorporate longitudinal cohort designs, standardized sampling and contamination-control protocols, microbial source-tracking approaches, and multi-omics analyses to clarify the biological significance of oral–gastric microbial interactions. In addition, genus-level associations should be interpreted with caution, as microorganisms such as Lactobacillus exhibit strain-specific and context-dependent functions, and enrichment at the genus level does not necessarily indicate a protective role in GC.

Gastric Mucosal Microbiota

The gastric mucosa constitutes the primary microbial niche in which gastric carcinogenesis develops. Studies based on 16S rRNA gene sequencing, shotgun metagenomics, and integrated meta-analyses consistently indicate that the composition of the gastric mucosal microbiota varies across the spectrum from chronic gastritis and PLGC. However, these microbial profiles are also strongly influenced by H. pylori infection, gastric acidity, biopsy location, and methodological differences. Consequently, interpretation of disease-associated microbial alterations requires careful consideration of these confounding factors.

Among these variables, H. pylori infection remains the dominant determinant of gastric mucosal microbial composition and represents one of the major sources of heterogeneity across gastric microbiome studies. A biopsy-based sequencing study showed that Helicobacter increased from 0.91% to 68.22% of the gastric mucosal community following H. pylori colonization, accompanied by marked reductions in the relative abundance of Firmicutes, Proteobacteria, and Bacteroidetes.¹⁷ Importantly, these changes were largely confined to gastric mucosal samples, whereas microbial profiles in gastric juice and feces were much less affected, emphasizing the tissue-specific impact of H. pylori. Accordingly, future microbiome studies should routinely stratify or adjust for H. pylori infection status when evaluating GC-associated microbial alterations. As gastric mucosal lesions progress, multiple studies have reported gradual shifts in microbial composition. Genera including Streptococcus, Veillonella, Gemella, Actinobacillus, and Haemophilus are frequently detected in non-malignant gastric mucosa, whereas Acinetobacter has been reported to increase progressively during the development of PLGC, independent of H. pylori infection status, suggesting its potential value as a candidate microbial marker associated with disease progression rather than as a confirmed driver of malignant transformation.¹⁷

Evidence from meta-analyses further supports reproducible alterations in the gastric mucosal microbiota across independent cohorts. After adjustment for age, sex, geographic origin, and H. pylori infection, GC tissues showed enrichment of Veillonella, Fusobacterium, Prevotella, Stenotrophomonas, Streptococcus, and Lactobacillus, whereas Shewanella, Halomonas, Helicobacter, Bifidobacterium, and Bacillus were relatively depleted compared with superficial gastritis.¹⁸ Notably, several enriched genera are also common members of the oral microbiota, a finding that is consistent with, but does not by itself establish, oral-to-gastric microbial transmission.

Differences in microbial composition have also been reported according to H. pylori infection status. In H. pylori-negative GC, enrichment of Lactobacillus, Streptococcus, and Ochrobactrum has been observed together with depletion of Pseudomonas and Faecalibacterium. In contrast, H. pylori-positive GC is additionally characterized by increased Peptostreptococcus and reduced abundance of several commensal genera, including Bacteroides, Enterococcus, Sphingomonas, and Cupriavidus.¹⁹ These observations suggest that microbial alterations associated with GC differ according to the underlying gastric ecological context and should therefore be interpreted within the framework of H. pylori status rather than as universal disease signatures.

It should also be noted that enrichment of Lactobacillus in GC should not be interpreted as uniformly protective. Although certain probiotic Lactobacillus strains have demonstrated beneficial effects in experimental models, several sequencing studies have consistently reported increased abundance of the genus in GC tissues and in conditions associated with reduced gastric acidity. These findings indicate that genus-level enrichment may reflect altered gastric ecology rather than beneficial biological activity, highlighting the importance of distinguishing strain-specific probiotic effects from taxonomic associations.

Beyond disease stage, the gastric mucosal microbiota exhibits substantial spatial heterogeneity. A metagenomic study of advanced GC from northwestern China reported similar phylum-level composition between tumor and adjacent tissues, dominated by Proteobacteria, Firmicutes, and Bacteroidetes, whereas species-level composition differed considerably. Tumor tissues were enriched in Serratia surfactantfaciens, Pseudomonas protegens, and Treponema pectinovorum, whereas adjacent tissues contained higher abundance of H. pylori, Prevotella jejuni, Leptotrichia spp., and Streptococcus infantis.²⁰ Another cohort of 132 GC patients found preferential localization of Helicobacter in adjacent non-tumor tissues, whereas increased abundance of Halomonas, Prevotella, and Shewanella was associated with more advanced disease.²¹ Although these observations suggest potential prognostic relevance, independent validation is still required before clinical application.

Interpretation of gastric mucosal microbiome studies also requires consideration of technical limitations. Because gastric biopsy specimens represent low-biomass samples, microbial profiles are particularly susceptible to contamination introduced during endoscopy, DNA extraction, library preparation, and sequencing. Furthermore, taxa commonly detected in GC studies—including Streptococcus, Prevotella, Veillonella, and Neisseria—are abundant members of the oral microbiota and may reflect oral carryover rather than true gastric colonization. Standardized sampling procedures, inclusion of appropriate negative controls, and careful reporting of biopsy site, gastric pH, medication exposure, and H. pylori status are therefore essential for improving reproducibility across studies.

Despite accumulating evidence linking gastric mucosal microbial alterations with GC, several challenges remain. Reported changes in α-diversity remain inconsistent across studies, likely owing to differences in study populations, sampling strategies, sequencing platforms, and analytical pipelines.^22,23 Moreover, most available studies are observational and describe taxonomic associations rather than causal mechanisms. Future work combining standardized prospective cohorts, strain-level metagenomics, functional multi-omics, and experimental validation will be required to clarify whether specific gastric microorganisms actively contribute to gastric carcinogenesis or primarily reflect changes in the tumor microenvironment.

Gastric Fluid Microbiota

The gastric fluid microbiota represents a distinct microbial compartment within the gastric lumen and provides complementary information to mucosa-associated microbial communities. Although the highly acidic gastric environment was traditionally considered unfavorable for microbial survival, culture-independent sequencing studies have demonstrated that gastric fluid contains a detectable, albeit low-biomass, microbial community whose composition varies across physiological and pathological conditions.

Recent studies have reported significant differences in the gastric fluid microbiota between patients with GC and healthy individuals. These differences remained after adjustment for host characteristics, including age, sex, and body mass index, suggesting that alterations in gastric fluid microbial composition are associated with GC rather than solely reflecting inter-individual variation.²⁴ At the phylum level, an increased relative abundance of Firmicutes has been reported in GC-associated gastric fluid. At the genus level, Streptococcus and Lentimicrobium were enriched, whereas Neisseria, Veillonella, Prevotella, Alloprevotella, and Haemophilus showed reduced relative abundance compared with healthy controls.²⁴ These observations indicate that the microbial composition of gastric fluid changes during gastric carcinogenesis, although the functional significance of these alterations remains to be established.

Several microbial features appear to overlap between gastric fluid and gastric mucosal samples. For example, enrichment of oral-associated genera and reduced abundance of several commensal taxa have been reported in both compartments. These findings are consistent with coordinated alterations across the gastric microbial ecosystem; however, they do not establish that identical microorganisms colonize both niches or that microbial changes in one compartment directly drive those in another.¹⁷

Because gastric fluid is continuously exposed to swallowed oral microorganisms and reflects the physicochemical conditions of the gastric lumen, it has been proposed as an intermediate compartment linking the oral cavity and the gastric mucosa. Nevertheless, whether oral-derived microorganisms establish persistent colonization in the stomach or simply represent transient passage remains uncertain and requires validation through strain-level tracking and longitudinal studies.

Interpretation of gastric fluid microbiome studies also requires caution. Like gastric mucosal specimens, gastric fluid is a low-biomass sample that is susceptible to contamination from the oral cavity during endoscopy and sample collection. In addition, microbial composition may be influenced by gastric pH, proton pump inhibitor use, fasting status, sampling procedures, and H. pylori infection. These factors should be carefully controlled and reported to improve comparability across studies and to avoid overinterpretation of disease-associated microbial signatures.

Intestinal Microbiota

Compared with the gastric microbiota, the intestinal microbiota is substantially more diverse and is influenced by a broader range of host and environmental factors, including dietary habits, geographic location, medication exposure, age, and systemic metabolic status. Consequently, alterations observed in fecal microbiota are generally characterized by greater inter-individual variability and should be interpreted as reflecting the intestinal microbial ecosystem rather than direct changes within the gastric microenvironment.

Longitudinal studies have reported dynamic changes in fecal microbial composition during the progression of PLGC. Patients with superficial gastritis showed enrichment of Akkermansia and Catenibacterium, whereas increased abundance of Lactobacillus has been reported in atrophic gastritis and intraepithelial neoplasia. Enrichment of Holdemanella was observed in patients with intestinal metaplasia and intraepithelial neoplasia.¹⁷ However, compared with gastric mucosal microbiota, fecal microbial alterations demonstrate considerably lower consistency across studies, and few taxa have been reproducibly associated with specific stages of gastric carcinogenesis. These findings suggest that fecal microbiota may better reflect systemic physiological and metabolic status than localized microbial changes occurring in the stomach.

Meta-analyses have consistently identified differences in fecal microbial community composition between patients with GC and healthy controls.^19,25 Although significant alterations in β-diversity have frequently been reported, changes in α-diversity remain inconsistent among studies, likely owing to differences in study populations, sequencing methodologies, geographic regions, and analytical pipelines. Across most cohorts, the intestinal microbiota remained dominated by Bacteroidetes, Firmicutes, and Proteobacteria, with shifts in the relative abundance of multiple bacterial taxa rather than the emergence of a uniform GC-specific microbial profile.

Several genera, including Prevotella, Escherichia, Streptococcus, Enterobacter, Klebsiella, and Succinivibrio, have been reported to be enriched in fecal samples from GC patients, whereas butyrate-producing genera such as Faecalibacterium, Roseburia, Lachnospira, and members of the genus Clostridium are frequently reduced. Because these bacteria participate in short-chain fatty acid (SCFA) production, immune regulation, and intestinal barrier maintenance, these compositional differences may be associated with altered intestinal metabolic function.²⁶ However, current evidence is largely observational, and whether these microbial alterations contribute to gastric carcinogenesis or represent secondary consequences of disease-associated physiological changes remains unclear.

Notably, several bacterial genera, including Lactobacillus and Streptococcus, have been detected in both gastric tissues and fecal samples from patients with GC.¹⁹ Nevertheless, overlap at the genus level does not necessarily indicate microbial migration or direct ecological connectivity between the stomach and intestine. Given the substantial physiological differences between these anatomical sites, shared taxonomic signatures may also reflect common host factors, such as reduced gastric acidity, dietary changes, antibiotic exposure, or systemic inflammation. Furthermore, enrichment of the genus Lactobacillus should not be interpreted uniformly as beneficial or detrimental because strain-specific biological functions differ considerably, and genus-level sequencing cannot distinguish probiotic strains from organisms associated with disease.

Overall, fecal microbiota analysis provides valuable information regarding host–microbiota interactions and may facilitate biomarker discovery for GC. However, because fecal samples primarily represent colonic microbial ecology rather than the gastric niche, their findings should be interpreted as complementary to, rather than substitutes for, gastric mucosal or gastric fluid microbiome analyses. Future studies integrating paired gastric tissue, gastric fluid, oral, and fecal samples with strain-level sequencing and functional multi-omics will be necessary to clarify microbial interactions across gastrointestinal compartments and their relevance to gastric carcinogenesis.

The Oral–Intestinal Axis and Gastric Cancer

Increasing evidence indicates that microbial alterations associated with GC extend beyond a single anatomical compartment. Comparative analyses of oral, gastric, and fecal samples have identified partially overlapping microbial signatures, suggesting that changes occurring in different regions of the gastrointestinal tract may be interconnected. In this Review, the oral–gastric–intestinal axis refers to the bidirectional interactions among oral microorganisms, gastric and intestinal microbial communities, microbial metabolites, and host mucosal and immune responses, rather than implying direct microbial migration or a defined causal pathway.

Comparative microbial profiling has demonstrated compositional differences in both oral and intestinal microbiota in patients with GC. Oral microbial communities frequently show reduced abundance of several commensal taxa together with increased abundance of genera associated with inflammatory conditions, whereas fecal samples often contain higher relative abundance of bacteria commonly detected in the oral cavity. For example, members of the genus Streptococcus, including Streptococcus anginosus, together with several Lactobacillus species, have been reported in both oral and fecal samples from patients with GC, whereas Bacteroides ovatus and Fusicatenibacter saccharivorans are frequently depleted.²⁷ Strain-level analyses further identified genetically related Streptococcus strains in oral and intestinal samples, findings that are consistent with potential cross-compartment dissemination. However, whether these microorganisms establish persistent colonization or directly contribute to GC remains to be determined.

Microbial metabolites provide another potential mechanism linking different gastrointestinal compartments. Several studies have implicated gut microbiota-derived metabolites, including trimethylamine N-oxide (TMAO), together with lipopolysaccharide (LPS) produced by Gram-negative bacteria, in inflammatory signaling, epithelial injury, and metabolic alterations associated with gastric disease.^28,29 In addition, metabolomic studies of H. pylori -associated chronic gastritis and CAG have demonstrated disturbances in amino acid, lipid, and bile acid metabolism, supporting an association between microbial compositional changes and altered host metabolic pathways during disease progression.³⁰ Nevertheless, most available evidence remains correlative, and the specific microbial species and metabolites responsible for these metabolic alterations have not been fully established.

Evidence from experimental models also suggests that certain oral pathogens may influence the gastric microenvironment. For example, Porphyromonas gingivalis has been reported to survive gastric transit under experimental conditions, alter gastric microbial composition, affect bile acid metabolism, and activate β-catenin signaling, changes that were associated with intestinal metaplasia-like lesions.³¹ However, the relevance of these findings to human gastric carcinogenesis remains uncertain, as direct evidence for stable gastric colonization by oral pathogens is currently limited.

Overall, available evidence supports interactions among oral, gastric, and intestinal microbial compartments during GC, although the directionality and causality of these relationships remain incompletely understood. Future studies integrating longitudinal sampling, strain-resolved metagenomics, microbial source-tracking, metabolomics, and functional validation in experimental models will be important for determining whether shared microbial signatures represent microbial transmission, common host responses, or parallel ecological changes across different gastrointestinal niches. Such studies may help clarify the biological relevance of microbiota-associated alterations and their potential clinical applications.

Experimental Evidence That Traditional Chinese Medicine Targets Helicobacter pylori and Protects the Gastric Mucosa

Experimental studies have shown that several TCM formulas and plant-derived compounds exhibit activity against H. pylori in vitro or in animal models of H. pylori-associated gastritis and CAG (Table 1). These effects include inhibition of bacterial growth or virulence, attenuation of mucosal inflammation, and improvement of histological gastric injury (Figure 2). Because most available evidence is derived from preclinical models, these findings should be regarded as mechanistic evidence rather than proof of clinical efficacy for preventing GC or PLGC. Moreover, although some studies suggest that herbal interventions cause less disruption of gastric microbial communities than antibiotic therapy, direct comparative evidence in humans remains limited.

Table 1.

Experimental Evidence for Traditional Chinese Medicine Formulas and Natural Products Targeting Helicobacter pylori and Protecting the Gastric Mucosa

Herbal Medicine/Formula	Experimental Model	Major Bioactive Components	Proposed Mechanisms	Key Findings	PMID
Alpinia officinarum Hance	Mice with HAG	Flavonoids (galangin, kaempferol, kaempferide)	Inhibit the MAPK cascade, block IL-17/MAPK and epithelial inflammatory signaling, reduce IL-8 secretion, suppress H. pylori colonization, and alleviate gastric mucosal pathological injury	Its ethanol extract markedly ameliorates gastric mucosal lesions in HAG mice	[32]
Flavonoid-rich herbal extracts	In vitro bacterial MIC assays + cellular experiments	Quercetin, catechin, epicatechin, rutin	Inhibit urease activity, damage bacterial genetic material, suppress bacterial protein synthesis to exert anti-H. pylori effects	Extract contains 19.61% quercetin, 13.72% catechin, 11.76% epicatechin and 11.76% rutin	[33]
Banxia Xiexin decoction (BXXXT)	In vitro culture of drug-resistant H. pylori; mice with acute gastritis induced by drug-resistant H. pylori	Berberine, quercetin, baicalin, luteolin, gallic acid, rosmarinic acid, aloe-emodin	Direct antibacterial activity; enhance host T-cell immune responses; target urease-related factors, CFAs, CagA and VacA to inhibit bacterial colonization and virulence, thus mitigating gastric inflammation	Multiple ingredients exert synergistic antibacterial effects and effectively relieve drug-resistant H. pylori-induced acute gastritis in mice	[34]
Berberine (BBR)	Rats with H. pylori-induced chronic atrophic gastritis (CAG); GES-1 cells infected with H. pylori	Berberine	Suppress the IRF8–IFN-γ axis and downstream inflammatory genes/proteins, reduce levels of pro-inflammatory cytokines IL-17, CXCL1 and CXCL9, and relieve H. pylori-triggered gastric inflammation and atrophy	Significantly alleviates H. pylori-mediated gastric inflammatory and atrophic lesions	[35]
Patchouli alcohol (PA)	In vitro H. pylori culture model	Patchouli alcohol	Inhibit urease activity, weaken the capacity of H. pylori to adapt to gastric acid and colonize gastric mucosa	PA robustly inhibits urease activity of H. pylori in vitro	[36]
Canarium album Raeusch.	In vitro H. pylori culture model	Phenolic compounds (ethyl acetate extract QGEAE shows the strongest activity)	Disrupt bacterial morphology and ultrastructure, inhibit urease activity, downregulate virulence genes vacA and cagA, and impair colonization and pathogenicity of H. pylori	MIC = 39–625 μg/mL; MBC = 78–1250 μg/mL	[37]
Syzygium aromaticum	In vitro culture of drug-susceptible and drug-resistant H. pylori strains	Aqueous extract, 75% ethanol extract	Destroy bacterial ultrastructure, downregulate cagA, disrupt tricarboxylic acid and pyruvate metabolism, and block host PI3K/Akt and MAPK inflammatory cascades to attenuate bacterial virulence	MIC = 160–320 μg/mL; MBC < 4 × MIC; no antagonism when combined with clarithromycin, metronidazole, levofloxacin or amoxicillin	[38]
Phellodendron chinense CK Schneid	In vitro culture of drug-susceptible and drug-resistant H. pylori strains	Berberine, palmatine, jatrorrhizine and 4 other antibacterial compounds (palmatine exhibits optimal activity)	Disrupt bacterial ultrastructure, inhibit urease, downregulate virulence genes encoding adhesins, flagella, urease and cytotoxins, and suppress bacterial adhesion to host cells	MIC = 40–160 μg/mL; compatible with amoxicillin, metronidazole, levofloxacin and clarithromycin without antagonism	[39]
Non-medicinal parts (stem, leaf, flower) of Sanguisorba officinalis L.	In vitro culture of standard and clinical resistant H. pylori isolates	Total polyphenols, total flavonoids, gallic acid, ellagic acid	Disrupt bacterial morphology, cell wall and ultrastructure, modulate bacterial gene expression and interfere with metabolic pathways	MIC = 80–1280 μg/mL; MBC = 80–2560 μg/mL; no antagonism with four common clinical antibiotics	[40]
Dried ginger	Four standard/clinical H. pylori strains in vitro	63 constituents including glycosides, terpenoids and phenolics	Target sulfhydryl residues and Ni2⁺ in the urease active site via slow-binding uncompetitive inhibition to reduce bacterial virulence	MIC = 0.05–1.50 mg/mL; IC50 for urease inhibition = 0.49 mg/mL	[41]
Terminalia bellirica (Gaertn). Roxb.	In vitro H. pylori culture; mice infected with H. pylori SS1 strain	Polyphenols (chebulagic acid, chebulinic acid, corilagin, gallic acid, ellagic acid)	In vitro: suppress urease, reduce adhesion and downregulate vacA; in vivo: reduce gastric H. pylori load, alleviate inflammation, repair gastric glands and preserve gut homeostasis without dysbiosis	In vitro MIC = 160 μg/mL; high-dose treatment reduces gastric bacterial load by 92.97% (close to 99.81% of triple therapy); lowers TNF-α and IL-1β	[42]

Abbreviations: HAG, H. pylori-associated gastritis; MIC, minimum inhibitory concentration; minimum bactericidal concentration; GES-1, human gastric epithelial cell line GES-1; AGS, human gastric adenocarcinoma cell line; MFC, murine forestomach carcinoma.

Figure 2.

Traditional Chinese Medicine and Natural Compounds Prevent Gastric Precancerous Lesions and Gastric Cancer through Anti-Helicobacter pylori Activity, Microbiota Remodeling, and Host Signaling Regulation.

Classical Herbal Formulas Targeting H. pylori

Banxia Xiexin Decoction (BXXXT) has demonstrated antibacterial activity against both antibiotic-sensitive and antibiotic-resistant H. pylori strains. Experimental studies indicate that several constituents, including berberine, baicalin, quercetin, and luteolin, contribute to these effects through complementary mechanisms. In vitro and murine studies suggest that BXXXT inhibits urease activity and suppresses the virulence factors CagA and VacA, thereby reducing bacterial colonization and toxin production. In parallel, it modulates T-cell-associated inflammatory responses and decreases gastric mucosal inflammatory infiltration, resulting in improved histological injury in murine models of drug-resistant H. pylori-induced gastritis.³⁴ Although these findings support further investigation of BXXXT as an adjunctive therapy, clinical validation remains unavailable.

The ethanol extract of Alpinia officinarum (EAO) contains abundant flavonoids, including galangin and kaempferol, and has been evaluated in murine models of H. pylori-associated gastritis. Integrated network pharmacology combined with experimental validation suggested that these flavonoids suppress IL-17/MAPK signaling, reduce IL-8 production, inhibit gastric H. pylori colonization, and attenuate gastric mucosal inflammation, leading to improved histological injury scores in experimental animals.³² Likewise, flavonoid-rich herbal extracts containing quercetin, catechin, and rutin inhibit H. pylori growth in vitro by suppressing urease activity and interfering with bacterial DNA integrity and protein synthesis.³³ However, whether these antibacterial effects translate into reduced GC risk remains unknown.

Bioactive Compounds and Herbal Extracts with Anti-H. pylori Activity

Alkaloids

Berberine (BBR), the major alkaloid isolated from Coptis chinensis and Phellodendron chinense, has been investigated in H. pylori-infected GES-1 cells and rat models of CAG. Mechanistically, berberine suppresses the IRF8–IFN-γ signaling pathway, resulting in reduced expression of inflammatory mediators including IFIT3, USP18, IRF1, and IFIT1, decreased production of IL-17 and CXCL1, and attenuation of H. pylori-associated gastric gland atrophy in experimental models.³⁵

Phellodendron chinense also contains several antibacterial alkaloids, including palmatine and jatrorrhizine, among which palmatine exhibits the strongest in vitro activity. Experimental studies have shown that these alkaloids inhibit both antibiotic-sensitive and resistant H. pylori strains by disrupting bacterial ultrastructure, suppressing urease activity, and downregulating flagellar- and toxin-related virulence genes, thereby reducing bacterial adhesion to gastric epithelial cells.³⁹

Terpenoids and Essential Oils

Patchouli alcohol, the principal sesquiterpene isolated from Pogostemon cablin, inhibits H. pylori urease activity, thereby impairing bacterial acid tolerance and colonization in experimental systems.³⁶

Similarly, extracts of Zingiber officinale (ginger) contain numerous terpenoids, phenolic acids, and glycosides that inhibit both laboratory and clinical H. pylori isolates. Biochemical studies suggest that ginger-derived compounds inhibit urease by interacting with catalytic sulfhydryl groups and nickel ions within the enzyme active site through a slow-binding uncompetitive mechanism, thereby reducing bacterial virulence.⁴¹

Polyphenol- and Tannin-Rich Medicinal Plants

Several medicinal plants enriched in polyphenols or hydrolyzable tannins have also demonstrated anti-H. pylori activity in vitro. The ethyl acetate extract of Canarium album inhibits bacterial growth by disrupting cell integrity, suppressing urease activity, and reducing expression of the virulence genes vacA and cagA.³⁷

Water and ethanol extracts of Syzygium aromaticum (clove) inhibit both antibiotic-sensitive and resistant H. pylori isolates. Metabolomic analyses indicate that these extracts interfere with bacterial central carbon metabolism, including the tricarboxylic acid cycle and pyruvate metabolism, while simultaneously suppressing host PI3K/Akt and MAPK inflammatory signaling pathways.³⁸

Polyphenol-rich extracts prepared from the stems, leaves, and flowers of Sanguisorba officinalis inhibit drug-resistant H. pylori by disrupting bacterial cell wall integrity and altering bacterial metabolic pathways, without detectable antagonism toward commonly used antibiotics in vitro.⁴⁰

Among currently investigated medicinal plants, Terminalia chebula has been evaluated in both in vitro and animal studies. Rich in hydrolyzable tannins such as chebulagic acid and corilagin, it inhibits urease activity, reduces bacterial adhesion, and suppresses vacA expression in vitro. In a murine infection model, high-dose T. chebula markedly reduced gastric H. pylori burden, decreased gastric TNF-α and IL-1β levels, and improved gastric gland morphology.⁴² Interestingly, this study also reported that, compared with standard triple-antibiotic therapy, T. chebula induced relatively smaller changes in gastric microbial composition during treatment. Nevertheless, because these observations were generated in a single animal model, whether herbal therapy consistently preserves gastric microbial communities better than antibiotics requires confirmation in well-controlled clinical studies.

Collectively, current evidence indicates that several herbal formulas and plant-derived compounds possess anti-H. pylori activity in vitro and in experimental models. Their reported mechanisms include inhibition of bacterial virulence, modulation of host inflammatory responses, and improvement of gastric mucosal injury. However, most studies remain preclinical, and few have directly evaluated microbiota-mediated mechanisms or long-term prevention of GC or PLGC. Therefore, these findings should be interpreted as mechanistic evidence supporting further investigation rather than as confirmation of clinical efficacy.

Traditional Chinese Medicine Formulas Ameliorate Chronic Atrophic Gastritis, Gastric Precancerous Lesions, and Gastric Cancer Through Microbiota Modulation

Beyond their direct anti-H. pylori activity, accumulating evidence suggests that natural compounds, bioactive herbal constituents, and TCM formulas exert therapeutic effects throughout gastric carcinogenesis by modulating microbiota–host interactions (Table 2). Reported mechanisms include remodeling of the gastrointestinal microbiota, alterations in microbiota-derived metabolites, attenuation of oxidative stress and inflammatory signaling, and regulation of programmed cell death pathways, particularly ferroptosis and pyroptosis. These interconnected processes collectively contribute to the restoration of gastrointestinal homeostasis and the suppression of disease progression from CAG to PLGC and GC. However, the current evidence remains largely preclinical. Although several studies have integrated microbiome profiling with metabolomics or fecal microbiota transplantation (FMT) to strengthen mechanistic insights, direct causal evidence demonstrating that microbiota remodeling mediates the therapeutic effects of TCM is still limited.

Table 2.

Experimental Evidence That Traditional Chinese Medicine Formulas and Natural Compounds Modulate the Microbiota to Prevent Gastric Precancerous Lesions and Gastric Cancer

Disease Subtype	TCM Formula/Natural Compound	Experimental Model	Major bioactive Components	Microbiota-Related Mechanisms	Core Therapeutic Outcomes	PMID
CAG	Xiaojianzhong Tang (XJZ)	CAG rat model	Albiflorin, paeoniflorin, liquiritin, paeonol, 6-gingerol, glycyrrhizic acid	Remodel gut microbiota; regulate bile acid-metabolizing genera (Butyricimonas, Desulfovibrio, Bacteroides, Parabacteroides, Acetobacter, Alistipes); restore homeostasis of bile acid and amino acid metabolism	Markedly alleviate gastric pathological lesions; reverse metabolic disturbances of cholic acid, deoxycholic acid, and L-isoleucine	[43]
	Huangqi Jianzhong Tang (HQJZ)	CAG rat model	Multiple synergistic components (no single dominant constituent defined)	Reduce abundances of pathobionts (Acetobacter, Desulfovibrio, Escherichia, Shigella); correct conjugated bile acid disorders and modulate primary bile acid biosynthesis	Improve gastric mucosal injury; regulated bile acids are host-microbe co-metabolites correlated with Bacteroides acidifaciens and Prevotella copri	[44]
	Huazhuo Jiedu Decoction (HZJD)	MNNG plus irregular fasting/sodium salicylate-induced CAG rat model	Multi-component formula containing 11 herbs	Remodel gut microbiota, enrich beneficial Turicibacter and suppress pathobionts Desulfococcus and Escherichia; reverse 21 differential metabolites linked to central carbon metabolism in cancer	Attenuate gastric tissue damage; altered microbiota correlates with L-leucine, urea, trimethylamine and choline	[45]
	Weifuchun capsule (WFC)	MNNG-induced GES-1 cell model + CAG animal model	Ginsenosides Rb1/Rc/Re/20(R)-Rh1, quercetin, ursolic acid, naringin, rutin (58 total compounds dominated by flavonoids, triterpenoids and organic acids)	Regulate TLR/NF-κB/NOD-like receptor inflammatory signaling; inhibit pro-inflammatory cytokines; modulate T cell and macrophage function; downregulate TLR2, CD14 and oncogenic HES6	Suppress chronic inflammation and delay progression of precancerous gastric lesions; enrich Lachnospiraceae to restore gut diversity post-surgery	[46]
	Qinghuayin (QHY)	CAG rat model	Multi-component formula (no single dominant constituent defined)	Improve gut microbial diversity and stability; elevate Firmicutes and enrich probiotic genera Ruminococcus, Lactobacillus, Bifidobacterium to maintain eubiosis	Relieve gastric mucosal damage; superior to antibiotics without disrupting commensal flora	[47]
PLGC	Dendrobium polysaccharides	MNNG-induced PLGC rat model	Water-soluble polysaccharides from Dendrobium	Activate NRF2 antioxidant pathway to upregulate HO-1 and NQO1; modulate Wnt/β-catenin and betaine metabolism; alter abundances of Lactobacillus, Bifidobacterium, Akkermansia, Bacteroides, Prevotella	Delay progression of precancerous lesions; microbiota data are mainly from healthy/metabolic syndrome models with limited PLGC-specific evidence	[48–50]
	Jianpi Huayu Jiedu Decoction (JHJD)	Mice with PLGC induced by H. pylori plus MNU	Modified Sijunzi Decoction with multiple synergistic ingredients	Restore gut diversity, reverse linoleic acid dysregulation, downregulate pro-oxidative enzymes, activate SLC7A11/GPX4 and inhibit ferroptosis in hyperplastic epithelial cells	Repair gastric lesions and reduce oxidative stress via the gut microbiota–linoleic acid–ferroptosis axis	[51]
	Huopo Xialing Decoction (HPXLD)	PLGC mouse model induced by MNNG and irregular diet	Flavonoids, isoflavonoids, carboxylic acids	Remodel gut microbiota, boost diversity and enrich Bacteroidetes, Actinobacteria, Proteobacteria and Bifidobacterium; regulate tryptophan metabolism	Mitigate glandular atrophy and inflammatory infiltration and suppress pro-inflammatory cytokines	[52]
	Weizhuan’an prescription	PLGC rat model	Notoginsenoside R1, ginsenosides, astragaloside IV, polydatin, kaempferol, quercetin	Elevate beneficial Lactobacillus and Veillonella; suppress pathobionts Proteobacteria and Pseudomonas; reduce IL-2, IL-4, IL-13 and MCP-1 to restrain inflammatory microenvironment	Alleviate gastric pathological damage and slow malignant progression of precancerous lesions	[53]
	Weifuchun capsule (WFC)	Rat models of gastric intestinal metaplasia/dysplasia induced by MNNG, ethanol and irregular diet; in vitro GES-1/BMDM cell models	Ginsenosides, quercetin, ursolic acid and other compounds	Inhibit NF-κB activation, block p65 binding to the CDX2 promoter, downregulate CDX2 transcription and suppress inflammation-driven intestinal metaplasia and dysplasia	Stabilize normal gastric epithelial phenotype and delay precancerous progression	[54]
Gastric cancer anti-tumor effects	Modified Gexia-Zhuyu Tang (GZT)	MFC gastric cancer xenograft mouse model	4-methylcatechol, ailanthone, 18β-glycyrrhetinic acid and others	Remodel gut microbiota, enrich beneficial Prevotella, Psychrobacter, Paraprevotella, Alistipes and suppress Helicobacter, Desulfovibrio, Bacteroides; activate NLRP3/ASC/Caspase-1 inflammasome to trigger pyroptosis	Suppress gastric tumor growth and metastasis, downregulate CD147, VEGF and MMP-9; anti-tumor efficacy relies on gut microbiota remodeling	[55]
	Shenxia Kuanzhong Decoction (SXKZD)	In vitro AGS human gastric cancer cell model	IPA	Inhibit TNF/IL-17 inflammatory cascades; remodel gut flora to enrich Lactobacillus plantarum and Akkermansia muciniphila, remodel tumor metabolism and boost anti-tumor immunity	Rh2 inhibits AGS proliferation and TNFα expression; IPA stably binds TNFα to exert synergistic anti-inflammatory and anti-tumor effects	[56]
	Weifuchun capsule (WFC)	Gastric cancer cell lines and tumor-bearing animal models	Ginsenosides, quercetin, rutin and others	Suppress malignant phenotypes through the miR-26a-5p/MAPK/KPNA2 axis	Dual efficacy in reversing precancerous lesions and inhibiting gastric cancer progression	[57]

Abbreviations: TCM, traditional Chinese medicine; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; CAG, Chronic atrophic gastritis; PLGC, Gastric precancerous lesions; IPA, Ginsenoside Rh2,3-indolepropionic acid; BMDMs, bone marrow-derived macrophages; AGS, human gastric adenocarcinoma cell line.

TCM Formulas Alleviate Chronic Atrophic Gastritis

Xiaojianzhong Tang (XJZ) is a classical TCM formula traditionally used to warm the middle burner and replenish deficiency. Ultra-performance liquid chromatography (UPLC) analysis has identified its major bioactive constituents, including albiflorin, paeoniflorin, liquiritin, paeonol, 6-gingerol, and glycyrrhizic acid. In a rat model of CAG, integrated analyses combining 16S rRNA sequencing, untargeted metabolomics, and molecular docking demonstrated that XJZ markedly alleviated gut microbiota dysbiosis and modulated several bile acid-associated bacterial genera, including Butyricimonas, Desulfovibrio, Bacteroides, Parabacteroides, Acetobacter, and Alistipes. Concomitantly, XJZ normalized multiple dysregulated metabolites involved in bile acid and amino acid metabolism, including cholic acid, deoxycholic acid, glycoursodeoxycholic acid, taurochenodeoxycholic acid, docosahexaenoic acid (DHA), and L-isoleucine. These findings suggest that XJZ ameliorates CAG by restoring gastrointestinal microbial and metabolic homeostasis through coordinated modulation of the gut microbiota–bile acid metabolic axis, thereby contributing to gastric mucosal protection.⁴³

Huangqi Jianzhong Tang (HQJZ) has likewise demonstrated pronounced gastroprotective effects in experimental CAG. Multi-omics analyses integrating 16S rRNA sequencing, UHPLC-QTOF-MS-based untargeted metabolomics, and MetOrigin metabolite source tracing revealed that HQJZ effectively corrected abnormalities in conjugated bile acid metabolism while reducing the relative abundance of potentially pathogenic bacteria, including Acetobacter, Desulfovibrio, Escherichia, and Shigella. Notably, several differentially regulated bile acid metabolites were identified as microbiota–host co-metabolites involved predominantly in primary bile acid biosynthesis, and their restoration was closely associated with alterations in Bacteroides acidifaciens and Prevotella copri. Collectively, these findings indicate that HQJZ may improve the CAG microenvironment by remodeling the gut microbial community and re-establishing bile acid metabolic homeostasis.⁴⁴

Hua-Zhuo-Jie-Du Decoction (HZJD), a formula composed of 11 medicinal herbs, has also demonstrated protective effects in a rat model of CAG induced by MNNG, irregular fasting, and sodium salicylate. Integrated 16S rRNA sequencing and LC-MS-based untargeted metabolomics showed that HZJD substantially attenuated gastric mucosal injury and reversed alterations in 21 differential metabolites, particularly those involved in central carbon metabolism associated with cancer. In parallel, HZJD remodeled the gut microbiota by enriching beneficial taxa such as Turicibacter while suppressing the expansion of potentially pathogenic genera including Desulfococcus and Escherichia. Correlation analyses further revealed strong associations between microbial alterations and key metabolites, including L-leucine, urea, trimethylamine, and choline, suggesting that coordinated regulation of the gut microbiota–metabolite network may underlie the therapeutic effects of HZJD against CAG.⁴⁵

Weifuchun Capsule (WFC) is a widely used Chinese patent medicine for the treatment of chronic gastritis and gastric precancerous lesions. Chemical profiling has identified 58 major bioactive constituents, including ginsenosides Rb1, Rc, Re, and 20(R)-Rh1, quercetin, ursolic acid, naringin, and rutin, with flavonoids, triterpenoids, and organic acids representing the predominant chemical classes. In MNNG-induced GES-1 cell and experimental CAG models, WFC was shown to suppress chronic inflammation primarily through regulation of TLR/NF-κB and NOD-like receptor signaling pathways, thereby reducing the production of inflammatory cytokines such as IL-1β and IL-6, modulating T-cell and macrophage function, and downregulating the expression of TLR2, CD14, and the gastric cancer-associated molecule HES6. These effects collectively attenuated chronic inflammatory responses and delayed the progression of gastric precancerous lesions.⁴⁶

Qinghuayin (QHY) has likewise exhibited notable microbiota-modulating activity in experimental CAG. According to 16S rRNA sequencing analyses, QHY significantly increased gut microbial diversity and community stability, enhanced the relative abundance of Firmicutes, and enriched beneficial genera including Ruminococcus, Lactobacillus, and Bifidobacterium. In contrast, antibiotic treatment markedly reduced microbial richness and shifted the dominant phylum from Firmicutes toward Bacteroidetes, indicating that indiscriminate antimicrobial therapy may disrupt gastrointestinal microbial homeostasis. These findings suggest that, rather than exerting simple antibacterial effects, QHY restores microbial ecological balance by promoting the recovery of beneficial microorganisms, thereby contributing to the amelioration of CAG.⁴⁷

TCM Intervention in Gastric Precancerous Lesions

Dendrobium polysaccharides, the major polysaccharide fraction isolated from Dendrobium officinale, have been investigated in N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced models of PLGC. Animal studies showed activation of the NRF2/HO-1/NQO1 antioxidant pathway, attenuation of oxidative stress-associated mucosal injury, and suppression of Wnt/β-catenin signaling, accompanied by normalization of several metabolites, including betaine.^43,44 Separate microbiome studies reported alterations in the abundance of Lactobacillus, Bifidobacterium, Akkermansia, Bacteroides, and Prevotella.⁴⁵ However, these microbiota findings were generated primarily in healthy volunteers or metabolic disease models rather than PLGC models. Therefore, direct evidence that gut microbiota remodeling mediates the protective effects of Dendrobium polysaccharides during GC remains unavailable.

Jianpi Huayu Jiedu Decoction (JHJD) has been evaluated in a mouse model of PLGC induced by H. pylori infection and N-methyl-N-nitrosourea.⁴⁶ Integrated analyses combining 16S rRNA sequencing, metabolomics, and molecular assays showed improved gastric histopathology, increased microbial diversity, and partial normalization of linoleic acid metabolism. Mechanistically, JHJD reduced expression of the pro-oxidant enzymes ALOX15 and CYP1B1 while increasing SLC7A11 and GPX4 expression, findings that were accompanied by reduced ferroptosis and increased apoptosis of dysplastic gastric epithelial cells.⁴⁶ Because microbiota depletion or FMT validation was not performed, these results indicate an association among microbial alterations, metabolic remodeling, and ferroptosis rather than establishing a causal microbiota-dependent mechanism.

Huo Po Xia Ling Decoction (HPXLD) has also been examined in an MNNG-induced mouse model of PLGC combined with dietary intervention.⁴⁷ Treatment reduced gastric gland atrophy and inflammatory cell infiltration and was accompanied by increased relative abundance of Bacteroidota, Actinobacteriota, and Bifidobacterium. Metabolomic analyses further suggested alterations in tryptophan metabolism.⁴⁷ Although these observations support an association between microbiota composition and metabolic remodeling, functional validation of the microbiota-dependent mechanism has not yet been reported.

Weizhuan’an Prescription has been investigated in experimental PLGC models and was associated with improved gastric pathology together with changes in the gastric mucosal microbiota.⁴⁸ Treatment increased the abundance of Lactobacillus and Veillonella, reduced Proteobacteria and Pseudomonas, and decreased inflammatory cytokines including IL-2, IL-4, IL-13, and MCP-1.⁴⁸ These findings suggest that modulation of gastric mucosal microbial communities may accompany attenuation of chronic inflammation, although whether these microbial changes directly contribute to disease modification remains to be determined.

Weifuchun (WFC) has demonstrated activity in rat models of gastric intestinal metaplasia and dysplasia induced by MNNG, ethanol, and dietary intervention, as well as in GES-1 and bone marrow-derived macrophage (BMDM) models. WFC inhibited NF-κB activation, reduced p65 binding to the CDX2 promoter, and suppressed CDX2 transcription, thereby attenuating inflammation-associated intestinal metaplasia and dysplasia.⁴⁹ Although WFC has been reported to influence inflammatory signaling, this study did not directly investigate microbiota-mediated mechanisms.

Anti-Tumor Effects of TCM in Gastric Cancer

Modified Gexia-Zhuyu Tang (GZT) has been investigated in gastric tumor-bearing mice using 16S rRNA sequencing and FMT.⁵⁰ Treatment inhibited tumor growth and metastasis, reduced expression of CD147, VEGF, and MMP-9, increased the abundance of Prevotella, Psychrobacter, Paraprevotella, and Alistipes, and reduced Helicobacter, Desulfovibrio, and Bacteroides. Activation of the NLRP3/ASC/Caspase-1 pathway and increased pyroptosis markers were also observed.⁵⁰ Importantly, FMT experiments partially transferred the antitumor phenotype, providing stronger evidence that gut microbiota contributed to the biological effects of GZT than is available for most other herbal interventions.

ShenXia KuanZhong Decoction (SXKZD) has been studied using network pharmacology, molecular docking, and in vitro gastric cancer models. Ginsenoside Rh2 and 3-indolepropionic acid (IPA) were identified as candidate active constituents. Treatment was associated with enrichment of Lactobacillus plantarum and Akkermansia muciniphila, suppression of TNF and IL-17 signaling, and inhibition of gastric cancer cell proliferation. However, because these findings derive primarily from computational analyses and cell-based experiments, further in vivo validation is required to determine whether microbiota remodeling contributes directly to the observed antitumor effects.⁵¹

Beyond its activity in PLGC models, WFC has also been reported to suppress malignant phenotypes of GC cells through the miR-26a-5p/MAPK/KPNA2 signaling pathway.⁵² Nevertheless, the microbiota was not directly evaluated in this study, and therefore its antitumor mechanism should be interpreted independently from microbiota-associated effects.

Clinical Studies on Traditional Chinese Medicine Formulas Targeting the Microbiota in Gastric Cancer and Precancerous Lesions

Clinical Intervention Studies in Patients with Gastric Precancerous Lesions

WFC, a classical herbal formula composed of Panax ginseng, Rabdosia amethystoides, and Citrus aurantium, has been widely used in China for chronic gastritis and PLGC. In a randomized controlled trial involving patients with Helicobacter pylori-negative PLGC, six months of WFC treatment was associated with significant improvement in gastric mucosal atrophy and intestinal metaplasia compared with the control group⁵³ (Table 3). Exploratory microbiome analyses further demonstrated alterations in gut microbial composition, including increased microbial richness and changes in community structure, together with reduced relative abundance of Parabacteroides.⁵³ Because microbiota profiling was performed as an observational component of the trial, these findings indicate an association between microbial changes and clinical improvement but do not establish that microbiota modulation mediates the therapeutic effects of WFC. Further validation in independent cohorts is required before specific taxa, such as Parabacteroides, can be considered reliable biomarkers of treatment response.

Table 3.

Representative Clinical Studies Evaluating Traditional Chinese Medicine for Gastric Precancerous Lesions and Gastric Cancer with Microbiota- or Metabolism-Related Mechanisms

TCM Intervention	Study Population	Study Design and Intervention	Proposed Microbiota- and Host-Related Mechanisms	Clinical Outcomes	Limitations	Reference
Weifuchun (WFC)	Patients with Helicobacter pylori-negative PLGC	Randomized controlled trial; continuous oral intervention for 6 months	1. Gut microbiota: Improves overall microbial diversity and community composition, significantly decreases the relative abundance of Parabacteroides.	Markedly alleviates gastric mucosal atrophy and intestinal metaplasia; greatly elevates the remission rate of clinical symptoms.	Long-term follow-up data is absent; the causal relationship between Parabacteroides and lesion improvement has not been experimentally verified.	[58]
			2. Core mechanism: Targeted regulation of specific gut taxa facilitates the reversal of gastric precancerous lesions.
Modified Bazhen Decoction	Patients after laparoscopic radical gastrectomy	Randomized controlled trial; 2-week adjunctive therapy based on routine postoperative care	1. Gut microbiota: Raises microbial richness (Ace, Chao indices); enriches Firmicutes, Bacteroidetes, Actinobacteria, and reduces the abundance of Proteobacteria.	Significantly shortens the recovery time of bowel sounds, first flatus and defecation; improves TCM syndrome scores; no statistically significant between-group difference in adverse event incidence.	The exact sample size is unreported; only short-term efficacy was observed; long-term dynamics of gut microbiota and gastrointestinal function remain unevaluated.	[59]
			2. Gastrointestinal hormones: Upregulates GAS, MTLand VIP.
			3. Immunity: Elevates CD4⁺ count and CD4⁺/CD8⁺ ratio to boost systemic immune function.
Jianpi Yangzheng Xiaozheng Decoction	Gastric cancer patients undergoing chemotherapy	Randomized controlled trial; combined administration with chemotherapy for 6 months	1. Metabolomics: Corrects disturbed amino acid metabolism (L-glutamine, L-leucine, etc).; modulates pentose phosphate pathway and glutathione metabolism; inhibits gluconolactone-related metabolism.	Greatly mitigates chemotherapy-induced leukopenia, thrombocytopenia and gastrointestinal side effects; significantly increases KPS scores.	The trial enrolled a small cohort; gut microbiota detection was not conducted; upstream microbiota-dependent metabolic regulatory pathways remain unclarified.	[60]
			2. Core mechanism: Ameliorates tumor metabolic reprogramming to achieve chemotherapy synergism and toxicity reduction.
Modified Shenling Baizhu Powder	Post-gastrectomy patients treated with FOLFOX4 chemotherapy	Randomized controlled trial; 12-week adjuvant intervention during chemotherapy cycles	1. Gut microbiota: Enrichment of beneficial Lactobacillus and Bifidobacterium; suppression of opportunistic pathogens (Escherichia coli, Enterococcus, Staphylococcus, Peptostreptococcus).	Significantly relieves chemotherapy-associated nausea, vomiting, diarrhea and anorexia, and improves patients’ quality of life; no intergroup difference in other adverse event rates.	Limited sample size; long-term therapeutic efficacy and microbial homeostasis were not monitored; integrated multi-omics analyses are lacking.	[61]
			2. Intestinal barrier: Reduces plasma DAO, D-lactate and endotoxin to restore mucosal barrier integrity.
			3. Immunity: Downregulates Th17 and Treg levels and balances the Th17/Treg ratio.

Abbreviations: TCM, traditional Chinese medicine; PLGC, gastric precancerous lesions; GAS, gastrin; MTL, motilin; VIP, vasoactive intestinal peptide; DAO, diamine oxidase; KPS, Karnofsky Performance Status; FOLFOX4, fluorouracil, leucovorin, and oxaliplatin regimen; Th17, T helper 17 cells; Treg, regulatory T cells.

Adjuvant Intervention Studies in Patients After Radical Gastrectomy

Modified Bazhen Decoction (BZD) has been evaluated as an adjunct to conventional postoperative care following laparoscopic radical gastrectomy (Table 3). In a randomized controlled trial, two weeks of BZD treatment shortened the recovery time of bowel sounds, first flatus, and first defecation, while also improving traditional Chinese medicine symptom scores.⁵⁴ The intervention was accompanied by increased serum concentrations of gastrin, motilin, and vasoactive intestinal peptide, together with higher CD4⁺ cell counts and an increased CD4⁺/CD8⁺ ratio. Exploratory microbiota analyses demonstrated increased microbial richness (Ace and Chao indices), increased relative abundance of Firmicutes, Bacteroidetes, and Actinobacteria, and reduced abundance of Proteobacteria, whereas α-diversity indices (Shannon and Simpson) remained unchanged. No significant differences in adverse events were observed between groups.⁵⁴ Although these findings suggest that postoperative recovery was accompanied by alterations in gut microbial composition and immune-related parameters, the study was not designed to determine whether microbial changes contributed directly to the clinical benefits.

Jianpi Yangzheng Xiaozheng Decoction has also been investigated as an adjunct to chemotherapy in patients with GC (Table 3). In a randomized controlled trial, six months of treatment reduced chemotherapy-associated leukopenia, thrombocytopenia, and gastrointestinal adverse events while improving Karnofsky Performance Status (KPS) scores.⁵⁵ Serum metabolomic analyses identified alterations in amino acid metabolism, including L-glutamine, L-leucine, L-isoleucine, and L-valine, together with changes in the pentose phosphate pathway, glutathione metabolism, and other amino acid metabolic pathways.⁵⁵ These metabolomic findings suggest that the formula may influence host metabolic responses during chemotherapy. However, because the study enrolled a relatively small number of participants and did not evaluate the gut microbiota directly, larger studies are needed to confirm these observations.

A modified Shenling Baizhu Powder (SLBZS) has been evaluated in patients receiving radical gastrectomy followed by chemotherapy (Table 3). After 12 weeks of treatment, patients receiving SLBZS experienced lower incidences of chemotherapy-related nausea, vomiting, diarrhea, and anorexia, accompanied by improved quality-of-life measures.⁵⁶ The intervention was also associated with reduced circulating levels of diamine oxidase (DAO), D-lactate, and endotoxin, suggesting improved intestinal barrier function, together with changes in Th17- and Treg-cell populations. Microbiological analyses showed increased abundance of Lactobacillus and Bifidobacterium and reduced abundance of potentially pathogenic bacteria, including Escherichia coli, Enterococcus, Staphylococcus, and Peptostreptococcus.⁵⁶ These findings indicate that clinical improvement was accompanied by concurrent changes in intestinal barrier-related biomarkers, immune parameters, and gut microbial composition. However, given the relatively small sample size and single-center design, the contribution of microbiota modulation to treatment efficacy remains uncertain and requires confirmation in larger multicenter studies.

Conclusion and Perspectives

Growing evidence indicates that alterations in the gastrointestinal microbiota are associated with multiple stages of gastric carcinogenesis, extending from chronic gastritis and PLGC to established GC.^57,58 Rather than representing a single microbial niche, the gastrointestinal microbial ecosystem comprises compartment-specific communities within the oral cavity, gastric mucosa, gastric fluid, and intestine, each exhibiting distinct ecological characteristics and disease-associated alterations. Although several bacterial genera, including Streptococcus, Lactobacillus, Prevotella, and Veillonella, have been repeatedly reported in association with GC, their biological significance is highly dependent on the sampling compartment, Helicobacter pylori infection status, gastric acidity, and sequencing methodology. Therefore, interpretation of microbiome data requires careful consideration of sampling strategy, contamination control in low-biomass gastric specimens, and potential oral carryover.

Experimental studies suggest that TCM formulas and naturally derived compounds may influence several processes relevant to gastric carcinogenesis, including H. pylori colonization, mucosal inflammation, epithelial barrier integrity, microbial metabolite production, and programmed cell death.⁵⁹ These observations support the hypothesis that herbal medicines may exert therapeutic effects partly through bidirectional interactions among herbal constituents, gastrointestinal microbial communities, microbial metabolites, and host immune and mucosal responses. However, for most formulas, the causal contribution of microbiota modulation remains incompletely established because mechanistic evidence is derived predominantly from animal models and in vitro experiments. Furthermore, whether microbial alterations represent primary therapeutic mechanisms or secondary consequences of disease improvement remains unclear.

Current clinical evidence remains limited. Randomized controlled trials of formulas such as Weifuchun, modified Bazhen Decoction, Jianpi Yangzheng Xiaozheng Decoction, and modified Shenling Baizhu Powder suggest potential benefits in patients with PLGC or GC, including improvements in histopathological changes, postoperative gastrointestinal recovery, treatment tolerance, and selected microbiota-related outcomes. Nevertheless, these studies generally involve relatively small sample sizes, short follow-up periods, heterogeneous outcome measures, and limited microbiome analyses.^60,61 Consequently, existing clinical evidence should be considered preliminary rather than definitive, and the efficacy of microbiota-targeted herbal interventions for preventing progression to GC remains to be confirmed.

Several important challenges should be addressed to facilitate clinical translation. First, standardized protocols are needed for gastric microbiome studies, including specimen collection, contamination control, DNA extraction, sequencing platforms, bioinformatic pipelines, and reporting standards, particularly for low-biomass gastric mucosal and gastric fluid samples. Second, future investigations should integrate strain-level metagenomics, metatranscriptomics, metabolomics, and spatial microbiome profiling with experimental validation to distinguish microbial associations from causal mechanisms. Third, patient stratification according to H. pylori status, gastric pathology, medication exposure (particularly proton pump inhibitors and antibiotics), dietary patterns, and molecular subtypes of GC will likely improve reproducibility and identify patient populations most likely to benefit from microbiota-directed interventions.

From a therapeutic perspective, future clinical trials should also evaluate the safety and compatibility of herbal formulas when administered alongside standard treatments, including H. pylori eradication regimens, chemotherapy, immune checkpoint inhibitors, anticoagulants, and acid-suppressive medications. Given the substantial variability in herbal composition, manufacturing processes, and dosing regimens, rigorous quality control and formula standardization will be essential for reproducible clinical outcomes. In addition, whether specific herbal formulas preserve resident gastric and intestinal commensal microorganisms more effectively than conventional antimicrobial therapies deserves further investigation.

Overall, current evidence supports continued investigation of microbiota-associated mechanisms underlying TCM interventions in gastric diseases. However, translating these findings into clinical practice will require well-designed multicenter randomized controlled trials with standardized herbal formulations, longitudinal microbiome assessment, integrated multi-omics analyses, and mechanistic validation. Such studies will help determine whether microbiota-directed herbal interventions can provide clinically meaningful benefits for the prevention, risk stratification, and management of gastric precancerous lesions and gastric cancer.

Data Sharing Statement

All relevant data are included in the article.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All the authors agreed to submit the manuscript to this journal for consideration and the results, data, and figures in this manuscript have not been published and not under consideration for publication elsewhere.

Disclosure

The authors have no financial or other conflicts of interest to declare.