Gastrointestinal microbiota in treatment of gastric precancerous lesions and gastric cancer by Western and traditional Chinese medicine

Abstract

Gastric precancerous lesions (GPL) represent a crucial stage in the complex process of gastric carcinogenesis that leads to gastric cancer (GC), one of the most prevalent cancers and a major source of cancer mortality worldwide. Many studies have identified the gastrointestinal microbiota, or gut microbiota, as an important contributor to both the pathogenesis and treatment of GPL and GC, thus understanding its role in this transition is crucial. The purpose of this literature review is to introduce the current landscape of microbiota research associated with GPL and GC, with an emphasis on Helicobacter pylori (H. pylori) driven microbial dysbiosis and its modulation through Western medicine and traditional Chinese medicine (TCM) approaches. By elucidating the underlying mechanisms of H. pylori colonization, patterns, and interactions among microbiota, as well as the influence of microbial metabolites, this review highlights crucial driving factors of gastric carcinogenesis. The role of microbiota in conventional interventions, including H. pylori eradication, immunotherapy, as well as TCM herbal decoctions, is also discussed to provide a detailed understanding of the complex interactions between therapy and microbiota and how it could be potentially targeted for effective management of GPL and GC. Ultimately, microbiota-targeting therapeutics may represent a new path toward early detection, targeted treatment, improved prognosis, and potentially reduced incidence of GPL and GC.

Key Words: Gastric precancerous lesions; Gastric cancer; Microbiota; Dysbiosis; Western medicine; Traditional Chinese medicine

Core Tip: The development of gastric precancerous lesions (GPL) and gastric cancer (GC) is often driven by Helicobacter pylori infection and is closely linked to changes in the gastrointestinal microbiota. Both Western medicine and traditional Chinese medicine offer therapeutic approaches that modulate the microbiota through various mechanisms, thereby influencing gastric carcinogenesis and treatment outcomes. Consequently, targeting the microbiota represents an encouraging approach for improving the diagnosis, treatment, and overall management of GPL and GC.

INTRODUCTION

Gastric cancer (GC) is a leading cause of gastrointestinal cancer burden worldwide, ranking second in incidence after colorectal cancer, with significant differences in age-standardized incidence and mortality rates based on geography and socioeconomic status[1]. The occurrence of GC is highly correlated with the prevalence of gastric precancerous lesions (GPL), premalignant stages of the Correa cascade that increases the risk of developing gastric adenocarcinoma[2], thus recognition of these early stages enables prompt identification, intervention, and prevention. Helicobacter pylori (H. pylori) infection has been identified as a major risk factor of GPL and GC[3], but recent studies have highlighted an increasingly important role of the gastrointestinal microbiota, microbial communities located within the gastrointestinal tract that are in symbiosis with the host[4], in disease progression. However, microbial dysbiosis, characterized by changes in the composition, diversity, or richness of the microbiota, can lead to chronic inflammation, metabolic dysregulation, and immune disruption, all of which contribute to carcinogenesis. In contrast, microbial resurgence toward homeostasis may improve both host immunity and therapeutic responses. Consequently, the microbiome, or collection of microbial communities that inhabit and interact with the human body[5], represents a double-edged sword that affects both disease progression and patient outcome. Here, we present an up-to-date review of the current research regarding the dual role of the gastrointestinal microbiota, where dysbiosis may contribute to disease progression and homeostasis may serve as protection against carcinogenicity while evaluating Western medicine and traditional Chinese medicine (TCM) approaches in the treatment of GPL and GC.

GASTROINTESTINAL MICROBIOTA IN GASTRIC PATHOGENESIS

Mechanisms of H. pylori pathogenesis

The role of H. pylori in gastric pathogenesis has been the focus of many studies, with a particular emphasis on its multifaceted mechanisms leading to GPL and GC. Figure 1 illustrates the common mechanisms of H. pylori pathogenesis. In addition to direct colonization, recent studies have shown that H. pylori contributes to disease progression by establishing a tumor-conducive environment through immune modulation, alterations in the gastric microbiota, and activation of oncogenic pathways. The ability to structurally adapt is one of the first strategies through which pathogens have improved their persistence. Biofilm formation has been a central feature of H. pylori, as it not only aids in bacterial survival, but also leads to chronic infection and inflammation, making its eradication more difficult[6]. Su et al[7] further illustrated the importance of bacterial motility in pathogenic survival by identifying FliW2, a flagellar assembly factor, as an antagonist of the global regulator CsrA needed for bacterial motility, colonization, and persistence in the gastric microenvironment. These evasive mechanisms allow H. pylori to persist within the host, disrupting immune responses by suppressing antibacterial chemokines and Th1 cell-mediated bacterial clearance[8]. In addition to immune modulation, H. pylori induces NLRP3 inflammasome activation in macrophages, further exacerbating the inflammatory microenvironment by promoting M1 macrophage polarization[9]. Phospholipase A, an enzyme produced by H. pylori that breaks down the phospholipids in cell membranes, is also an important factor in disrupting macrophage autophagy, promoting host apoptosis, and enhancing bacterial survival[10]. Aside from these diverse immune evasion mechanisms, H. pylori can also modify the susceptibility of host cells to ferroptosis through the regulation of glutathione metabolism, lipid peroxidation, and fatty acid synthesis[11]. Additionally, H. pylori can activate central oncogenic signaling cascades, such as the YAP1-CTGF oncogenic axis through the upregulation of PIEZO1 and NF-κB signaling[12]. This promotes fibroblast infiltration, collagen accumulation, and tumor stiffness, all of which are critical to GC development. Epigenetic dysregulation also plays an important role in H. pylori’s pathogenesis. For example, a study found that infection with CagA-positive H. pylori increased FTO expression, promoting m6A demethylation and stabilization of HB-EGF, driving epithelial-mesenchymal transition (EMT) and gastric tumor progression[13]. Notably, the CagA-driven oncogenic effects persisted even after H. pylori eradication, suggesting that H. pylori induces permanent molecular damage. Another study found that inhibition of the m6A methyltransferase METTL14 promoted gastric carcinogenesis via activation of a novel VAMP3/LC3C-c-Met signaling pathway[14]. However, epigenetic modification may also mediate caspase-8 activation and subsequently increase GC cell sensitivity to fluorouracil chemotherapy by promoting apoptosis and pyroptosis[15]. Furthermore, H. pylori may directly influence genomic stability, such as suppressing POLD1-dependent DNA repair or causing recurrent DNA breaks at fragile replication sites to increase genomic instability and DNA damage accumulation[16,17]. A recent study also found a novel H. pylori virulence factor called SlyD that promoted gastric intestinal metaplasia (IM) through the upregulation of TPT1[18]. Interestingly, this effect seems to be mediated by nucleotide depletion rather than by the previously implicated cag PAI virulence factors. Accumulating evidence suggests that H. pylori employs diverse strategies to evade host immunity, creates a tumor-inducive environment, and contributes to gastric carcinogenesis.

Figure 1  Mechanisms of Helicobacter pylori pathogenesis. H. pylori: Helicobacter pylori.

Microbial effects and interactions of H. pylori

In addition to driving cancer progression, H. pylori reshapes the gut microbiota and indirectly influences bacterial survival and host responses. In children, H. pylori infection was shown to significantly reduce gastric microbial diversity, evidenced by decreased abundance of six bacterial phyla and eight genera, as well as increased growth of H. pylori itself[19]. This shift was accompanied by the upregulation of immune response-associated genes, including FOXP3, IL-10, TGF-β1, and IL-17A, resulting in an immunosuppressive, pro-inflammatory environment. Sex-specific differences in microbial compositions have also been observed in H. pylori infection, as well as increased gastric inflammation, IM, and lesions in males compared to females, suggesting potential interactions between H. pylori and sex hormones[20]. In GC patients, increased proportions of Firmicutes (particularly Lactobacillus and Veillonella), Bacteroidetes (such as Prevotella), and others like Peptostreptococcus, Dialister, and Streptococcus anginosus (S. anginosus) were observed[21,22]. This was accompanied by significant alterations in 69 metabolites, particularly triglycerides and phosphatidylcholines. The evidence suggests that changes in the microbiota not only alter its composition, but also impact downstream metabolites and host metabolism, potentially influencing gastric carcinogenesis.

Not only does H. pylori invade the gastric mucosa, it interacts with other microbial species, host cells, and metabolites to indirectly influence disease progression. For example, H. pylori facilitates the invasion of non-H. pylori bacteria into the lamina propria[23] and together disrupts the microbial balance. The influence of oral microbes via the oral-gastric microbial axis has also been extensively studied, with epidemiologic evidence indicating an association between poor oral hygiene and increased GC risk[24]. Among these, S. anginosus, a microbe commonly found in the oral cavity, has been identified as a key factor in promoting gastric inflammation, atrophy, and tumorigenesis[25]. Under normal health conditions, oral microbes are unable to survive in the stomach’s highly acidic environment. However, as pH levels decrease as a result of H. pylori infection, species like S. anginosus can colonize the stomach and induce physiological changes, such as increased inflammation and cell proliferation, gastric atrophy, metaplasia, and low-grade dysplasia[26]. These findings highlight the interdependence between H. pylori infection and oral microbial colonization in the carcinogenic progression of the stomach.

Microbial dysbiosis as a driving factor

Microbial dysbiosis, characterized by alterations in the gastric microbiota towards the dominance of pathogens and reduction in microbial diversity, has emerged as a key factor in gastric carcinogenesis. In recent years, several studies have emphasized the complex interplay between microbial dysbiosis and the pathogenesis of GPL and GC. Figure 2 illustrates the microbial changes in the progression of gastric cancer. Reductions in microbial alpha diversity have been observed in the early development of GPL from gastritis, implicating multiple opportunistic pathogens in this process[27]. As the disease progressed to GC, a significant enrichment of specific opportunistic pathobionts, including Fusobacterium, Prevotella, Veillonella, Parvimonas, and Peptostreptococcus, accompanied by depletion of beneficial commensal microbes, such as Bifidobacterium, Blautia, and Bacillus, was identified[28]. This was further corroborated by a recent study that also observed a decrease in beneficial Bifidobacterium and Faecalibacterium in GC patients, accompanied by elevated expression of the immunosuppressive markers PD-L1 and IL-10 in immune cells[29]. Such microbial shifts indicate that enrichment of pathobionts and loss of beneficial microbial communities create a pro-inflammatory environment conducive to carcinogenesis. Another study similarly observed a significant reduction in microbial diversity in GC tissues, together with increased abundances of Helicobacter and Lactobacillus, particularly in samples with microsatellite instability-high characteristics[30]. Zhang et al[31] identified the enrichment of potentially pathogenic genera, such as Streptococcus, Gemella, Escherichia-Shigella, and Fusobacterium, accompanied by a reduced abundance of beneficial microbes, including Haemophilus, Neisseria, Faecalibacterium, and Romboutsia. It is also important to address heterogeneity observed in GC tissues, with higher proportions of certain genera like Porphyromonas, Catonella, and Proteus in proximal GC and others in distal GC[32]. Despite this, no significant changes were observed in the overall microbial diversity and richness. However, when comparing GC tumor tissues to their adjacent non-tumor tissues, an abundance of Lactobacillus, Streptococcus, and Bacteroides was observed[33]. Supporting this, Peng et al[34] reported an enrichment of Oceanobacter, Methylobacterium, and Syntrophomonas, with intratumoral Methylobacterium inversely associated with immune infiltration and significantly correlated with poor prognosis. Streptococcus and Pseudomonas also correlated with worse prognosis[35]. Specifically, S. anginosus was found to directly promote tumor cell proliferation and metastasis, as well as suppress CD8+ T cell differentiation and infiltration. Enrichment of these pathogenic species within the tumor microenvironment suggests that selective accentuation of certain microbial communities can manipulate immune responses and drive gastric carcinogenesis.

Figure 2  Microbial changes in the progression of gastric cancer.

Role of microbial metabolites

Microbial metabolites have been recognized as significant contributors to gastric carcinogenesis through complex interactions between microbiota and host metabolic pathways. Elevated levels of amino acids, carbohydrates, glycerophospholipids, and nucleosides were identified in GC tissues compared to non-tumor tissues[33], with the majority of differential metabolites correlated with distinct microbes. Short-chain fatty acid (SCFA) pathways were also impaired among GC patients, reflecting their roles in inflammation and microbial dysbiosis[36]. Importantly, acetate promoted gastric adenocarcinoma cell proliferation at lower concentrations but induced apoptosis at higher concentrations. Mechanistically, this may be due to the upregulation of pro-inflammatory cytokines (e.g., IL-8, IL-1β, and TNF-α) and induction of apoptosis through caspase activation. Kaźmierczak-Siedlecka et al[37] further elaborated on the dual nature of microbial metabolites in cancer progression. For example, certain SCFAs exhibit protective anticancer properties, whereas metabolites like polyamines and N-nitroso compounds may elevate cancer risk by promoting DNA damage and cellular proliferation. Metabolome analysis also revealed that metabolites within distal GC were primarily involved in sphingolipid signaling, arginine biosynthesis, and glutamate metabolism, while those in proximal GC were predominantly involved in hormone metabolism[32]. This suggests substantial tissue heterogenicity between the two locations, resulting in distinct metabolic profiles that may influence the tumor microenvironment. Triglycerides and phosphatidylcholines were also identified as having stronger correlations with Peptostreptococcus and Lactobacillus in GC[22]. The interplay between microbial metabolites and host metabolism also impacts immune regulation, such as the inhibition of PD-L1 and IL-10 expression in GC patients’ immune cells by butyrate[29]. Taken together, these findings underscore the critical and diverse contributions of microbial metabolites to the complex biology of gastric carcinogenesis and their opposing context-dependent roles in the gastric microenvironment. Therefore, direct intervention in microbial metabolic processes or indirect modulation of microbiota composition represents highly interesting new avenues for clinically innovative mucosal therapies for GC that aim to disrupt carcinogenic processes, reduce inflammation, and recover immune competence to ultimately affect GC outcome.

Gut microbiota as biomarkers for GPL and GC

Accumulating evidence indicates that microbial dysbiosis contributes significantly to gastric carcinogenesis, making the microbiota promising diagnostic biomarkers. Changes in specific bacterial species, including Gemella, Veillonella, Streptococcus, Actinobacillus, and Hemophilus, were observed in the progression of GPL and predictive models based on H. pylori-positive gastric and fecal microbiota samples successfully identified GPL risk[27]. Stage-specific microbial signatures were also identified in H. pylori-negative patients. Specifically, an increased abundance of Ralstonia and Rhodococcus correlated with IM and dysplasia, while Burkholderiaceae showed progressive enrichment from atrophic gastritis to dysplasia[38]. Beyond the gastric microbiota, changes in the oral microbiota have been consistently linked to GC and its precursors. This includes an enrichment of oral Slackia, Selenomonas, Bergeyella, and Capnocytophaga[39], and salivary Fusobacterium[40], as well as Leptotrichia on the tongue coating[41], suggesting the oral microbiota as non-invasive potential biomarkers. At the tissue level, numerous studies[38,42-46] reported Streptococcus enrichment as biomarkers for GC risk, associated with increased inflammation and impaired anti-tumor immunity. Streptococcus lutetiensis, in particular, has been linked to oxidative stress and suppression of IL-17 signaling, which promotes immune evasion and tumor progression[45]. Similarly, Fusobacterium has been repeatedly implicated in GC progression and poor prognosis[28,46,47]. Specifically, Fusobacterium nucleatum was found to promote genetic instability, ERBB2 and TP53 mutations, as well as immune suppression[47]. Other microbes, including Prevotella intermedia, Pseudomonas, Acinetobacter, and Streptomyces, also highly correlated with gastric carcinogenesis, promoting GC cell proliferation, migration, and invasion[48,49]. In addition to an enrichment of opportunistic pathogens, the depletion of commensal bacteria also influences host responses. Reductions in commensal bacteria like Bifidobacterium, Bacillus, and Blautia were observed in GC compared to gastritis[28]. Ai et al[48] also revealed a decrease in Lysobacter, a core genus in normal gastric tissue, as an indication of compromised mucosal integrity in GC. Furthermore, microbial taxa such as Clostridioides difficile, Aspergillus fumigatus, and Fusarium pseudograminearum were significantly associated with tumor immune subtypes, suggesting microbial influences on immune cell infiltration and the tumor microenvironment[50]. Clinical application of these stage-specific changes, such as the Resident Gastric Microbiota Dysbiosis Test proposed by Zaramella et al[51], demonstrated a high specificity (88.9%) in differentiating patients at higher risk of progression to high-grade dysplasia or GC from atrophic gastritis. Overall, these results highlight the diagnostic potential of the gastric microbiota as non-invasive biomarkers and risk-stratification markers of gastric carcinogenesis, though future studies should further validate microbial signatures across diverse populations to enable clinical application.

WESTERN MEDICINE APPROACHES TARGETING MICROBIOTA

H. pylori eradication and effects on microbiota

H. pylori eradication has become a mainstay in GC prevention, with a growing consensus favoring its use in high-risk populations and extending to population-based prevention. The 2020 Taipei global consensus[52] strongly recommended eradication not only in asymptomatic individuals but also in first-degree relatives of GC patients and patients with early GC after curative endoscopic resection. Early H. pylori detection and eradication have shown strong preventive efficacy in GC, especially in high GC incidence areas. In support of this, a large-scale cluster randomized trial involving 180284 participants found a 13% reduction in overall GC incidence after treatment, and a 19% reduction among those with successful H. pylori eradication[53]. In particular, there was a 35% decrease in GC incidence, along with a 43% decrease in mortality among younger populations aged 25-45 years.

Despite these profound benefits, an increasing amount of evidence reveals profound and sometimes complex changes to the gut microbiome after eradication therapy. In a metaproteomic analysis, notable microbial shifts were observed immediately after quadruple therapy, including a reversal in microbial-to-host protein abundance and significant enrichment in several pathobionts[54]. This also resulted in changes in host function, including altered SCFA production and increased antibiotic resistance. However, eradication therapy still effectively reduced inflammation and H. pylori-mediated carcinogenesis, indicating clear therapeutic efficacy despite microbial disturbances. Liou et al[55] also noted short-term disturbances of the microbiota and transient increases of antibiotic resistance genes following H. pylori eradication. Another study offered promise, as successful H. pylori eradication restored gastric microbial diversity to levels comparable to non-infected individuals and increased beneficial populations like Bifidobacterium[56]. However, failed treatments were associated with increases in drug-resistant functional orthologs, underscoring the risks of incomplete bacterial clearance. Due to the complexity of H. pylori’s relationship with the microbiota, Sitkin et al[57] recommended against universal eradication, especially because it may result in adverse microbiome alterations, such as an increase in pathogenic taxa like Proteobacteria and Enterobacteriaceae. As such, a more individualized, risk-benefit approach to eradication is recommended, especially for the elderly or individuals who have experienced repeated eradication failures.

The long-term evaluation of microbiota recovery and pathogenic persistence after successful H. pylori eradication is also of high importance. The long-term recovery of the microbiota and the persistence of pathogenic microbial signatures after successful H. pylori eradication need to be further evaluated. Distinct microbes like Acinetobacter lwoffii and S. anginosus have been linked to chronic inflammation, gastric atrophy, and IM post-eradication[58], suggesting persistent microbial imbalances despite eradication. Conversely, Wiklund et al[59] provided reassuring epidemiological evidence, demonstrating that gastric non-cardia adenocarcinoma incidence was substantially decreased following eradication therapy, and returned to background population levels approximately 11 years post-treatment. This also reflects the value of long-term monitoring of microbiota dynamics following eradication. With that said, future therapeutic directions should prioritize personalized, microbiota-based approaches to enhance the long-term efficacy, safety, and outcome of H. pylori eradication.

Probiotic supplementation and microbiota modulation

The use of probiotics as adjunctive strategies against H. pylori infection is gaining recognition due to their ability to restore microbial balance, reduce adverse effects, and potentially improve clinical outcomes. Probiotics, such as those in the Lactobacillus and Bifidobacterium genera, have demonstrated great promise in their ability to modulate gut microbiota composition, affect immune responses, and mitigate inflammation-induced toxicity[60]. Clinical studies have provided evidence in support of these benefits after eradication therapy. Table 1 summarizes the mechanisms of action of probiotic strains. For example, FitzGerald et al[61] showed that multi-strain probiotic formulations containing Lactobacillus paracasei and Lacticaseibacillus rhamnosus promoted microbiota composition recovery following H. pylori eradication. Similarly, a multicenter randomized clinical trial by He et al[62] reported that probiotic supplementation counteracted the decrease in the beneficial Bacteroidetes associated with antibiotic resistance, but did not have a direct impact on H. pylori eradication rate. In line with this are the results of a large international registry study involving over 36000 patients, which identified significant beneficial effects of probiotic supplementation in patients undergoing H. pylori eradication therapy[63]. In particular, the addition of Lactobacillus strains significantly improved eradication efficacy, especially in Eastern European populations treated with triple and bismuth-based quadruple therapies. Moreover, supplementation with Bifidobacterium and Saccharomyces species reduced adverse events, demonstrating the clinical advantages of probiotics. Other studies have shown that specific probiotic strains may contribute more directly to fighting inflammation, boosting immunity, and preventing harmful bacterial colonization. For instance, Zheng et al[64] demonstrated that the use of a probiotic combination containing Lactobacillus plantarum, L. rhamnosus, L. acidophilus, and Bifidobacterium animalis significantly improved postoperative outcomes through modulation of inflammation and gut barrier integrity and restoration of gut microbiota diversity. These effects were achieved through downregulation of inflammatory signaling pathways, maintenance of intestinal barrier integrity, and enhancement of mucosal immunity. Similarly, Lai et al[65] identified Parabacteroides goldsteinii MTS01 as a novel probiotic candidate that significantly attenuated gastric inflammation, restored gut microbiota composition, and neutralized H. pylori virulence factors (VacA and CagA). In parallel, Do et al[66] demonstrated that Lactobacillus rhamnosus JB3 significantly inhibited H. pylori adhesion by interfering with Lewis antigen-dependent adherence mechanisms and type IV secretion system-mediated cellular interactions. Lactobacillus crispatus FSCDJY67 L3 showed direct aggregation with H. pylori, reduced gastric bacterial load, and alleviated gastrointestinal symptoms while preserving microbiota composition and host physiology[67]. These studies highlight the potential of probiotic supplementation in targeted microbial modulation and pathogen suppression. Probiotics also modulate inflammatory processes that are involved in gastric carcinogenesis. He et al[68] demonstrated that Lactobacillus salivarius and L. rhamnosus administration significantly reduced GPL and inflammation in an INS-GAS mouse model through downregulation of key inflammatory signaling pathways, including NF-κB, IL-17, and TNF, as well as restoration of microbial diversity and beneficial, anti-inflammatory bacterial taxa, such as Bacteroides and Faecalibaculum. In line with these observations, Chen et al[69] identified novel strains of Weizmannia coagulans, notably strain BCF-01, with potent anti-H. pylori and anti-inflammatory activities. The underlying mechanisms involved suppression of the TLR4-NF-κB-pyroptosis signaling axis, restoration of disrupted microbiota, and improvement of mucosal barrier integrity.

Table 1 Mechanisms of action of probiotic strains.

Probiotic strain(s)	Mechanism of action	Evidence	Ref.
Lactobacillus paracasei and Lacticaseibacillus rhamnosus	Microbiota restoration	Double-blind RCT	FitzGerald et al[61]
Bifidobacterium Tetragenous	Microbiota restoration	Multicenter RCT	He et al[62]
Lactobacillus, Bifidobacterium, and Saccharomyces	Efficacy and safety enhancement	Observational study	Casas Deza et al[63]
Lactobacillus plantarum MH-301, L. rhamnosus LGG-18, L. acidophilus, and Bifidobacterium animalis subsp. lactis LPL-RH	Anti-inflammatory effect, barrier protection, immune modulation	Clinical and in vivo study	Zheng et al[64]
Parabacteroides goldsteinii MTS01	Anti-inflammatory and anti-H. pylori effects	In vivo study	Lai et al[65]
Lactobacillus rhamnosus JB3	Anti-H. pylori effect, host membrane modulation	In vitro study	Do et al[66]
Lactobacillus crispatus FSCDJY67 L3	Symptom relief, anti-H. pylori effect	Double-blind RCT	Hong et al[67]
Lactobacillus salivarius and Lactobacillus rhamnosus	Microbiota restoration, anti-inflammatory effect	In vivo study	He et al[68]
Weizmannia coagulans BCF-01	Microbiota restoration, anti-inflammatory effect, pyroptosis reduction	In vitro and in vivo study	Chen et al[69]
Lactobacillus gasseri BIO6369 and Lacticaseibacillus rhamnosus BIO5326	Anti-inflammatory and anti-H. pylori effects	In vitro study	Jauvain et al[70]
Lacticaseibacillus pacasei	Microbiota restoration, anti-inflammatory and anti-H. pylori effects, host cell modulation	In vitro and in vivo study	Yao et al[71]
Lactiplantibacillus plantarum ZJ316	Microbiota restoration, anti-inflammatory effect, barrier protection	In vivo study	Wu et al[72]

H. pylori: Helicobacter pylori; RCT: Randomized control trial.

Further highlighting the diverse therapeutic mechanisms of probiotics, Jauvain et al[70] revealed anti-carcinogenic activity with certain Lactobacillaceae strains, particularly Lactobacillus gasseri BIO6369 and Lacticaseibacillus rhamnosus BIO5326, both of which significantly reduced EMT and inflammatory marker expression, and preserved epithelial barrier integrity in H. pylori-infected gastric epithelial cells. Furthermore, indole-3-lactic acid produced by Lacticaseibacillus paracasei was found to have potent antimicrobial and anti-inflammatory activities, which suppressed H. pylori by inhibiting urease activity and bacterial adhesion, while simultaneously alleviating host inflammation, reducing oxidative stress, and restoring microbial diversity in vivo[71]. Similarly, Wu et al[72] demonstrated that Lactiplantibacillus plantarum ZJ316 markedly alleviated intestinal inflammation, protected gastrointestinal barrier integrity, and restored microbiota composition by decreasing the expression of proinflammatory cytokines and inhibiting the IκBα/NF-κB signaling pathway. Taken together, these studies demonstrate the efficacy of probiotics as beneficial adjunctive strategies capable of restoring microbial equilibrium and, more importantly, alleviating adverse effects while potentially reducing the risk for GPL and GC.

Role of microbiota in immunotherapy

The role of the microbiota in modulating immunotherapy has been identified as a significant area of research, highlighting the profound impact of gut microbes and their metabolites on host immune responses and therapeutic efficacy. For example, systemic administration of Bifidobacterium has been shown to enhance anti-CD47 immunotherapy efficacy by activating dendritic cell cross-priming and STING-dependent interferon responses in the tumor microenvironment[73]. Another study focused on the role of microbial-tumor antigen cross-reactivity, which can potentially enhance anti-tumor effects or alternatively increase autoimmunity risk[74]. Zhang et al[75] observed a positive correlation between gut microbial diversity, particularly beneficial bacteria like Ruminococcus, Bacteroides, and Akkermansia, and CAR-T cell therapy efficacy. However, antibiotic-induced dysbiosis exacerbated CAR-T-associated neurotoxicity, underscoring the importance of maintaining microbial homeostasis in immunotherapeutic regimens.

Recent studies have identified unique microbial signatures associated with responsiveness to immunotherapy through various mechanisms. Among them, Akkermansia muciniphila and Dorea formicigenerans have been recognized as predictors of immunotherapeutic efficacy in GC patients[76]. Kim et al[77] identified TANB77, a novel bacterial clade, as a reliable marker of favorable responses to immune checkpoint inhibitors. Importantly, pilin-like proteins isolated from TANB77 enhanced anti-PD-1 therapy, illustrating the potential of microbiota-derived biomolecules as candidates for therapeutic development. Moreover, bacterial species such as Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium also promoted CD8+ T cell activation and enhanced anti-PD-1 responses, whereas Akkermansia muciniphila and Enterococcus hirae boosted efficacy by promoting dendritic cell activation and IL-12 production[60]. Additionally, Jiang et al[78] revealed paradoxical beneficial effects from traditionally pathogenic bacteria, such as Fusobacterium nucleatum, which enhanced anti-PD-L1 responses via the STING pathway. The variance in immunotherapeutic effects has also been observed in Lactobacillus strains[79], highlighting both the dual functions of microbiota and the significance of individualized microbiota-targeted strategies.

Microbiota-derived metabolites are also key players in immune modulation and immunotherapy response. Chrysostomou et al[60] noted that microbial metabolites, such as SCFAs, bile acids, and inosine, have variable effects on immunotherapy efficacy. Propionic and butyric acids, for instance, improve CD8+ T cell activity but have opposing effects in different types of immunotherapies. Inosine, particularly from Bifidobacterium pseudolongum, has been found to significantly enhance the efficacy of immune checkpoint inhibitors through T cell activation[80]. Hexa-acylated lipopolysaccharides have also been identified as enhancers of anti-PD-1 efficacy[81]. Furthermore, polysaccharide metabolites exhibit immunomodulatory potential, such as exopolysaccharides from Lacticaseibacillus rhamnosus that enhanced immune function and alleviated chemotherapy-induced immunosuppression[82]. In addition, Cheng et al[83] identified tryptophan derivatives, bile acids, and SCFAs to be important modulators of NK and CD8+ T cell activity, significantly affecting immunotherapeutic efficacy and outcome. Other studies highlighted the role of microbiota in regulating immune cell ferroptosis, emphasizing its importance in tumor microenvironment immunosuppression and therapeutic responsiveness[84,85].

TCM INTERVENTIONS

Relationship between TCM theory and gut microbiota

TCM emphasizes a holistic understanding of health and modern medicine has provided a way to explore the interplay between medicinal herbs and the gut microbiota. Central to this understanding is the property theory of Chinese Materia Medica (CMM), a fundamental ideology that guides the theoretical basis and clinical application of TCM. One of its components is the five-flavor theory, which classifies CMMs into five flavors based on taste and medical functions. Its connection to the gut microbiota has been explored by several studies. Yang et al[86] systematically explored the relationship between 14 CMMs with distinct flavors and their effects on the gut microbiota, finding specific microbial functional gene groups strongly and differentially responding to each flavor. In alignment with this, Su et al[87] detailed mechanisms whereby mild-natured and bitter-flavored TCMs modulate the microbiome by enhancing beneficial bacteria, such as Bacteroides, Akkermansia, Lactobacillus, and Bifidobacterium, while inhibiting pathogenic species like Helicobacter, Enterococcus, Desulfovibrio, and Escherichia-Shigella. Yang et al[88] also observed that sweet- and bitter-flavored CMMs had a significant dual-modulatory effect by favoring beneficial microbiota and diminishing pathogens. This change in microbial compositional also influenced metabolite production, leading to the increase of beneficial metabolites (SCFAs, serotonin, indoles, and GABA) and reduction of harmful metabolites (trimethylamine N-oxide and lipopolysaccharides), which may influence disease progression through a "TCM-microbiota-metabolite-signaling-disease" axis[87]. Another study has indicated that cold-natured and sweet-flavored TCM herbs selectively enriched beneficial microbiota, such as Akkermansia, Lactobacillus, Bacteroides, and Bifidobacterium, and suppressed pathogenic genera, including Helicobacter, Enterococcus, and Streptococcus[89]. The selective microbial modulation not only validates the TCM theory but also highlights its therapeutic potential.

In addition to flavors, the property theory also classifies CMMs as hot, warm, cool, or cold-natured based on their intrinsic nature. Regarding this, Zhang et al[90] provided insights by demonstrating that cold-natured TCMs caused significant changes in microbial diversity, while hot-natured TCMs did not have significant effects on the microbiota. Similar results were also observed by Li et al[91] on the gut microbiome and host metabolism. Moreover, it was observed that warm-natured herbs mainly enriched beneficial microbiota, while cold-natured herbs enriched beneficial and inhibited harmful species[88]. In particular, CMMs with specific meridian tropism, such as Jueyin and Taiyin, had a more pronounced influence, supporting the intricate relationship between TCM classifications and microbial alterations.

Furthermore, Gong et al[92] pointed out that the gut microbiota can actively metabolize TCM ingredients, such as flavonoids, alkaloids, and polysaccharides, producing metabolites that can enhance systemic bioavailability and therapeutic efficacy, as well as affect host metabolism. These bioactive compounds may change the microbial composition, which also affects the safety and efficacy profiles of herbal decoctions[93]. Luo et al[94] further illustrated how TCM ingredients, especially polysaccharides and bioactive compounds, act to restore microbial balance, regulate microbial metabolism, protect intestinal barrier integrity, and promote immune function. Although some TCM herbs may modify the microbiome, the consistent association of specific compounds with favorable gut microbial alterations highlights the delicate relationship between TCM and the microbiota, which could yield therapeutic opportunities for improvement and toxicity mitigation.

Gut microbiota modulation of TCM decoctions

The targeted microbial effects of TCM treatments in digestive diseases have been revealed in clinical settings. For example, Chaihu Shugan San has been shown to alter the bacterial community structure and increase the rate of gastric emptying in patients with functional dyspepsia, and Dachengqi decoction reduced inflammation and promoted gastrointestinal function recovery in patients with mild acute pancreatitis[95,96]. Other TCM therapies have been found to modify microbial diversity and composition, while simultaneously increasing microbiota-derived SCFA production[97]. Several TCM decoctions have also demonstrated clinical efficacy in treating non-alcoholic fatty liver disease by mitigating microbial dysbiosis, such as Spleen-strengthening and Liver-draining Formula, Lingguizhugan decoction, and Qushi Huayu decoction[98-100]. The anti-cancer and immunomodulatory effects of TCM decoctions are also evident. Xiao-Chai-Hu-Tang exerted anti-cancer effects by modulating the microbiota-mediated TLR4/MyD88/NF-κB signaling pathway to mitigate colorectal tumor growth[101]. Additionally, Yiqi Huayu Jiedu decoction has been shown to reduce the risk of postoperative recurrence and metastasis of GC, while Quxie Capsule increased the levels of CD4+ T cells and beneficial bacteria such as Actinobacteria and Lachnospiraceae in patients with metastatic colorectal cancer[102,103]. TCM has also been applied in combination with group psychotherapy to manage psychological distress in colorectal cancer survivors, which resulted in increased abundance in several microbial communities[104].

The influence of TCM decoctions on microbial species in GPL and GC treatment has also been extensively revealed through in vivo experimentation. For example, Weizhuan’an decoction improved gastric mucosal pathology by increasing beneficial bacteria like Lactobacillus and Veillonella, while inhibiting pathogens like Proteobacteria and Pseudomonas[105]. These changes mitigated inflammation-driven gastric pathology and microbial dysbiosis, evidenced by an observed reduction in the expression of inflammatory cytokines (IL-2, IL-4, IL-13, and MCP-1). Similarly, Weifuchun decoction, comprising Panax ginseng, Isodon amethystoides, and Fructus Aurantii, has been shown to ameliorate GPL by regulating the gut microbiota, evidenced by a significant reduction in the pathogenic Parabacteroides[106]. Its therapeutic mechanisms also include immunoregulation via the Toll-like receptor pathway and HES6 signaling[107], inhibition of gastric IM and dysplasia through NF-κB-mediated reduction of CDX2[108], as well as suppression of GC malignancy by downregulating KPNA2 via miR-26a-5p and MAPK signaling inhibition[109]. Another formula, Huangqi Jianzhong decoction, attenuated gastric IM via a gut microbiota-thyroid axis, promoting butyrate-producing bacteria (Allobaculum, Bifidobacterium), thereby restoring thyroid function and mitochondrial integrity[110]. Modified Gexia Zhuyu Tang (GZT) also demonstrated modulatory effects on the gut microbiota as part of its anti-tumor activity[111]. Specifically, GZT restored gut microbiota diversity, inhibited tumor growth and metastasis-related proteins (CD147, VEGF, MMP-9), as well as induced caspase-1-dependent pyroptosis.

These findings support both the clinical efficacy and mechanistic effects of TCM decoctions on the gut microbiota. However, only a limited number of TCM decoctions have been investigated through both clinical and experimental studies, especially in the field of GPL and GC treatment. Further research is needed to elucidate their underlying mechanisms in greater depth. Additionally, studies on the long-term efficacy and safety of TCM decoctions remain scarce. Aspects like the duration of microbial recovery and the possibility of relapse following treatment are not well understood, highlighting the need for more long-term follow-up studies to address these gaps.

Gut microbiota modulation of TCM herbs and compounds

In addition to whole decoctions, individual TCM herbs and their active compounds represent a key area of research and have demonstrated great potential. Herbs such as Poria cocos, Coptis chinensis, and Glycyrrhiza uralensis are used in a wide range of formulations. Notably, these herbs exhibit protective effects in the treatment of various digestive system diseases through shared mechanisms, including regulation of the gut microbiota, inflammation, and immune responses. For example, Poria cocos, a medicinal fungus known for its anti-inflammatory and immunomodulatory effects, has demonstrated significant regulatory effects on the gut microbiota. Its fungal polysaccharides have been shown to enrich a variety of anti-inflammatory microbial species, including Phascolarctobacterium faecium, Bacteroides dorei, and Parabacteroides distasonis[112]. In ulcerative colitis, Poria cocos restores microbial dysbiosis and reduces inflammatory responses by regulating pathways such as NF-κB[113-115]. Additionally, Poria cocos has also been shown to modulate the gut microbiota to improve barrier function and immune activities in antibiotic-associated diarrhea, ameliorate nonalcoholic steatohepatitis and inflammation via the NF-κB/CCL3/CCR1 signaling axis, as well as exert protective effects against cisplatin-induced intestinal injury[116-119]. Coptis chinensis and its active compounds, such as berberine and coptisine, also exhibit modulatory effects on the gut microbiota. Numerous studies have demonstrated that Coptis chinensis exerts its therapeutic effects against ulcerative colitis by regulating microbial imbalance, restoring mucosal integrity, and modulating inflammation through mechanisms, such as the TXNIP/NLRP3 inflammasome, AhR/IL-22, and PLA2-COX-2-PGE2-EP2 pathways[120-124]. The gut microbiota is a key player responsible for the protective effects of Coptis chinensis against gastric mucosal damage and, interestingly, also mediated the transformation of coptisine into its metabolite which demonstrated superior anti-colitis effects[125,126]. Glycyrrhiza uralensis, commonly known as Chinese licorice root, also acts on the gut microbiota to exert its protective effects against various digestive diseases. The herb itself has been shown to alleviate colitis and liver injury through regulation of the gut microbiota and various pathways, such as NF-κB and FXR/Nrf2[127-129]. Studies on Glycyrrhiza polysaccharides and flavonoids further revealed its anti-tumor, anti-inflammatory, and immune modulation effects, including targeting the TLRs/NF-κB pathway, increasing key immune factors, and promoting mucosal barrier repair, as well as promoting beneficial bacteria and their metabolites[130-135].

Other effects of TCM herbs and compounds

Single-herb extracts and compounds derived from TCM have attracted the interest of many researchers due to their anti-H. pylori and anticancer properties. Many studies have elucidated various mechanisms through which these TCM-derived substances exert therapeutic effects, including antimicrobial action, immune modulation, regulation of metabolism, apoptosis induction, and overcoming chemotherapy resistance.

Several TCM extracts have demonstrated anti-H. pylori properties. For example, extracts from Canarium album Raeusch. disrupted bacterial morphology, inhibited urease activity, and downregulated crucial virulence genes[136]. In addition to structural disruption and virulence suppression, Syzygium aromaticum extracts uniquely modulated the tricarboxylic acid cycle and pyruvate metabolism, while attenuating oncogenic pathways, particularly PI3K-Akt and MAPK, in both antibiotic-sensitive and antibiotic-resistant H. pylori strains[137]. Similarly, extracts of Sanguisorba officinalis L. and P. chinense Schneid. demonstrated various antimicrobial activities, active against antibiotic-resistant strains with no antagonistic effects in association with conventional antibiotics[138,139]. Moreover, dried ginger extracts inhibited H. pylori growth and urease enzyme activity through molecular interactions with sulfhydryl groups and nickel ions, revealing a scientific basis for the medicinal applications of ginger[140]. Phenolic compounds from Terminalia bellirica also exhibit selective inhibition of important enteric bacteria functions, such as adhesion and urease activity while showing minimal adverse effects against beneficial gastric microbiota[141]. The organic acid extracts from sea buckthorn were also reported to inhibit the expression of virulence factors and biofilm formation, as well as the production of proinflammatory cytokines by gastric epithelial cells infected with H. pylori[142].

In addition to antimicrobial activity, several TCM-derived compounds showed potential anticancer effects in gastric diseases. Actinidia chinensis extracts, for instance, were found to promote apoptosis, induce ferroptosis in GC cells, and reduce the mesenchymal phenotype associated with metastasis, highlighting its antineoplastic potential[143]. It has also been reported that polysaccharides from Actinidia eriantha were able to induce polarization of tumor-associated macrophages toward an M1 antitumor phenotype by inhibiting PD-1/PD-L1 interactions, thus promoting immune responses against tumors[144]. Atractylenolide III extracted from Atractylodes rhizome alleviated microvascular abnormalities and angiogenesis by downregulating Delta-like ligand 4, thereby alleviating gastric IM and dysplasia[145]. Moreover, ginsenoside Rb1 derived from ginseng has also been demonstrated to be effective in preventing gastric malignant transformation via inhibition of β-catenin nuclear translocation and TCF4 elicited signaling[146]. Furthermore, hydroxysafflor yellow B, isolated from Carthamus tinctorius L., induced apoptosis through mitochondrial pathways characterized by elevated APAF-1, cytochrome C, and BAX expression, providing an effective targeted anticancer approach[147]. Moreover, the flavanone polyphenol naringenin suppresses gastric IM progression by downregulating MTTP/APOB axis signaling, thereby reducing metastasis risk and potentially enhancing survival in GC patients[148].

Expanding the therapeutic scope of TCM-derived compounds, Chu et al[149] demonstrated that terpene extracts from Celastrus orbiculatus inhibited actin cytoskeleton remodeling by interfering with PTBP1-mediated alternative splicing regulation of ACTN4, disrupting pathways crucial for gastric carcinogenesis. In GPL patients, it was shown that Panax notoginseng saponins modulated the autophagic process via the PI3K/AKT/mTOR pathway, supporting mucosal repair[150]. Ginsenoside compound K also reversed chemoresistance in GC cells through the inhibition of the PI3K/Akt pathway and reversing EMT, which indicates the potential use of ginsenoside compound K for chemoresistant tumors as an adjunct therapy[151]. These studies not only reflect the multifaceted mechanisms of TCM-derived compounds, but also provide a scientific basis for clinical application of TCM-based therapy in GPL and GC.

CONCLUSION

Taken together, accumulating evidence suggests that the gastrointestinal microbiota is an important contributor to the development of GPL and GC. However, fully understanding the molecular mechanisms underlying gastric carcinogenesis remains a significant challenge, given the complex interplay between pathogenic colonization, microbial dysbiosis, microbial metabolites, and host responses. Both Western medicine and TCM interventions have shown promising therapeutic efficacy in the treatment of GPL and GC, but not without limitations and side effects. In the context of microbiota, a considerable number of studies have established correlations between specific microbial species and variations in host response or treatment efficacy, but direct causality remains uncertain. While TCM treatments have demonstrated effectiveness, there is a lack of both clinical and experimental evidence evaluating their long-term effects on microbiota recovery. Despite these research gaps, the efficacy of both Western medicine and TCM approaches is evident, and perhaps their integration could provide a more comprehensive therapeutic strategy. This may involve targeted interventions against carcinogenic microbes for increased specificity within the human body. Additionally, combination therapies that incorporate Western drugs and TCM active compounds may be developed to maximize treatment efficacy. These strategies could be further personalized according to the patient’s microbiome signature to tackle the issues of microbiome heterogeneity and interindividual variability. Nevertheless, additional in-depth studies are necessary to not only address the gaps in gastric disease and microbiota research, but also to develop an optimal integrative approach for early diagnosis, targeted treatment, and improved prognosis for GPL and GC patients.

ACKNOWLEDGEMENTS

The author would like to express sincere gratitude to Huizhong Jiang for providing valuable guidance and oversight throughout the preparation of this manuscript.