INTRODUCTION
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-associated deaths globally. Despite declining incidence rates, it continues to pose a considerable public health challenge[1]. A critical precursor in its development is chronic atrophic gastritis (CAG), a precancerous mucosal lesion that represents a cornerstone in the disease’s pathogenesis[2,3]. CAG is characterized by the progressive loss of gastric glands and the presence of intestinal metaplasia, significantly increasing the risk of GC[4]. Typically, the pathological process evolves sequentially. It starts from non-atrophic gastritis. Then it progresses to CAG. Subsequently, it leads to intestinal metaplasia and dysplasia. Ultimately it progresses to adenocarcinoma[2,5]. Several factors have been identified in the pathogenesis of CAG, including persistent Helicobacter pylori infection, autoimmune responses, bile reflux, aging, and poor dietary patterns[6,7]. However, the diagnosis of CAG is mainly challenging because it does not present distinctive clinical features[8]. If left untreated, CAG may advance to precancerous lesions of GC, which in turn elevates the risk of GC. Therefore, implementing early therapeutic measures at the CAG stage is essential to prevent the development of GC.
MECHANISMS OF TRADITIONAL CHINESE MEDICINE IN CAG
Traditional Chinese medicine (TCM) is recognized as a well-established natural practice. It provides a holistic and individualized approach to managing chronic conditions. This approach is particularly applicable to CAG, its precancerous stages, and GC[8]. TCM is rooted in a unique theoretical framework and a long history of practice. It focuses on the patient’s specific constitution, symptoms, and underlying causes. It aims to address both the manifestations and root of the disease[9]. Recent clinical and experimental studies have confirmed that TCM acted through multi-channel and multi-target mechanisms[10]. It demonstrated a distinct therapeutic impact by comprehensively regulating the gastric mucosal protection system[10]. Its principal advantages include enhancing the gastric mucosal defense barrier, improving microcirculation, modulating gut microbiota, inflammation and immune responses, and promoting high-quality healing of lesions[11-13]. This multifaceted action can be exemplified by various classic formulations. Examples include Chaihu Shugan San, Yiqi Jiedu Huayu decoction, and Weiqi Decoction[8,9,14]. However, available therapeutic strategies to successfully reverse gastric mucosal atrophy are still limited.
Recently, Qin et al[15] published a study in the World Journal of Gastroenterology presented a novel research on the role of Anwei decoction (AWD) in alleviating CAG by modulating the gut microbiota-metabolite axis and NLR family pyrin domain containing 3 (NLRP3) inflammasome activity, which has remarkably attracted scholars’ attention. The mentioned study demonstrated that AWD, a TCM derived from classical Chinese medicine, significantly improved gastric mucosal pathological damage in CAG model rats[16]. More compellingly, the mentioned study revealed a dual mechanism of action for AWD: It directly inhibited NLRP3 inflammasome activation in gastric tissue while systemically reshaping disrupted gut microbiota and their metabolic profiles, exerting therapeutic effects through the “gut-stomach axis”. This provided a convincing answer to the core question “Can modern science reveal the mysteries of traditional formulas?” This research provided crucial scientific evidence for treating CAG and the findings could be considerably valuable for advancing traditional therapeutic approaches particularly for functional disorders.
Qin et al[15] represented a significant advance by elucidating the mechanisms of AWD in CAG. This advance promotes the development of novel treatment strategies. Firstly, it could provide robust experimental evidence, confirming the efficacy of AWD in improving CAG outcomes. AWD treatment led to an improvement in the histological scores of gastric mucosal injury in their model, reduced inflammatory cell infiltration, and alleviated glandular atrophy. The most notable innovation lies in elucidating a dual mechanism. On the one hand, the study clearly demonstrated that AWD directly suppressed the activation of the NLRP3 inflammasome pathway in gastric tissues, which was manifested by the reduced expression levels of NLRP3, ASC, and Caspase-1 proteins, as well as downstream inflammatory cytokines (interleukin-1β and interleukin-18). The NLRP3 inflammasome has been served as a key mediator of chronic inflammation, participating in the pathogenesis of multiple gastrointestinal diseases, making it a relevant therapeutic target[17,18]. Beyond the NLRP3 inflammasome-gut microbiota axis emphasized in this study, prior research demonstrated that AWD may also exert effects by regulating endoplasmic reticulum stress and autophagy pathways[16]. Future research will concentrate on integrating these fragmented mechanistic insights to delineate a more comprehensive multi-target action network for AWD. On the other hand, and perhaps more innovatively, the study assessed the role of the gut microbiota and metabolites. Using 16S rRNA gene sequencing, Qin et al[15] indicated that AWD administration significantly reversed CAG-induced gut microbiota dysbiosis. The effect was achieved by increasing the abundance rates of beneficial genera, such as Lactobacillus and Bacteroides. Meanwhile, AWD suppressed potentially pathogenic bacteria, involving Escherichia coli and Proteobacteria[19]. Non-targeted metabolomics further revealed that AWD restored the disrupted serum and gastric tissue metabolomes, particularly influencing glycerophospholipid metabolism, which is critical for maintaining cell membrane integrity and enhancing cellular signaling[20]. The key innovation of the study lies in the integrative analysis of these datasets. A coherent “microbiota-metabolism-inflammation” network was constructed through correlation analysis. This network showed a systemic association among improved gastric inflammation, the restoration of healthy gut microbiota, and its metabolic products. This integrated perspective aligns with TCM theory, providing a clear representation of its core principles in the framework of modern biomedical networks[21]. Firstly, it treats the gut microbiota and its metabolites as integral components of the internal environment, influencing gastric health, recognizing as a manifestation of TCM’s holistic perspective. Secondly, dysbiosis under CAG conditions and enhanced gastric inflammatory responses can be interpreted as “yin-yang imbalance” in the body’s internal environment. The AWD aims to restore this “yin-yang equilibrium” and homeostasis through bidirectional regulation (i.e., inhibiting harmful inflammation while promoting beneficial microbiota)[22]. From a modern scientific perspective, AWD’s regulation of the “gut-stomach axis” can be understood as a promoting harmonious spleen-stomach function by restoring intestinal microecological balance. This highly aligns with TCM theories, in which the spleen governs transformation and transportation, the stomach governs reception and holding, and the spleen-stomach complex constitutes the foundation of acquired constitution. Thus, this research not only provided molecular-level evidence, but also outlined a modern scientific interpretation of the traditional wisdom underlying the multi-targeted, systemic regulation of Chinese herbal formulas.
Several TCM formulas were used to treat CAG, such as Banxia Xiexin Tang Decoction and Xiangsha Liujunzi Decoction. These formulas demonstrated the diversity of Chinese herbal formulas. This diversity stemmed from their adoption of distinct therapeutic principles. These principles covered liver qi regulation, spleen-stomach harmonization, and heat-clearing detoxification[23,24]. Several formulas could enhance the overall abundance of “lactic acid bacteria” or “beneficial bacteria”. In contrast, the AWD studied by Qin et al[15] significantly elevated the relative abundance of Lactobacillus species. Meanwhile, this treatment visibly reduced potentially harmful bacterial groups, such as Spirochaetota. Its targeted promotion of beneficial genera/species and suppression of specific harmful phyla indicate a more refined regulatory mechanism. The distinctive aspect of its modern mechanistic research lies in the systematic focus on modulating specific beneficial bacterial genera (e.g., Lactobacillus) and critical metabolic pathways (e.g., glycerophospholipid metabolism). It straightforwardly links the microbiota-metabolite network with the inhibition of NLRP3 inflammasome in the stomach, providing concrete biological evidence for the “gut-stomach axis” theory. This contributes uniquely to the depth and integration of mechanism interpretation.
Although Qin et al[15] provided a powerful proof of concept, several issues require resolution in future studies. The research was conducted in rodent models, and the translational applicability of these findings to human CAG patients must be determined through carefully designed clinical trials. Clinical translation remains the main concentration of subsequent research. Currently, advancing AWD into rigorously designed clinical studies represents a crucial step toward validating its efficacy in humans and progressing toward clinical application. The complex composition of AWD, while reflecting its holistic nature, poses challenges in identifying specific active components being responsible for its effects[25]. Future studies employing network pharmacology will precisely reveal key compounds[11]. Furthermore, the exact causal relationship among specific gut microbial shifts, metabolite alterations, and gastric inflammation suppression requires further validation. In addition, fecal microbiota transplantation from AWD-treated donors into germ-free or antibiotic-treated CAG models could help elucidate the causal role of the gut microbiota[26]. Clinically, it is crucial to investigate how AWD integrates with existing standard-of-care treatments, including Helicobacter pylori eradication therapy[27,28]. An important question is whether AWD can function synergistically with antibiotics to enhance mucosal healing. Furthermore, it remains to be determined whether this therapeutic approach is universally effective for all CAG patients or has particular efficacy in those with specific microbial or metabolic profiles. Therefore, it is crucial to recognize that the transition from animal models to human clinical applications presents numerous challenges. These include ensuring batch consistency in the chemical composition of AWD formulations, identifying the molecular basis for their in vivo efficacy and pharmacokinetic characteristics, and designing clinical trial protocols that adequately account for human CAG disease heterogeneity, individual variations in gut microbiota, and concomitant medication use. To navigate these translational hurdles, strategic measures are recommended. First, employing standardized herbal extracts is essential[29]. Techniques like chromatographic fingerprinting should be applied to ensure batch consistency[30,31]. Second, the key bioactive compounds must be identified. Techniques such as liquid chromatography-mass spectrometry are suitable for this purpose[32]. Subsequently, pharmacokinetic studies can delineate the absorption, distribution, metabolism, and excretion profiles of these compounds[33]. This will clarify the molecular basis of efficacy. Furthermore, adaptive clinical trial designs are advisable. Incorporating microbiome or metabolic biomarkers into these designs can better account for patient heterogeneity. This approach also refines efficacy assessment in targeted subgroups.
