Recommendations for chronic atrophic gastritis research: Highlighting sex-related factors, gastric microbiota, and in-depth mechanistic validation

Abstract

Chronic atrophic gastritis (CAG) serves as a well-recognized precancerous lesion of gastric cancer, and research on its treatment has attracted considerable attention. With advances in technology and research, the factors contributing to the onset and progression of CAG are becoming increasingly clear. Traditional Chinese medicine (TCM) has shown good therapeutic potential for CAG; however, objective deficiencies in the experimental design and the still-unclear mechanism of some studies, limit the broader clinical application of TCM. Therefore, this paper intends to propose and summarize the following issues: (1) Is it necessary to pay attention to the sex-related factors in CAG research? (2) Why is gastric microbiota detection important in CAG research? and (3) How to further improve mechanism research in TCM studies?

Key Words: Chronic atrophic gastritis; Sex-related factors; Gastric microbiota; Traditional Chinese medicine

Core Tip: Recently, several studies on chronic atrophic gastritis (CAG) have demonstrated the significant therapeutic efficacy of traditional Chinese medicine (TCM). Based on recent advances, it is necessary to emphasize the importance of sex-related factors and the gastric microbiota detection in CAG research, as well as to further improve mechanism research with more sufficient experimental evidence in TCM studies.

INTRODUCTION

Chronic atrophic gastritis (CAG) is a chronic inflammatory disease characterized by atrophy and thinning of the gastric mucosal glands, often accompanied by intestinal metaplasia or atypical hyperplasia[1,2]. According to Correa’s cascade theory, CAG serves as a well-recognized precancerous lesion of gastric cancer (GC)[3]. Compared with general population, patients with CAG have a significantly higher risk of developing GC[4,5]. Thus, early diagnosis and intervention of CAG are critical to prevent malignant transformation[6,7]. Currently, clinical management of CAG primarily including Helicobacter pylori (H. pylori) eradication and gastric mucosal protective agents[8,9]. However, current treatment strategies have relatively limited therapeutic efficacy. The good therapeutic effects of traditional Chinese medicine (TCM) make it a treatment option in CAG[10]. The therapeutic effects of some therapies are mediated by mechanisms such as inhibition of inflammatory factors, regulation of the microbiota, and modulation of metabolism[11-15] (Table 1). Since some studies have certain limitations in experimental design and the specific targets of TCM intervention in CAG remain unclear, these factors largely limit the elucidation of its mechanisms and its broader clinical application. Therefore, this article aims to explore the related core issues in order to further advance the field.

Table 1 Traditional Chinese medicine research for treating chronic atrophic gastritis.

Ref.	Medicine name	Experimental models	Main findings
[11]	Anwei decoction	Wistar rats (MNNG)	Inflammation↓ NLRP3↓
[12]	Weierning	SD rats (sodium salicylate, alcohol, ammonium hydroxide)	Inflammation↓ apoptosis↓
[13]	Weifuchun capsule	SD rats (MNNG, ethanol)	Regulating immune response, inflammation↓
[14]	Granule Dendrobii	Wistar rats (MNNG)	Inflammation↓ PCNA↓ Bcl-2↓
[15]	Astragali Radix	SD rats (ammonia solution, deoxycholic acid, irregular fasting)	Regulating gut microbiota and metabolic

IS IT NECESSARY TO PAY ATTENTION TO THE SEX-RELATED FACTORS IN CAG RESEARCH?

As a critical biological variable, sex-related factor should be fully considered in research[16,17]. Biological sex bias is prevalent across some fields[18-22], including gastroenterology, and must be fully accounted for in study design and analysis[23].

Most studies indicate that no significant sex-related discrepancy in CAG incidence[24]. However, as a precancerous condition, CAG exhibits a marked gender disparity in the outcome of malignant transformation, with a marked male predominance in GC incidence[25,26]. Sex differences in GC suggest that male CAG patients may have a higher risk of disease progression. This view is supported by animal models: In the MNNG-induced model of rats, compared with female rats, intact male rats exhibited more pronounced progression of gastric precancerous lesions (inflammation, atrophy, and dysplasia), activation of Shh signaling, and elevated expression levels of cyclin D1/cdk4, as well as higher GC incidence and tumor burden[27,28]. Notably, castrated rats had a lower incidence of GC with less change in the lamina muscularis mucosae than did the nontreated male rats. In addition, in the H. pylori-induced GC model of hypergastrinemic insulin-gastrin mice, the ovariectomized (OVX) female mice exhibited significantly more severe gastritis, while estradiol (E2) treatment alleviated the severity of gastritis[29]. These findings indicate that sex differences in CAG to GC progression may be sex hormones-dependent[30,31], with male rats showing more severe CAG pathological phenotypes and accelerated progression toward precancerous lesions. It also leads us to speculate whether the therapeutic efficacy of medicine differs between male and female rats.

Some CAG experiments included only a single sex or lacked sex-stratified subgroup analysis in the experimental results. Therefore, it is recommended that sex-related factors be incorporated into experimental design and data analysis. Additionally, if it is necessary to further clarify the influence of sex-related factors, the inclusion of OVX-induced estrogen deprivation in female animals[29] and castration-induced androgen deprivation in male animals[32] into the experimental design would further enhance the reliability and persuasiveness of the study evidence.

WHY IS GASTRIC MICROBIOTA DETECTION IMPORTANT IN CAG RESEARCH?

Gut microbiota serves several functions, considered as the most significant one in health and disease[33,34]. The stomach was long thought to be sterile, and the discovery of H. pylori advanced research on digestive diseases and extragastric diseases[35-39]. In recent years, it has been discovered that beyond H. pylori infection, the stomach harbors a complex and distinct microbial ecosystem[40,41]. Therefore, based on the progress of the research, we should distinguish between the intestinal microbiota and gastric microbiota. Moreover, given that the stomach constitutes the core pathophysiological site of the disease, gastric microbiota is of greater importance in CAG research. The currently identified gastric microbiota changes on gastric diseases are listed in Table 2[42-48]. For example, the composition of the gastric microbiota differed markedly between precancerous stages and GC, with GC patients presenting significantly decreased microbial diversity and elevated relative abundance of Lactobacillus[42]. Furthermore, a recent study demonstrated that GC patients exhibited increased abundance of Streptococcus anginosus in the gastric mucosa, a pathogen capable of promoting gastric inflammation, atrophy, and tumorigenesis in mice[43]. Accordingly, direct detection of dynamic changes in the gastric mucosal microbiota during CAG progression would more accurately identify candidate pathogenic bacteria and clarify the therapeutic mechanisms.

Table 2 The changes in the gastric microbiota associated with gastric diseases.

Ref.	Year	Sample type	Main findings
[44]	2014	Non-atrophic gastritis (NAG), intestinal metaplasia (IM) and intestinal-type gastric cancer (GC) patients	GC patients: Lactobacillus coleohominis, and Lachnospiraceae↑
[45]	2016	Chronic gastritis and GC patients	GC patients: Lactobacillus, Escherichia-Shigella, Nitrospirae, Burkholderia fungorum, and Lachnospiraceae↑
[42]	2018	Chronic gastritis and gastric carcinoma patients	GC patients: Lactobacillus, Citrobacter, and Phyllobacterium↑
[46]	2021	Superficial gastritis (SG), atrophic gastritis (AG), gastric intraepithelial neoplasia, and GC patients	GC patients: Oral bacteria including Parvimonas, Eikenella, and Prevotella-2↑; Environmental bacteria including Kroppenstedtia, Lentibacillus, and Oceanobacillus↑
[47]	2021	Normal people, advanced AG with IM, and early GC	From controls to IM then to cancer: Gemella, and Streptococcus↑
[43]	2024	SG, AG, IM and GC patients; mice	During the progression of GC: Streptococcus anginosus↑. Streptococcus anginosus promoting gastric inflammation, atrophy, and tumorigenesis
[48]	2025	NAG patients and CAG patients	Peptostreptococcus, fusobacterium, prevotella, sphingomonas and bacteroides were the essential features that distinguish AG from NAG and altered various metabolic pathways

CAG: Chronic atrophic gastritis.

HOW TO FURTHER IMPROVE MECHANISM RESEARCH IN TCM STUDIES?

The overall development of TCM research is accumulating more evidence regarding overall therapeutic efficacy and driving deeper exploration into specific mechanisms. Key components were applied directly to disease models for efficacy assessment[49,50]. Further, it was recommended that a stepwise approach could be adopted to verify the interaction between key compounds and specific targets. First, perform virtual screening of key compounds targeting the specific target[51-53], followed by validation of their binding affinity using surface plasmon resonance[54,55] or isothermal titration calorimetry[56,57]. Additionally, the functional inhibition of the specific target by active compounds could be further validated via in vitro experiments using specific target-activated cells or selective specific target inhibitors[58,59]. Beyond traditional animal or cell models, in vitro gastrointestinal simulation systems such as SHIME are well suited for TCM, rare or expensive bioactive compounds, and microbiota-related in gastrointestinal research, providing predictive and complementary benefits[60-62]. Therefore, for TCM research, many experimental options are available for further mechanistic exploration.

CONCLUSION

In CAG research, the integration of TCM with modern technology is a growing trend. Nonetheless, the aforementioned issues require further attention, including the consideration of sex-related factors, investigation into gastric microbiota, and more experimental validation mechanism. Addressing these limitations not only enhances the credibility and rigor of the original study, but also significantly advances a more personalized, mechanism-based, and clinically adoptable understanding of TCM.