Letter to the Editor: Integrative mechanistic exploration in gastrointestinal therapeutics: Exemplified by Chaihu-Shugan-San for chronic atrophic gastritis

Abstract

Gastroenterology is embracing integrative research, bridging traditional therapies with modern biomedical science. Chronic atrophic gastritis (CAG), a significant precancerous condition, exemplifies the need for such approaches, as current management strategies remain partially effective. In this context, Song et al published in the recent issue of the World Journal of Gastroenterology provided a compelling case study that systematically investigated the classic traditional Chinese medicine formula, Chaihu-Shugan-San, using network pharmacology prediction, molecular docking, in vivo validation in an N-methyl-N’-nitro-N-nitrosoguanidine-induced rat model, and 16S rRNA sequencing of gut microbiota. The research demonstrated that Chaihu-Shugan-San alleviates CAG by inhibiting nuclear factor kappa B-mediated inflammatory cascades and apoptosis, while promoting a favorable shift in gut microbial ecology. This editorial appraises this study design as a model for the mechanistic exploration of complex botanicals, highlighting its strengths in target identification and multi-omics integration. It critically discusses inherent limitations, including the translational gap between rodent models and human pathophysiology, and the lack of adjustment for key confounders, such as Helicobacter pylori status. This article argues that the future of gastrointestinal pharmacology in precancerous conditions lies in fostering integrative research, including clinical trials to validate preclinical findings, standardized phytochemical profiles, and composite biomarkers that combine inflammatory indices (systemic inflammatory response index), microbial signatures, and traditional diagnostic markers to guide personalized stage-specific interventions for CAG.

Key Words: Chronic atrophic gastritis; Chaihu-Shugan-San; Network pharmacology; Nuclear factor-kappa B; Gut microbiota; Integrative medicine; Translational research

Core Tip: This paper emphasizes that the research of Song et al is an example of the integrated research of gastroenterology. Through the combination of network pharmacology, experimental validation and microbiome analysis, this study clarified how Chaihu-Shugan-San can improve chronic atrophic gastritis by double inhibiting inflammation and apoptosis driven by nuclear factor kappa B, and regulating intestinal flora. This paper critically evaluates this methodology as a blueprint for future research on complex botanical drugs, and emphasizes the need for subsequent clinical trials, standardization of phytochemistry, and the development of integrated biomarker groups, in order to translate these mechanistic insights into personalized clinical practice for precancerous lesions.

TO THE EDITOR

Chronic atrophic gastritis (CAG) is a persistent clinical challenge in gastroenterology located on a continuous spectrum of precancerous lesions that develop into gastric adenocarcinoma[1,2]. CAG is characterized by glandular atrophy, chronic inflammation, and frequent intestinal metaplasia. Treatment must extend beyond Helicobacter pylori eradication to address inflammation and apoptosis imbalance. Concurrently, global interest in traditional and botanical drugs is resurging, driven by their empirical value and potential for mechanism discovery. This trend requires innovative research frameworks to clarify the complex, multitarget mechanisms of such interventions.

However, a methodological gap persists between high-throughput computer prediction and biological verification. Network pharmacology has become a powerful tool for hypothesizing potential targets and pathways of complex mixtures (traditional Chinese medicinal compounds). However, its predictive value depends on rigorous experimental verification[3,4]. A study by Song et al[5] published in the recent issue of the World Journal of Gastroenterology exemplifies combining computational prediction with multilevel experimental verification of Chaihu-Shugan-San (CSS) in CAG[6,7]. This study verified the efficacy of CSS and clarified its dual mechanism of inhibiting nuclear factor kappa B (NF-κB) pathway and regulating intestinal flora. This study aimed to present these findings within contemporary gastroenterology research, critically evaluate their methodology, and discuss their implications for future CAG therapeutics and integrated research designs.

RESEARCH DESIGN

The research design adopted by Song et al[5] reflects the logical progression from “system prediction” to “target verification” and “overall effect evaluation”. The active components of CSS were screened through network pharmacology, and its CAG-related core targets, such as tumor necrosis factor, interleukin (IL)-6, IL-1β, Bax, B-cell lymphoma 2, and caspase-3, were predicted. Enrichment analysis showed that NF-κB pathway as key, providing a clear hypothesis for subsequent experiments. This study used N-methyl-N’-nitro-N-nitrosoguanidine combined with an irregular diet to establish a rat CAG model that can better simulate the morphological and inflammatory characteristics of human CAG and provide a reliable pathological background for mechanistic studies.

The core advantage of the research lies in its multi-level verification strategy. In the molecular and biochemical level, western blotting, enzyme-linked immunosorbent assay, and caspase activity detection directly confirmed the inhibition of CSS on key proteins of NF-κB pathway [phosphorylated-inhibitor of nuclear factor kappa B (IκB) α and phosphorylated-p65] and downregulation of pro-inflammatory cytokines (tumor necrosis factor-α, IL-1 β, and IL-6) and pro-apoptotic proteins (Bax and caspase-3/9) and upregulation of anti-apoptotic protein B-cell lymphoma 2. This provides solid molecular evidence for network pharmacological prediction. Histopathological, detailed histological evaluation of gastric mucosa quantitatively analyzed the number, thickness, inflammation score, and intestinal metaplasia area of glands, objectively confirming the repair effect of CSS on structural damage of gastric mucosa and directly correlating molecular changes with functional improvement. In system biology, introducing16S rRNA sequencing to analyze intestinal flora is a highlight. Studies have found that CSS can regulate the composition of intestinal microorganisms and increase the abundance of beneficial bacteria involved in the production of short-chain fatty acids. This suggests that the role of CSS may extend beyond the local gastric mucosa and involve the systematic regulation through the “gut-stomach axis”, which opens up a new perspective for understanding its overall efficacy.

KEY FINDINGS

The most prominent study finding is the clarification of the core mechanism of CSS in alleviating CAG by inhibiting NF-κB pathway, which is a pivotal transcription factor that regulates inflammation, immune response, and cell survival. In the pathological environment of CAG, various injury factors activate the IκB kinase complex, leading to IκBα phosphorylation and ubiquitination degradation, thereby releasing NF-κB into the nucleus and starting the transcription of pro-inflammatory factors and pro-apoptotic genes. Song et al[5] confirmed that CSS treatment can significantly inhibit the phosphorylation of IκBα and p65, reduce the nuclear translocation of NF-κB, and curb the vicious cycle of inflammation and apoptosis from the upstream.

Additionally, this study linked the regulatory effect of CSS on the intestinal flora to its protective effect on the gastric mucosa. Intestinal dysbacteriosis can affect the distal organs via various mechanisms. After CSS intervention, the abundance of beneficial flora was restored, which may indirectly create a favorable microenvironment for gastric mucosal repair by increasing the production of short-chain fatty acids and reducing the burden of systemic inflammation. This “multitarget, multisystem” mode of action is the embodiment of a holistic view of traditional Chinese compounds in modern biology.

CRITICAL APPRAISAL

Song et al[5] made contributed considerably to our understanding of the mechanism of CSS in CAG treatment. This integrated method has provided a commendable example of research on plant medicine. However, several limitations should be considered. Although the N-methyl-N’-nitro-N-nitrosoguanidine -induced chemical injury model is classic, its pathogenesis differs from that of human CAG. The key confounding factor of Helicobacter pylori infection was excluded in the study, limiting the direct extrapolation of the research conclusions to the most common clinical subtypes. Although two dose groups have been established, the complete dose-effect relationship and minimum effective dose should be explored for the future standardization of preparations. Although network pharmacology predicts multiple targets, the experimental focus is mainly on the NF-κB pathway, and research on other potential pathways is relatively few.

FUTURE PERSPECTIVES

This study provides convincing preclinical evidence for CSS in CAG treatment; however, several key directions must be addressed to translate it into various clinical practices[8]. First, there is an urgent need to design a rigorous multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of CSS in patients with CAG regarding endpoint indicators, such as endoscopic and histological improvement. Second, the follow-up study should be combined with spectrum-effect relationship analysis (correlating the chemical fingerprint of CSS with its biological efficacy to identify active constituent groups) to clarify the “component groups” or “molecular combinations” that play a core therapeutic role in CSS and establish quality control standards based on active ingredients for consistency of preparations. Third, we explored the synergy between CSS and existing standard therapies and developed a biomarker-based prediction model that integrated the inflammation index, specific microbial characteristic spectrum, and pepsinogen ratio to achieve precise intervention. Finally, using multi-omics technology to explore other signaling networks regulated by CSS without bias and sterile animals or fecal bacterial transplantation experiments to directly verify the causal role of intestinal flora in the efficacy of CSS will further deepen our understanding of its mechanism.

CONCLUSION

Overall, the study of Song et al[5] transformed the clinical challenges of traditional Chinese medicine prescriptions into scientific propositions that can be elaborated in modern biological languages. Its integrated research strategy of “computational prediction in vivo validation system analysis” provides a replicable model for exploring mechanisms of complex botanical drugs. This study clarified the specific protective mechanism of CSS on the gastric mucosa and provided a potential drug treatment for CAG. Promoting such integrative research to connect traditional knowledge with modern science holds strategic significance for developing more effective, personalized treatments for gastrointestinal diseases and improving patient prognosis.