Letter to the Editor: Unresolved questions regarding Anwei decoction’s role in chronic atrophic gastritis

Abstract

In this article, we comment on a recent study published in the World Journal of Gastroenterology by Qin et al that evaluated the therapeutic effects of Anwei decoction in a rat model of chronic atrophic gastritis. The authors report improvements in gastric inflammation, glandular atrophy, and intestinal metaplasia, alongside extensive serum compound profiling. While these findings are encouraging, we highlight specific methodological limitations that warrant further clarification. First, attributing efficacy primarily to the nucleotide-binding oligomerization domain-like receptor protein 3/caspase-1/interleukin-1β pathway may overlook the multifactorial nature of chronic atrophic gastritis. Second, reliance on the N-methyl-N’-nitro-N-nitrosoguanidine-induced model limits extrapolation to other etiologies, particularly Helicobacter pylori-associated or autoimmune gastritis. Finally, the biological relevance of the mass-spectrometry - identified serum compounds remains uncertain without functional assays and pharmacokinetic validation. This article highlights priorities for future research on the microbiome, pharmacology, and long-term clinical outcomes to strengthen the translational value of Anwei decoction.

Key Words: Anwei decoction; Chronic atrophic gastritis; Inflammatory pathways; Microbiome modulation; Pharmacokinetics; Disease models

Core Tip: While Anwei decoction shows promise in a rat chronic atrophic gastritis model, key questions regarding its mechanism beyond nucleotide-binding oligomerization domain-like receptor protein 3 inhibition, efficacy across distinct etiologies, the causal role of microbiome shifts, the pharmacokinetics of active components, and long-term anti-cancer effects remain unanswered. Addressing these gaps through rigorous model validation and functional assays is crucial for the clinical translation of this traditional Chinese medicine formulation.

TO THE EDITOR

We read with great interest the article published in the World Journal of Gastroenterology by Qin et al[1], which reported the therapeutic effects of Anwei decoction (AWD) in a rat model of chronic atrophic gastritis (CAG). Their study integrates histopathology, analysis of inflammatory cytokines, serum compound profiling, 16S rRNA sequencing, and metabolomics, providing a comprehensive overview of AWD’s potential regulatory effects on gastric mucosal injury and immune activation. This multidimensional approach is commendable and contributes meaningfully to the ongoing efforts to elucidate the mechanisms by which traditional Chinese medicine formulations exert therapeutic benefits in chronic gastrointestinal disorders. While the findings presented are encouraging, several aspects of the study would benefit from further clarification to better contextualize AWD’s potential value in treating chronic gastric diseases.

MECHANISTIC SPECIFICITY

The authors identified suppression of the nucleotide-binding oligomerization domain-like receptor protein 3/caspase-1/interleukin-1β pathway as a key mechanism by which AWD alleviates gastric inflammation. Although this pathway plays a recognized role in the pathogenesis of CAG[2-4], the disease involves multiple aspects of inflammatory and cellular dysregulation, such as activation of the nuclear factor kappa B and signal transducers and activators of transcription 3 pathways, oxidative stress responses, disturbances in epithelial repair, and alterations in mucosal immunity[5-7]. Focusing on a single inflammasome-related axis offers important preliminary insight but may not fully capture the breadth of AWD’s effects. A broader investigation of parallel pathways would help clarify the drug’s action. For instance, future studies should examine markers of the nuclear factor kappa B pathway (e.g., p65 phosphorylation, and IκBα degradation), signal transducers and activators of transcription 3 activation, or key regulators of epithelial apoptosis (e.g., Bcl-2, and Bax), which are critical in CAG progression[8-10]. Such information would also assist in evaluating the specificity and therapeutic relevance of the observed molecular changes.

DISEASE MODEL GENERALIZATION

In addition, the exclusive use of the N-methyl-N’-nitro-N-nitrosoguanidine, a chemical carcinogenesis-associated model, leads to limitations regarding the generalizability of the results. Chemical induction successfully reproduces certain histological and inflammatory characteristics of CAG, yet it does not reflect the diverse etiologies encountered in clinical practice. Ideally, AWD should be validated in Helicobacter pylori-infected rodent models (e.g., Mongolian gerbils) or autoimmune gastritis models (e.g., murine model induced by neonatal thymectomy), which involve distinct immunological mechanisms[11,12]. Because AWD is a multicomponent herbal formulation with broad immunomodulatory properties[13], its effects may differ substantially across these varied pathological contexts. Validation of AWD in additional models that more closely parallel clinical disease would therefore enhance the translational significance of the findings and help determine whether AWD holds promise across a wider spectrum of CAG etiologies.

MICROBIOME CAUSALITY

The study’s microbiota-related findings are of particular interest, especially the growing recognition of the role of the gut-stomach axis, defined as the bidirectional crosstalk between intestinal flora and gastric mucosal immunity, in the pathology of chronic inflammatory disorders[14]. Qin et al[1] report notable changes in gut microbial composition and associated metabolites following AWD treatment. Furthermore, recent perspectives highlight the importance of the oral-gut axis in CAG pathogenesis[15], suggesting a broader ecological context for dysbiosis. However, it is important to distinguish between association and causation; currently, it is uncertain whether these alterations play a causal role in reducing gastric inflammation or represent downstream consequences of improved mucosal integrity. Experimental approaches such as fecal microbiota transplantation, gnotobiotic validation, or targeted manipulation of identified metabolites would help clarify the functional significance of microbiome changes. These mechanistic insights are essential to link the observed microbial shifts directly to therapeutic outcomes.

PHARMACOLOGICAL VALIDATION

The identification of circulating serum-derived compounds adds an important dimension to the pharmacological understanding of AWD. However, the biological significance of these constituents cannot be fully established without complementary assessments of their bioavailability, tissue distribution, and molecular activities. Crucially, mere detection by mass spectrometry does not equate to biological efficacy; it is therefore essential to distinguish between metabolites that are simply systemic byproducts and those that serve as true pharmacologically active constituents. Given the complexity of herbal formulas, distinguishing between compounds with meaningful pharmacological roles and those present as passive metabolites remains an essential task for future research. Integration of targeted metabolomics and in vitro functional assays could help pinpoint the components responsible for AWD’s anti-inflammatory or microbiota-modulating properties, thereby contributing to a clearer mechanistic framework.

LONG-TERM THERAPEUTIC POTENTIAL

Finally, although the authors suggest that AWD may prevent the progression of CAG toward gastric neoplasia, the study does not directly evaluate dysplasia, oncogenic signaling, or genomic instability. While suppression of chronic inflammation is undoubtedly beneficial, definitive conclusions regarding cancer prevention require long-term studies with explicit carcinogenesis endpoints. Establishing whether AWD influences pre-neoplastic changes will be critical for determining its potential role in modifying disease trajectory beyond symptom relief and mucosal repair.

CONCLUSION

In summary, Qin et al[1] present a thoughtfully designed study that advances our understanding of AWD’s therapeutic actions in CAG. Their work offers a strong foundation for future investigation, particularly regarding the intersection of inflammatory regulation, microbial ecology, and metabolic homeostasis. Addressing the mechanistic, etiological, and functional questions highlighted above will help clarify AWD’s clinical relevance and contribute to a more evidence-based understanding of this traditional Chinese medicine formulation. We appreciate the authors’ contribution to this important field.