Xiaohuafuning tang intervenes liver-depression-and-spleen-deficiency syndrome chronic-atrophic-gastritis by reshaping amino acid metabolism through gut Microbiota.

Background: Xiaohua Funing Tang (XHFND) is a decoction formula of traditional Chinese medicine (TCM) and possesses the potential to manage chronic atrophic gastritis (CAG) with liver depression and spleen deficiency (LDSD), but the mechanisms were still unclear.

Purpose: Our aim is to reveal the overall synergistic mechanisms of XHFND against CAG with LDSD.

Methods: Based on a CAG rat model with LDSD, this study combined metabolomics, gut microbiota, and network pharmacology techniques to demonstrate the XHFND mechanisms with multiple components and targets.

Results: Through the integration analysis of gut microbiome and metabolome using metorigin, we found that XHFND regulates arginine metabolism levels in the urea cycle by regulating the gut ecological environment and the host. The XHFND mainly promotes aspartate 1 metabolism by regulating the abundance of odoribacter, bacteroides, phocaeicola, lachnospire, and intestinimonas, intervened in the imbalance of arginine metabolism in CAG rats with LDSD, suppresses the pathogenic Th17 cell differentiation, and inhibits the gastric mucosa damage in rats. Through Cytoscape analysis of network pharmacology and metabolomics integration, we found that XHFND might regulate host phospholipid metabolism through PTEN and PIK3CA to inhibit the PI3K-AKT-TSC axis and then inhibit mTORC1 to control arginine metabolism in the urea cycle and produce polyamines, thereby inhibiting the pathogenic Th17 cell differentiation and preventing rat gastric mucosa damage. Intervention in arginine metabolism in the urea cycle is the primary pathway in which XHFND exerts its therapeutic effects. XHFND may mainly control the pathogenic Th17 cell differentiation in the gastric mucosa of model rats through the pathway.

Conclusion: This study indicated that XHFND might intervene in treating CAG with LDSD from multiple levels and perspectives to suppress the pathogenic Th17 cell differentiation, which aligns with the characteristics of TCM treatment. This study presents experimental evidence for the clinical use of XHFND and promotes the development of drugs for the therapy of CAG with LDSD.