Multi-omics analysis combined with network pharmacology revealed the mechanisms of rutaecarpine in chronic atrophic gastritis.

ETHNOPHARMACOLOGICAL RELEVANCE

Tetradium ruticarpum (A.Juss.) T.G.Hartley is a traditional Chinese medicine with a history of thousands of years, which plays an important role in the relief of gastric pain, indigestion, vomiting and diarrhea. Rutaecarpine (RUT) is one of the major active constituents of Tetradium ruticarpum (A.Juss.) T.G.Hartley with potential therapeutic activity in chronic atrophic gastritis (CAG). However, the mechanism of RUT to improve CAG is not well understood.

AIM OF THIS STUDY

This study aimed to evaluate the efficacy of RUT in treating CAG and its underlying mechanism.

MATERIALS AND METHODS

The CAG model of SD rats was established by induction with 0.1% ammonia and 20 mmol/L sodium deoxycholate solution, accompanied with irregular fasting cycle. The efficacy of RUT in treating CAG was assessed through pathological examination and serum biochemical indices including PP, IL-6, MTL, TNF-α, PG I, SS, PG II, IL-10 and GAS-17. Following this, network pharmacology, 16s rRNA sequencing, transcriptomics, and broadly targeted metabolomics were conducted to unravel the underlying mechanisms of RUT's action in CAG treatment. Ultimately, molecular docking, western blotting, and immunohistochemistry were employed to validate the critical targets and pathways involved in RUT's therapeutic approach for CAG.

RESULTS

RUT significantly improved body weight, gastric juice pH and gastric histologic injury in CAG rats. The results of serum biochemical indices showed that RUT significantly inhibited the expression levels of SS, GAS-17, IL-6 and TNF-α, and increased the levels of MTL, PP, PGI, PGII and IL-10. In addition, RUT apparently increased the expression of mucosal barrier proteins such as ZO-1, E-cadherin and claudin-4 and occludin. Network pharmacology in combination with transcriptomics revealed that the MAPK signaling pathway was the most important pathway for RUT treatment of CAG. Further analysis suggested that by regulating linoleic acid metabolism, metabolic pathways, etc. mainly related to energy metabolism, RUT intervention effectively ameliorated gastric tissue metabolic disorders in CAG rats. The 16S rRNA gene-based microbiota analysis revealed that RUT altered the composition of the intestinal microbiota and decreased the relative abundance of unclassified_Muribaculaceae. PICRUST analysis suggested that the differential bacteria may be involved in energy metabolism pathway regulation for the improvement of CAG. A comprehensive analysis of the transcriptome and metabolome showed that the RUT improved the differential metabolites through the regulation of TGER2, CBR1 and CTPS1 targets.

CONCLUSION

These findings indicated that RUT's mechanism of action in treating CAG was related to modulating the gut microbiota, influencing energy metabolism, and inhibiting the MAPK signaling pathway. This provided new insights into how RUT exerts its therapeutic effects on CAG.