Huangqin decoction improves chemotherapy-induced diarrhea by restoring the intestinal mechanical barrier and Lyn/snail/E-cadherin signaling pathway.

Objective

Huangqin Decoction (HQD) is a classic traditional Chinese formula with proven efficacy for treating chemotherapy-induced diarrhea (CID), but its underlying mechanisms are not adequately understood. This study aimed to investigate the mechanism by which HQD alleviates CID by regulating gut microbiota homeostasis and modulating the Lyn/Snail/E-cadherin signaling pathway, focusing on both the biological and mechanical barriers of the intestine.

Methods

Network pharmacology was employed to identify potential targets and pathways for HQD in treating CID. Subsequently, The CID model in mice was established by intraperitoneal injection of CPT-11. Pharmacological efficacy was evaluated using diarrhea scoring, body weight, food intake, colon length measurement, and HE staining. Furthermore, 16S rRNA sequencing and ELISA were performed to analyze its regulatory effects on gut microbiota and LPS levels. Finally, Molecular docking, IF, WB and RT-qPCR were combined to explore its regulatory effects on the Lyn/Snail/E-cadherin signaling pathway and intestinal barrier-related proteins.

Results

The core pathways of HQD against CID were mainly enriched in adherens junctions, tight junctions, bacterial response and the Lyn signaling pathway. HQD ameliorated diarrhea, body weight loss and colonic pathological injury in CID mice, meanwhile modulated gut microbiota and reduced colonic LPS levels. Mechanistically, its therapeutic effect was associated with inhibiting Lyn phosphorylation, reducing Snail/Slug nuclear translocation, upregulating the expression of intestinal barrier-related proteins, and restoring the intestinal mechanical barrier.

Conclusion

These results demonstrate that HQD exerts a therapeutic effect in ameliorating CID via remodeling gut microbiota structure, reducing LPS levels, and modulating the Lyn/Snail/E-cadherin signaling pathway.