Berberine Alleviates Citrobacter rodentium-Induced Colitis with Reduced Epithelial Gasdermin E-Mediated Pyroptosis

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine. Although current therapies can provide symptomatic relief, they are often associated with high costs and adverse effects. Coptis chinensis Franch., a traditional Chinese medicine long used for inflammatory intestinal conditions such as bacterial dysentery, is a promising alternative. However, the specific alkaloid components that inhibit cell death and alleviate colitis remain unclear. Major isoquinoline alkaloids from Coptis chinensis Franch. were screened in a TNF-α/cycloheximide (CHX)-induced epithelial cell death model using CCK-8 and Annexin V staining. Caspase-3 and GSDME cleavage, HMGB1 release, phosphorylation of ERK and JNK, and inflammatory gene expression were assessed by Western blotting and qPCR. In vivo, a Citrobacter rodentium-induced colitis model was established and mice were treated with a specific alkaloid. Disease severity, histopathological injury, bacterial burden, barrier-related structural markers, and colonic GSDME cleavage were then evaluated. Berberine (BBR) exhibited the strongest cytoprotective activity in the screening system, reducing epithelial cell death, reversing pyroptosis-associated morphology, and inhibiting GSDME cleavage. BBR also reduced HMGB1 release, attenuated the phosphorylation of ERK and JNK, and downregulated pro-inflammatory gene expression. In the C. rodentium-induced infectious colitis model, BBR alleviated body weight loss, diarrhea, colon shortening, and histopathological injury without significantly reducing bacterial burden under the present experimental conditions. In parallel, BBR enhanced Tjp1 and Muc2 expression, and diminished colonic GSDME cleavage in vivo. Collectively, these findings suggest that BBR is a promising candidate for colitis involving bacterial infection-associated epithelial pyroptosis, potentially via GSDME modulation.