Nitidine chloride alleviates DSS-induced ulcerative colitis in mice by modulating inflammation-intestinal barrier crosstalk and gut microbiota-metabolite interactions

Introduction Zanthoxylum nitidum (Roxb.) DC. is a traditional Chinese medicine widely used to treat digestive disorders. Nitidine chloride (NC) and its isomer chelerythrine chloride (CC) are the major bioactive benzophenanthridine alkaloids of Zanthoxylum nitidum , differing only in the methoxy substitution site on their molecular skeletons. However, whether this structural difference alters their pharmacological activities remains unclear. Methods This study established a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model to compare the therapeutic phenotypes of NC and CC and further elucidate the protective mechanisms of NC. Results Although both compounds alleviated UC, NC exhibited slightly superior effects in attenuating body weight loss and restoring several organ indices. Mechanistic analysis revealed that NC exerted protective effects against UC via dual regulation of inflammation-intestinal barrier crosstalk and gut microbiota-metabolite interactions. Specifically, NC disrupted the vicious crosstalk loop between intestinal inflammation and mucosal barrier damage. On the one hand, it suppressed excessive inflammatory responses by modulating pro-inflammatory cytokines and anti-inflammatory IL-10 in serum and colonic tissues, as well as downregulating colonic COX-2 expression. On the other hand, it restored intestinal barrier integrity by reducing serum levels of intestinal permeability markers diamine oxidase (DAO) and D-lactate, and upregulating tight junction proteins (Claudin-1, ZO-1) and MUC2. These effects blocked inflammatory infiltration induced by barrier leakage. Furthermore, 16S rRNA gene sequencing and metabolomics analysis showed that NC remodeled the dysregulated gut microbiota-metabolite interaction network in UC mice. NC significantly enriched beneficial intestinal bacteria such as Akkermansia and Limosilactobacillus . It also restored metabolic homeostasis of core pathways including glycerophospholipid metabolism, arachidonic acid metabolism, and branched-chain amino acid metabolism. Spearman correlation analysis further verified the close associations between differential microbial taxa and serum metabolites upon NC intervention. Moreover, network pharmacology and molecular docking provided preliminary in silico insights into potential target interactions of NC and CC. Conclusion Collectively, this study revealed that NC alleviated DSS-induced UC in mice by modulating inflammation-intestinal barrier crosstalk and gut microbiota-metabolite interactions. These findings provide pharmacodynamic mechanisms and experimental evidence supporting NC as a promising natural lead compound for anti-UC research, and lay a pharmacodynamic foundation for the modern development of Zanthoxylum nitidum .