Colon-targeted EGCG delivery remodels the gut microenvironment to enhance therapeutic efficacy in ulcerative colitis.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disorder characterized by epithelial barrier disruption, oxidative stress, and gut microbiota dysbiosis. Although epigallocatechin-3-gallate (EGCG) exhibits potent anti-inflammatory and antioxidant activities, its clinical application is limited by poor stability and low colonic bioavailability. Herein, EGCG-loaded Eudragit® S100-coated chitosan microparticles (EG@euCS MPs) were developed as a colon-targeted oral delivery platforms integrating mucoadhesive retention with pH-responsive release. EG@euCS MPs effectively protected EGCG during gastrointestinal transit and achieved sustained release under colonic conditions. In vitro, EG@euCS MPs enhanced cellular uptake, reduced oxidative stress, promoted anti-inflammatory macrophage polarization, and restored epithelial barrier integrity. In a dextran sulfate sodium (DSS)-induced colitis mice, EG@euCS MPs achieved prolonged colonic retention and significantly alleviated disease severity, as evidenced by improved clinical symptoms, reduced inflammatory responses, restored colon morphology, and enhanced tight junction expression. Importantly, integrated 16S rRNA sequencing, short-chain fatty acid profiling, and untargeted metabolomics revealed that EG@euCS MPs restored microbial and metabolic homeostasis, characterized by enrichment of beneficial taxa, including Akkermansia, increased acetate, propionate, and butyrate production, recovery of antioxidant and tryptophan-related metabolites, and attenuation of inflammatory lipid mediators. Collectively, EG@euCS MPs coordinate the regulation of inflammatory, microbial, and metabolic pathways, representing promising colon targeted therapeutics for UC.