Oral inulin prebiotic encapsulating Cortex Fraxini extracellular vesicles alleviates colitis and associated renal stress via reinforcing intestinal barriers and remodeling microbiota.

Background: Gut-kidney axis dysfunction contributes to extraintestinal complications in inflammatory bowel disease (IBD), yet effective therapeutic strategies targeting this axis remain limited. This study developed an oral prebiotic delivery system by encapsulating Cortex Fraxini-derived extracellular vesicles (CF-EVs) within an inulin-based hydrogel (CF-EVs@Inulin) and evaluated its therapeutic potential in ulcerative colitis and associated renal injury. Methods: CF-EVs were isolated and characterized for morphology and antioxidant activity. An inulin-based hydrogel was employed to encapsulate CF-EVs and improve gastrointestinal stability and colonic retention. Therapeutic efficacy was assessed in dextran sulfate sodium (DSS)-induced acute colitis mice, including antibiotic-pretreated groups. Gut microbiota composition, intestinal barrier integrity, intestinal permeability, lipopolysaccharide (LPS) translocation, renal TLR4/NF-κB signaling, and renal injury markers were analyzed. Results: CF-EVs exhibited typical vesicular morphology and potent ROS-scavenging activity. CF-EVs@Inulin showed enhanced gastrointestinal stability and prolonged retention in the colon. Treatment with CF-EVs@Inulin significantly ameliorated colitis symptoms, restored mucus and tight junction barriers, and remodeled gut microbiota composition. These protective effects were largely attenuated following microbiota depletion. Mechanistically, CF-EVs@Inulin reduced intestinal permeability and circulating LPS levels, suppressed renal TLR4/NF-κB activation, improved renal function, and decreased the expression of kidney injury markers KIM-1 and NGAL. Conclusion: CF-EVs@Inulin alleviates colitis-associated early renal stress by restoring intestinal barrier integrity and gut microbiota homeostasis, thereby interrupting the LPS-TLR4/NF-κB signaling pathway. These findings highlight the therapeutic potential of prebiotic-encapsulated CF-EVs as a promising strategy for ulcerative colitis and gut-kidney axis-related complications.