Colon-Targeted Codelivery of 6-Gingerol and Piperine Ameliorates Ulcerative Colitis via the Indole-AhR Axis

Ulcerative colitis (UC) requires therapeutic strategies that concurrently restore epithelial barrier integrity and suppress mucosal inflammation. Here, we developed a colon-targeted microparticle MC(6G+PIP) to synchronize the delivery of 6-gingerol (6G) and piperine (PIP). Nanostructured lipid carriers were coated with chitosan and konjac glucomannan to form microspheres (∼10.5 μm) with encapsulation efficiencies exceeding 90%. MC(6G+PIP) prevented premature release in gastric and intestinal fluids (<15%), while enabling sustained colonic release of 6G (82.91%) and PIP (81.64%). In DSS-induced colitis mice, MC(6G+PIP) accelerated body weight recovery (1.9-fold), reduced disease activity (2.62-fold), and lowered intestinal permeability by ∼50% as compared to MC(6G). Mechanistically, codelivery was associated with increased tryptophan-derived indole metabolites (1.66- and 3.28-fold vs MC(6G) and MC(PIP), respectively) and activation of the AhR-Cyp1a1 axis, contributing to improved epithelial repair and reduced inflammation. These findings highlighted a novel approach that combines targeted delivery with microbiota modulation for effective UC therapy.