The cholera toxin B subunit (CTB) is the nontoxic and homopentameric component of the holotoxin. Upon binding to GM1 ganglioside on the surface of epithelial cells, CTB mediates entry and retrograde transport through the endomembrane system and disengages the catalytic A subunit in the endoplasmic reticulum (ER). EPICERTIN (EPT) is a recombinant variant of CTB with a non-native C-terminal extension harboring an ER-retention motif, KDEL. We have found that increased ER-retention time resulting from this modification allowed EPT to induce an unfolded protein response and TGF-β signaling in colon epithelial cells, triggering wound healing activity in preclinical colitis models.