Ellagic Acid as a Natural Product-Based GPR35 Agonist for Ulcerative Colitis

Ulcerative Colitis (UC) represents a major global health burden characterized by chronic intestinal inflammation, dysbiosis, and limited therapeutic options. The G pro-tein-coupled receptor 35(GPR35), highly expressed in the gastrointestinal tract and immune cells, has emerged as a promising target for maintaining gut homeostasis and promoting mucosal repair. Here, we identified ellagic acid (EA), a natural polyphenol abundant in fruits and nuts, as a novel dietary agonist of GPR35 through Nanobit assay. Then we utilized molecular docking and molecular dynamics simulations to prove the binding ability of GPR35 and EA, and we further elucidated the binding site via point mutation. In a murine model of experimental colitis, EA administration significantly alleviated disease severity, as evidenced by improved body weight, disease activity index, and colon length. Notably, EA strongly promoted mucosal healing and preserved intestinal barrier integrity. Mechanistically, EA enhanced the migration and prolifera-tion of human colonic epithelial cells, an effect that was specifically abolished by the GPR35 antagonist CID2745687，indicating the key role GPR35 played in the intestinal repair. Our findings reveal a previously unrecognized role for EA as a natural GPR35 agonist with potent protective effects in colitis, highlighting the potential of polyphe-nol-rich diets as adjunctive strategies for IBD management by targeting mucosal repair pathways.