Artesunate promotes intestinal epithelial barrier repair by facilitating HMGCS2-dependent ketogenesis in experimental ulcerative colitis model mice.

Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by an impaired intestinal epithelial barrier. The complex etiology of UC includes genetic, environmental, immune and microbial factors. It has recently been proposed that dysregulated ketogenesis may play a role in the development of UC; however, the precise mechanism by which this occurs remains unclear. In this study, mice were treated with dextran sulfate sodium to induce UC. UC mice exhibited intestinal epithelial barrier dysfunction characterized by loss of tight junctions in intestinal epithelial cells (IECs) and an imbalance in the Th17/Treg ratio in the peripheral blood. A significant decrease in the ketogenic rate-limiting enzyme HMGCS2 was observed in the IECs of UC mice, which was responsible for the decrease of β-hydroxybutyric acid production. Notably, UC mice treated with artesunate (ART) showed increased HMGCS2 and ketogenesis, as well as restored Th17/Treg and recovered tight junction protein expression. These factors contributed to intestinal epithelial barrier repair and alleviated colitis. The addition of an AMPK inhibitor or mTOR activator effectively reversed the effects of ART on ketogenesis, thereby preventing subsequent restoration of the intestinal barrier. These findings were confirmed in vitro in DSS-treated colonocytes. In conclusion, ART facilitated intestinal epithelial barrier repair in UC by stimulating HMGCS2-dependent ketogenesis in IECs through the AMPK/mTOR signaling pathway.