Empagliflozin Restores the Colonic Mucous Barrier by an AMPK / SOX4 ‐Dependent Pathway in Glycogen Storage Disease Type Ib

Glycogen storage disease type Ib (GSD-Ib) is commonly associated with refractory inflammatory bowel disease (GSD-IBD). Although the SGLT2 inhibitor empagliflozin has demonstrated remarkable clinical efficacy, its direct effects on the intestinal epithelium remain poorly understood. This study aimed to determine whether empagliflozin directly restores the impaired colonic mucus barrier and to identify the underlying molecular pathway. In terms of efficacy, we integrated clinical evaluations of GSD-IBD patients with a novel murine model of epithelial injury induced by a defined bacterial consortium (EVS: Enterococcus, Veillonella, Streptococcus) and dextran sulfate sodium (DSS). In vitro, we employed Caco-2 cells and intestinal organoids, combined with pharmacological inhibition of AMPK and siRNA-mediated gene knockdown to elucidate the underlying molecular mechanisms. Clinical data indicated that empagliflozin promoted ulcer healing and enhanced mucin production in patients. In the EVS + DSS mouse model, empagliflozin treatment reduced disease severity and attenuated goblet cell depletion. We demonstrated that empagliflozin upregulates the transcription factor SOX4 in intestinal epithelial cells both in vivo and in vitro, an effect dependent on AMPK activation. Notably, siRNA knockdown of SOX4 abolished empagliflozin-induced MUC2 upregulation. Furthermore, pharmacological inhibition of AMPK suppressed the induction of MUC2, which could be rescued by SOX4 overexpression. Our findings uncover a novel, epithelium-intrinsic mechanism of action for empagliflozin: the activation of the AMPK/SOX4/MUC2 signaling axis to restore the colonic mucus barrier. These results provide a mechanistic foundation for the repurposing of SGLT2 inhibitors in conditions characterized by epithelial barrier dysfunction.