Intraduodenal administration of Reg3g improves gut barrier function and mitigates hepatic steatosis in mice.

Regenerating islet-derived protein 3 gamma (Reg3g), a gut peptide has been implicated in host defense and various physiological functions including metabolic regulation. Emerging evidence has demonstrated that peripheral administration of Reg3g results in improved glucose regulation as a gut hormone. In this study, we explored the therapeutic potential of Reg3g through intraduodenal infusion in mouse models of metabolic disorders. The objective of this study was to test the hypothesis that administered Reg3g into the intestinal lumen contributes to metabolic improvements by enhancing gut barrier function. Our mouse studies revealed that duodenal infusion of Reg3g reduces gut permeability and systemic endotoxemia. Studies with intestinal organoids supported the role of Reg3g in preserving cellular integrity and antioxidant gene expression under fructose-induced stress. Although Reg3g treatment results in little change to body weight, food intake, or glucose tolerance, Reg3g-treated mice exhibited reduced hepatic lipid accumulation along with the downregulation of lipogenic pathway genes. These data point toward the positive impact of Reg3g administration through intraduodenal infusion to regulate the intricate cross talk between gut barrier function and hepatic steatosis with the gut-liver axis.NEW & NOTEWORTHY This study shows that intraduodenal administration of the gut peptide, regenerating islet-derived protein 3 g (Reg3g), reduces hepatic lipid accumulation, improves gut barrier function, and lowers systemic endotoxemia in mouse models of metabolic disorders. These findings elucidate the therapeutic benefits of Reg3g administration into the gut.