Intestinal REG3G Protects Against Gastrointestinal Dysfunction in a Murine Model of Ethanol Intoxication and Burn Injury

Nearly half of the burn patients in the United States are under the influence of alcohol at the time of injury, and alcohol intoxication is associated with poor clinical outcomes. Ethanol has been shown to worsen burn-induced intestinal dysfunction and inflammation, facilitating bacterial translocation from the intestine to the mesenteric lymph nodes and systemic circulation. Regenerating islet-derived protein 3-gamma (REG3G), an antimicrobial peptide crucial for maintaining intestinal homeostasis, protects mice from ethanol-induced bacterial translocation. In this study, we utilized a murine model to determine whether REG3G protects against the combined effects of acute ethanol exposure and burn injury. Mice with intestinal epithelial cell-specific overexpression of REG3G (Reg3g-Tg) were evaluated for gut barrier function, intestinal and hepatic inflammatory cytokines, and antimicrobial peptide expression after ethanol and burn injury. Additionally, we performed 16S rRNA gene sequencing of fecal microbiota. Our results demonstrate that ethanol exposure before burn injury downregulates the antimicrobial peptide REG3G in the ileum, when compared to burn alone. Intestine-specific overexpression of REG3G reversed several gastrointestinal effects of the combined injury, reducing intestinal inflammation and preventing bacterial translocation to the lymph nodes. Moreover, Reg3g-Tg mice exhibited reduced liver inflammation after combined injury, suggesting that improving intestinal function can also influence extra-intestinal organs. These findings highlight the therapeutic potential of REG3G in mitigating the effects of burn injury and alcohol intoxication.