Liver X receptor agonists enhance intestinal repair in neonatal piglets with massive bowel resection.

Neonatal short bowel syndrome (SBS) often leads to intestinal failure and dependence on parenteral nutrition (PN). Given the role of liver X receptor (LXR) activation in lipid metabolism and mucosal repair, this study was designed to examine the effects of LXR agonist GW3965 on early adaptive responses in neonatal piglets with SBS. Seven-day-old Bama mini-piglets underwent 75% jejunoileal resection and were randomized into a control group (n = 6) and a GW3965-treated group (n = 4; 2 mg/kg/day administered via jugular vein). The effects of GW3965 on postresection intestinal responses and key molecular pathways were investigated using a combination of in vivo (piglets) and in vitro (human intestinal organoid) models. Administration of the LXR agonist GW3965 promoted significant improvements in gut barrier integrity and mucosal structure in the total parenteral nutrition-supported small-nowel resection piglet model during the 7-day postoperative period. GW3965 significantly increased villus height in the jejunum and ileum (both P < 0.05) and crypt depth throughout the remnant intestine and colon (all P < 0.05). Consistent with enhanced barrier function, treated piglets exhibited significantly lower serum lipopolysaccharide levels (P < 0.01) and elevated expression of tight junction proteins. GW3965 also promoted intestinal epithelial cell proliferation. Complementary in vitro studies confirmed that GW3965 directly stimulated the growth of human intestinal organoids. Notably, GW3965 altered colonic gene expression, upregulating markers typically associated with ileal identity. These findings suggest that targeting the LXR pathway may hold therapeutic potential for augmenting the intestinal regeneration.