Satb2 deletion in colon approach to treat short bowel syndrome

Loss of the transcription factor Satb2 converts mouse colonic epithelium into an ileal type. Here, we report that Satb2 gene deletion alleviates SBS by replacing diminished absorptive function and by inducing lymphovascular channels in the proximal colon. Enhanced nutrient absorption following Satb2 loss increased body weight and survival of mice with SBS. Deletion of SATB2 by adeno-associated viral delivery of CRISPR Split Cas9 to human colon organoids, followed by xenotransplantation into mice, resulted in ileal morphology and expression of ileal marker genes. This approach offers a feasible strategy for future treatment of SBS. Here we deleted Satb2 to remodel the colon into nutrient-absorbing ileum-like tissue in a mouse model of SBS. The resulting ileum-like colon developed lacteal vessels, subepithelial lymphatic channels normally restricted to the small intestine and responsible for fat absorption, indicating that Satb2 deletion directs formation of small intestinal structures in the colon.