The Protective Role of PYY in Intestinal Mucosal Defects Induced by SATB2 Deficiency in Inflammatory Bowel Disease

Background Impaired colonic mucosal repair is a critical issue in inflammatory bowel diseases (IBD). SATB2 is essential for maintaining colonic epithelial homeostasis, but its role in mucosal repair is unclear. Objective To investigate how SATB2 deficiency impairs colonic mucosal repair in IBD and assess the therapeutic potential of peptide YY (PYY) in enhancing colonic epithelial regeneration. Design Flow cytometry was used to assess SATB2’s role in colonic epithelial repair in a radiation injury model. SATB2 knockout mice were used to validate repair impairment. The effect of SATB2 loss on PYY expression was evaluated both in vivo and ex vivo. Molecular mechanisms of SATB2 regulation on PPAR-γ and the role of PYY were examined using confocal microscopy and immunoblotting. PYY’s role in epithelial repair was assessed in organoids from Crohn’s disease patients. Results Satb2 expression correlated with colonic mucosal repair. Satb2 loss impaired colonic epithelial repair, reducing goblet and enteroendocrine cells. The most prominent enteroendocrine hormone, PYY, showed a significant decrease in colonic mucosa after Satb2 loss. At the molecular level, Satb2 directly regulated the transcription of PPAR-γ. PYY could enter the nucleus and promote the transcription of downstream genes of PPAR-γ. PYY promoted epithelial repair more effectively than the PPAR-γ agonist rosiglitazone. Additionally, PYY enhanced colonic epithelial regeneration in Crohn’s disease patient-derived organoids. Conclusion The impairment of colonic epithelial repair resulting from Satb2 loss could be ameliorated through PYY supplementation, which facilitates coloninc epithelial repair by activating the transcription of downstream genes associated with PPAR-γ.