The protective role of PYY in intestinal mucosal defects induced by SATB2 deficiency in inflammatory bowel disease

TL;DR

This study shows that PYY can help repair intestinal damage caused by SATB2 deficiency in inflammatory bowel disease.

Contribution

The novel finding is that PYY rescues SATB2-deficient mucosal repair by activating PPAR-γ transcription.

Findings

SATB2 deficiency leads to defective colonic epithelial repair and reduced goblet and enteroendocrine cells.

PYY promotes epithelial regeneration in Crohn’s disease organoids better than rosiglitazone.

PYY activates PPAR-γ transcription, rescuing mucosal defects caused by SATB2 deficiency.

Abstract

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. In this study, flow cytometry was used to assess SATB2’s role in colonic epithelial repair in a radiation injury model. SATB2 knockout mice exhibited defective epithelial repair, with a marked reduction in goblet and enteroendocrine cells. Mechanistically, SATB2 directly regulated PPAR-γ transcription, and PYY was observed to translocate into the nucleus and promote the transcription of PPAR-γ target genes. In organoids derived from patients with Crohn’s disease, PYY supplementation significantly improved epithelial regeneration, outperforming the PPAR-γ agonist rosiglitazone. In conclusion, SATB2 deficiency impairs colonic epithelial repair, which can be rescued by PYY through activation of PPAR-γ-dependent transcription. These findings suggest that PYY may serve as a promising therapeutic molecule to promote epithelial repair in IBD.

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