PARD6B Deficiency Disrupts Gut Homeostasis and Drives Inflammatory Bowel Disease Progression

Background: Despite extensive research, the molecular mechanisms underlying inflammatory bowel disease (IBD) remain elusive, posing challenges for effective therapies. We investigated the Partitioning defective (Par) family, linked to IBD, and identified a novel defense mechanism involving PARD6B. We explored PARD6B role in intestinal epithelium and its link to IBD pathogenesis.
Methods:We analyzed colonic biopsy samples from IBD patients and intestinal epithelial cell-specific Pard6b-deficient mice (Pard6b IEC-KO). Histopathology, RNA sequencing, and microbiota analysis were conducted to evaluate epithelial integrity, goblet cell function, and gut microbiota composition.
Results:In IBD remission, PARD6B was downregulated and mislocalized. Single-cell RNA sequencing showed high pard6b expression in goblet and Paneth cells. In Pard6b IEC-KO mice, the colonic mucus layer was significantly thinner, and the number of Paneth cells was markedly reduced. Pard6b IEC-KO mice developed severe spontaneous enterocolitis, featuring crypt abscesses and massive immune cell infiltration, highlighting its indispensable role in intestinal homeostasis. RNA sequencing of IECs isolated from Pard6b IEC-KO mice revealed impaired goblet cell function, as indicated by decreased expression of Muc2, Agr2, and Clca1. Furthermore, Pard6b IEC-KO mice exhibited gut microbiota dysbiosis, and treatment of Pard6b IEC-KO mice with broad-spectrum antibiotics alleviated inflammation.
Conclusion: PARD6B is a key regulator of intestinal barrier function, maintaining goblet and Paneth cell homeostasis. Its dysregulation disrupts epithelial integrity and drives IBD. Targeting PARD6B may offer a novel therapeutic strategy for gut inflammation.