Loss of Intestinal Endosome-associated Protein Sorting Nexin 27 Disrupts Epithelial Barrier and Promotes Inflammation

SNX27, member of the sorting nexin (SNX) family, carries a unique PDZ domain and mediates recycling of endocytosed transmembrane proteins. SNX27 is critical for neurodevelopmental processes; however, its role in intestine remains unexplored. We aim to determine the previously unknown roles of SNX27 in regulating intestinal homeostasis, epithelial barrier integrity, and inflammatory responses.

We used available National Center for Biotechnology Information Gene Expression Omnibus and single-cell RNA sequencing datasets to analyze SNX27 expression in human inflammatory bowel disease (IBD). We generated a novel mouse model of SNX27 conditional deletion from intestinal epithelial cells (SNX27^ΔIEC) and challenged these mice with dextran sulfate sodium (DSS).

SNX27 expression was significantly lower in human IBD, including ulcerative colitis (UC) and Crohn's disease (CD). SNX27^ΔIEC mice had significantly lower bodyweight and exhibited increased proliferation and poor differentiation of secretory Paneth and goblet cells. We found reduced mucin layer and downregulation of crucial epithelial barrier proteins β-catenin, E-cadherin, ZO-1, ZO-2, and Claudin10 in SNX27^ΔIEC mice. SNX27^ΔIEC mice showed high intestinal permeability and spontaneously developed intestinal inflammation. Moreover, SNX27^ΔIEC mice were more susceptible towards DSS-induced colitis, compared with the SNX27^Loxp mice.

Overall, deletion of intestinal epithelial SNX27 weakens barrier functions and promotes inflammation. Our results indicate a novel role of SNX27 in regulating intestinal physiology and protecting against intestinal disorders. Thus, understanding the mechanisms of SNX27 downregulation in IBD will provide insights into new prevention and targets against chronic inflammation.