GATA6 deficiency leads to epithelial barrier dysfunction and enhances susceptibility to gut inflammation.

Abstract

BACKGROUND & AIMS\nIntestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBD), but the mechanisms that lead to such a defect are not fully understood. This study was aimed at characterizing the factors involved in the defective barrier function in IBD.\n\n\nMETHODS\nTranscriptome analysis was performed on colon samples taken from healthy controls (CTR) and IBD patients. Expression of GATA-binding factor 6 (GATA6), a transcription factor involved in intestinal epithelial cell differentiation, was evaluated in colon samples taken from CTR and IBD patients by real-time PCR and immunohistochemistry. Intestinal sections of wild-type and Gata6del mice, which exhibit a conditional Gata6 deletion in intestinal epithelial cells, either left untreated or receiving subcutaneous indomethacin or rectal trinitrobenzene sulfonic acid, were stained with hematoxylin and eosin. In parallel, some Gata6del mice received antibiotics to deplete intestinal flora. Mucosal inflammatory cell infiltration and cytokine production were evaluated by flow cytometry and real-time PCR respectively while tight junction proteins were examined by immunofluorescence. Intestinal barrier integrity was assessed by FITC-dextran assay.\n\n\nRESULTS\nMultiple genes involved in cell commitment/proliferation and wound healing were differentially expressed in IBD compared to CTR. Among these, GATA6 was significantly decreased in the IBD epithelium compared to CTR. In mice, conditional deletion of GATA6 in the intestinal epithelium induced primarily epithelial damage, diminished Zonula Occludens-1 expression and enhanced intestinal permeability, ultimately resulting in bacteria-driven local immune response and enhanced susceptibility to gut inflammation.\n\n\nCONCLUSIONS\nReduced expression of GATA6 promotes intestinal barrier dysfunction thus amplifying intestinal inflammatory pathology.