Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury

Abstract

The intestinal epithelial barrier is critical to limit potential harmful consequences from exposure to deleterious luminal contents on the organism. Although this barrier is functionally important along the entire gut, specific regional regulatory mechanisms involved in the maintenance of this barrier are poorly defined. Herein, we identified Gata4 as a crucial regulator of barrier integrity in the mouse proximal intestinal epithelium. Conditional deletion of Gata4 in the intestine led to a drastic increase in claudin-2 expression that was associated with an important increase of gut barrier permeability without causing overt spontaneous inflammation. Administration of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that causes enteritis, led to rapid and restricted proximal small intestinal injuries in Gata4 mutant mice as opposed to control mice. Comparative analysis of gene transcript profiles from indomethacin-challenged control and Gata4 mutant mice identified defects in epithelial cell survival, inflammatory cell recruitment and tissue repair mechanisms. Altogether, these observations identify Gata4 as a novel crucial regulator of the intestinal epithelial barrier and as a critical epithelial transcription factor implicated in the maintenance of proximal intestinal mucosal integrity after injury.

Mucosal RNA and protein expression as the next frontier in IBS: abnormal function despite morphologically intact small intestinal mucosa

“…Similar results have been described for the transcription factor GATA4, which is expressed in enterocytes of the duodenal and jejunal epithelium and, together with GATA6, plays an important role in the proliferation of crypt cells (14,18,87). A conditional villin-dependent deletion of GATA4 leads to decreased protein levels in the jejunum and an increased permeability to FITC-dextran and to noninvasive Salmonella typhimurium, together with higher CLDN2 expression and number of intraepithelial lymphocytes (93). In addition, the transcription factor EB, which is related with a correct formation of granules in Paneth cells, increased permeability (measured with FITC-dextran), bacterial translocation to the spleen, and defensin production.…”

NF-κB2 signalling in enteroids modulates enterocyte responses to secreted factors from bone marrow-derived dendritic cells

“…For instance, the Gata 4 transcription factor is highly expressed in all epithelial cells of the duodenum, but shows greatly reduced expression further down the cephalocaudal axis, with no expression being detected in the terminal ileum 26,27 . Gata 4 has been shown to activate jejunal-specific genes such as Clnd2 (encoding Claudin-2 protein) but represses ileal-specific genes such as Slc10a2 (solute carrier family 10, member 2) and Fabp6 (encoding fatty acid binding protein 6) 26,37 . Overexpression of Claudin-2 has been associated with inflammatory bowel disease and coeliac disease 38 and is also upregulated in the intestine within 1 h of experimentally induced sepsis 39 .…”

Intestinal Lipid Metabolism Genes Regulated by miRNAs

“…Chromogranin A (Chga) is a marker of enteroendocrine cells (Andres et al, 2015). Gata 4 is a marker of intestinal epithelial differentiation that is essential to preserve gut barrier function and mucosal integrity (Lepage et al, 2016). Intestinal alkaline phosphatase (Alpi) is a brush border enzyme that considerably diminishes the pro−inflammatory action of LPS (Parlato et al, 2018).…”