Epithelial GPX4 in the control of intestinal homeostasis

The FWF stand-alone project Epithelial Glutathione peroxidase 4 in the control of intestinal homeostasis investigates the regulation of the Crohns disease-associated risk gene GPX4 in intestinal epithelial cells and aims to dissect how GPX4-deficiency perturbs intestinal homeostasis. GPX4 acts as an anti-oxidative enzyme that specifically protects against oxidative stress and lipid peroxidation in a variety of cell types. Inflammatory bowel disease patients exhibit increased oxidative stress which is associated with an impaired anti-oxidative capacity and genome wide association studies highlighted a possible role for GPX4 in the pathogenesis of Crohns disease. However, little is known about the regulation and function of GPX4 in the intestine. Our preliminary experiments demonstrate that GPX4 expression is strongly reduced in intestinal epithelial cells of Crohns disease patients. Experimental evidence suggests that stress in the endoplasmic reticulum (which has been tightly linked to the development of intestinal inflammation) reduces GPX4 activity. We now aim to dissect mechanisms how this stress response mediates the suppression of GPX4 activity. Furthermore, we seek to explore the consequences of reduced GPX4 activity for intestinal-epithelial and gut homeostasis. To do so, we will generate mice lacking GPX4 specifically in the intestinal epithelium and assess their susceptibility to intestinal inflammation. Several studies in keratinocytes of the skin, kidney cells and neurons revealed that GPX4 is critically important to protect from cell death and inflammation. Hence, we aim to assess the role of intestinal epithelial cell death induced by GPX4-deficiency on disease processes of the intestine. Investigating the role of GPX4 in the intestinal epithelium will contribute to our understanding of the genetic risk association of GPX4 with Crohns disease. Our findings may serve as rationale to implicate novel treatment strategies for Crohns disease patients with an impaired anti-oxidative capacity.

The FWF stand-alone project P 29379 successfully established a biological function of intestinal epithelial Glutathione peroxidase 4 (GPX4) in maintaining gut homeostasis. Specifically, GPX4 protects against lipid peroxidation and inflammation in the gut that can be triggered by dietary polyunsaturated fatty acids. These findings are notable because GPX4 activity is impaired in patients with inflammatory bowel diseases and specifically Crohn's disease. As such, future studies may establish a critical role for dietary polyunsaturated fatty acids on the development or course of chronic remittent inflammatory disorders. The study was published in the highly esteemed journal Nature Communications in 2020 and discussed in several German and Austrian news outlets.