Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease
Lisa Mayr, Felix Grabherr, Julian Schwärzler, I Reitmeier, Felix Sommer, T Gehmacher, Lukas Niederreiter, Gui-Wei He, Barbara Ruder, Kai T. R. Kunz, Piotr Tymoszuk, Richard Hilbe, David Haschka, Clemens Feistritzer, Romana R. Gerner, Barbara Enrich, Nicole Przysiecki, Markus Seifert, Markus A. Keller, Georg Oberhuber, Susanne Sprung, Qitao Ran, Robert Koch, Maria Effenberger, Ivan Tancevski, Heinz Zoller, Alexander R. Moschen, Günter Weiß, Christoph Becker, Philip Rosenstiel, Arthur Kaser, Herbert Tilg, Timon E. Adolph
Abstract
The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.