Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease

Lisa Mayr, Felix Grabherr, Julian Schwärzler, Isabelle Reitmeier, Felix Sommer, Thomas 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 and Timon E. Adolph ()
Additional contact information
Lisa Mayr: Medical University of Innsbruck
Felix Grabherr: Medical University of Innsbruck
Julian Schwärzler: Medical University of Innsbruck
Isabelle Reitmeier: Medical University of Innsbruck
Felix Sommer: Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein
Thomas Gehmacher: Medical University of Innsbruck
Lukas Niederreiter: Medical University of Innsbruck
Gui-Wei He: University Medical Center Erlangen
Barbara Ruder: University Medical Center Erlangen
Kai T. R. Kunz: Medical University of Innsbruck
Piotr Tymoszuk: Medical University of Innsbruck
Richard Hilbe: Medical University of Innsbruck
David Haschka: Medical University of Innsbruck
Clemens Feistritzer: Medical University of Innsbruck
Romana R. Gerner: Medical University of Innsbruck
Barbara Enrich: Medical University of Innsbruck
Nicole Przysiecki: Medical University of Innsbruck
Markus Seifert: Medical University of Innsbruck
Markus A. Keller: Medical University of Innsbruck
Georg Oberhuber: Pathology Department of Innsbruck Medical University Hospital
Susanne Sprung: Medical University of Innsbruck
Qitao Ran: UT Health San Antonio
Robert Koch: Medical University of Innsbruck
Maria Effenberger: Medical University of Innsbruck
Ivan Tancevski: Medical University of Innsbruck
Heinz Zoller: Medical University of Innsbruck
Alexander R. Moschen: Medical University of Innsbruck
Günter Weiss: Medical University of Innsbruck
Christoph Becker: University Medical Center Erlangen
Philip Rosenstiel: Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein
Arthur Kaser: University of Cambridge
Herbert Tilg: Medical University of Innsbruck
Timon E. Adolph: Medical University of Innsbruck

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15646-6

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