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

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon over the last two decades that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ?-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails a risk for developing IBD. How dietary lipids fuel an inflammatory response in the intestine remains enigmatic. Glutathione peroxidase 4 (GPX4) protects against oxidative injury at cellular membranes (called lipid peroxidation) and guides cell fate. We report that small intestinal Crohn's disease (CD) epithelium exhibits impaired GPX4 activity and signs of lipid peroxidation (LPO). PUFAs and specifically AA trigger LPO and an inflammatory response of intestinal epithelial cells (IECs) involving interleukin 6 (IL-6) and the IL-8 homologue CXCL1, which is restricted by GPX4. While epithelial GPX4 does not control AA metabolism, cytokine production is governed by LPO, iron availability and acyl-CoA synthetase long-chain family member 4 (ACSL4). A PUFA-enriched Western diet evokes focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs (Gpx4+/-IEC), which cannot be explained by diet-induced alterations of fecal microbiota composition. AA elicits epithelial LPO and neutrophilic intestinal inflammation in iron-primed Gpx4+/-IEC mice and scavenging of LPO with a-tocopherol ameliorates PUFA-induced enteritis. Our model identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation resembling human CD.