Dietary lipids fuel GPX4-restricted enteritis resembling Crohn\u2019s disease

Lisa Mayr ,Qitao Ran ,Clemens Feistritzer ,Heinz Zoller ,Ivan Tancevski ,Felix Grabherr ,Romana R Gerner ,Gui Wei He ,Philip Rosenstiel ,Alexander R Moschen ,Günter Weiß ,Christoph Becker ,David Haschka ,Felix Sommer ,T Gehmacher ,Barbara Ruder ,Robert Koch ,Lukas Niederreiter ,Julian Schwärzler ,I Reitmeier ,Barbara Enrich ,Georg Oberhuber ,Kai T.r Kunz ,Nicole Przysiecki ,Richard Hilbe ,Piotr Tymoszuk ,Markus A Keller ,Markus Seifert ,Maria Effenberger ,Herbert Tilg ,Arthur Kaser ,Susanne Sprung ,Timon E Adolph

doi:10.1038/s41467-020-15646-6

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.

Highlights

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style
The increase in incidence of IBD parallels the increase in dietary intake of ω-6 polyunsaturated fatty acid (PUFA) such as arachidonic acid (AA), which is a major component of a Western diet and contained in meat and eggs[19]
In intestinal epithelial cells (IECs) with reduced Glutathione peroxidase 4 (GPX4) activity, PUFAs and AA induce the release of interleukin 6 (IL-6) and chemokine (C-X-C motif) ligand 1 (CXCL1) which is governed by iron availability, lipoxygenase-mediated lipid peroxidation (LPO) and Acsl[4]

Summary

Introduction

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Ferroptosis requires acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated membrane enrichment of the ω-6 PUFA arachidonic acid (AA), which is prone to oxidation[2,6,7] Deletion of both alleles of Gpx[4] culminates in organ injury of the kidney, brain, and skin, which is conceivably elicited or modulated by immune responses[3,8,9,10,11]. Mice that are exposed to a PUFA-enriched Western diet and that lack one Gpx[4] allele in IECs (Gpx4+/−IEC), but not wild-type (WT) mice, display signs of epithelial LPO and focal neutrophilic enteritis with granuloma-like accumulation of inflammatory cells. Our study exemplifies how PUFAs in a Western diet pose a risk for developing CD

Methods

Results

Conclusion