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; Timon E. Adolph

doi:10.1038/s41467-020-15646-6

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 OberhuberSusanne 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

Department of Cell Systems & Anatomy

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

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.

Original language	English (US)
Article number	1775
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15646-6
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Mayr, L., Grabherr, F., Schwärzler, J., Reitmeier, I., Sommer, F., Gehmacher, T., Niederreiter, L., He, G. W., Ruder, B., Kunz, K. T. R., Tymoszuk, P., Hilbe, R., Haschka, D., Feistritzer, C., Gerner, R. R., Enrich, B., Przysiecki, N., Seifert, M., Keller, M. A., ... Adolph, T. E. (2020). Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease. Nature communications, 11(1), Article 1775. https://doi.org/10.1038/s41467-020-15646-6

Mayr, L, Grabherr, F, Schwärzler, J, Reitmeier, I, Sommer, F, Gehmacher, T, Niederreiter, L, He, GW, Ruder, B, Kunz, KTR, Tymoszuk, P, Hilbe, R, Haschka, D, Feistritzer, C, Gerner, RR, Enrich, B, Przysiecki, N, Seifert, M, Keller, MA, Oberhuber, G, Sprung, S, Ran, Q, Koch, R, Effenberger, M, Tancevski, I, Zoller, H, Moschen, AR, Weiss, G, Becker, C, Rosenstiel, P, Kaser, A, Tilg, H & Adolph, TE 2020, 'Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease', Nature communications, vol. 11, no. 1, 1775. https://doi.org/10.1038/s41467-020-15646-6

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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{\textquoteright}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.",

author = "Lisa Mayr and Felix Grabherr and Julian Schw{\"a}rzler and Isabelle Reitmeier and Felix Sommer and Thomas Gehmacher and Lukas Niederreiter and He, {Gui Wei} and Barbara Ruder and Kunz, {Kai T.R.} and Piotr Tymoszuk and Richard Hilbe and David Haschka and Clemens Feistritzer and Gerner, {Romana R.} and Barbara Enrich and Nicole Przysiecki and Markus Seifert and Keller, {Markus A.} and Georg Oberhuber and Susanne Sprung and Qitao Ran and Robert Koch and Maria Effenberger and Ivan Tancevski and Heinz Zoller and Moschen, {Alexander R.} and G{\"u}nter Weiss and Christoph Becker and Philip Rosenstiel and Arthur Kaser and Herbert Tilg and Adolph, {Timon E.}",

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AU - Mayr, Lisa

AU - Grabherr, Felix

AU - Schwärzler, Julian

AU - Reitmeier, Isabelle

AU - Sommer, Felix

AU - Gehmacher, Thomas

AU - Niederreiter, Lukas

AU - He, Gui Wei

AU - Ruder, Barbara

AU - Kunz, Kai T.R.

AU - Tymoszuk, Piotr

AU - Hilbe, Richard

AU - Haschka, David

AU - Feistritzer, Clemens

AU - Gerner, Romana R.

AU - Enrich, Barbara

AU - Przysiecki, Nicole

AU - Seifert, Markus

AU - Keller, Markus A.

AU - Oberhuber, Georg

AU - Sprung, Susanne

AU - Ran, Qitao

AU - Koch, Robert

AU - Effenberger, Maria

AU - Tancevski, Ivan

AU - Zoller, Heinz

AU - Moschen, Alexander R.

AU - Weiss, Günter

AU - Becker, Christoph

AU - Rosenstiel, Philip

AU - Kaser, Arthur

AU - Tilg, Herbert

AU - Adolph, Timon E.

PY - 2020/12/1

Y1 - 2020/12/1

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

Abstract

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