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

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.

SUBMITTER: Mayr L

PROVIDER: S-EPMC7156516 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Mayr Lisa L Grabherr Felix F Schwärzler Julian J Reitmeier Isabelle I Sommer Felix F Gehmacher Thomas T Niederreiter Lukas L He Gui-Wei GW Ruder Barbara B Kunz Kai T R KTR Tymoszuk Piotr P Hilbe Richard R Haschka David D Feistritzer Clemens C Gerner Romana R RR Enrich Barbara B Przysiecki Nicole N Seifert Markus M Keller Markus A MA Oberhuber Georg G Sprung Susanne S Ran Qitao Q Koch Robert R Effenberger Maria M Tancevski Ivan I Zoller Heinz H Moschen Alexander R AR Weiss Günter G Becker Christoph C Rosenstiel Philip P Kaser Arthur A Tilg Herbert H Adolph Timon E TE

Nature communications 20200414 1

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 Cr ...[more]

PMID: 32286299

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Project description:BackgroundCrohn's disease (CD) exclusion diet combined with partial enteral nutrition (CDED + PEN) or exclusive enteral nutrition (EEN) is effective in inducing remission in mild-to-moderate pediatric CD. Although CDED + PEN is better tolerated and has higher compliance compared to EEN, a subset of patients does not achieve remission. Diet-induced remission is shown to be positively associated with specific changes in tryptophan-metabolites.ObjectivesTo investigate whether the abundance of baseline fecal tryptophan-metabolites predicts dietary therapy outcomes in pediatric CD.DesignDiagnostic accuracy study and secondary analysis of previously conducted Randomized Controlled Trial (RCT).MethodsTwenty-six patients from previously performed RCT of mild-to-moderate pediatric CD were included. The patients were classified as having clinical remission (R) (n = 19 in total; CDED + PEN = 10 and to EEN = 9) or No-Remission (NR) (n = 7 in total; CDED + PEN = 3 and EEN = 4) following 6 weeks of therapy, based on the Pediatric Crohn's Disease Activity Index score (⩽10 = remission). We performed a targeted quantitative analysis of 21 tryptophan-metabolites in baseline (t = 0) fecal samples from both groups, utilizing liquid chromatography coupled with quadrupole mass spectrometry. Receiver operator characteristic curve (ROC) and random forest analysis (RFA) were used to assess the predictive power of fecal tryptophan-metabolites for dietary outcomes at baseline. Ratios of tryptophan-metabolites were compared to investigate different downstream tryptophan pathways.ResultsBaseline fecal kynurenine level was significantly higher in NR compared to R for CDED + PEN (p = 0.02) and EEN (p = 0.04). ROC analysis highlighted the robust predictive power of kynurenine for CDED + PEN (area under the curve (AUC = 0.97)) and EEN (AUC = 0.88)-induced remission. RFA corroborated these observations. The ratio serotonin/kynurenine was the strongest predictor of CDED + PEN-induced remission (AUC = 1). The ratio 5-hydroxytryptophan/kynurenine (AUC = 0.88) predicted EEN-induced remission. By combining data from CDED + PEN and EEN, kynurenine (AUC = 0.91) and ratios of quinolinic acid/kynurenine (AUC = 0.93) and kynurenine/indole-3-acetic acid (AUC = 0.88) demonstrated strong predictive performance for dietary therapy-induced remission.ConclusionBaseline tryptophan metabolites have the potential to serve as a biomarker for dietary remission in pediatric CD. Some tryptophan metabolite ratios showed the most promising predictive capabilities. If confirmed in validation studies, baseline fecal tryptophan markers may be able to provide much-needed guidance to personalize dietary intervention within the management of pediatric CD.Trial registrationNCT01728870.

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

Publications

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

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