PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease

Julian Schwärzler, Lisa Mayr, Arnau Vich Vila, Felix Grabherr, Lukas Niederreiter, Maureen Philipp, Christoph Grander, Moritz Meyer, Almina Jukic, Simone Tröger, Barbara Enrich, Nicole Przysiecki, Markus Tschurtschenthaler, Felix Sommer, Irmgard Kronberger, Jakob Koch, Richard Hilbe, Michael W. Hess, Georg Oberhuber, Susanne SprungQitao Ran, Robert Koch, Maria Effenberger, Nicole C. Kaneider, Verena Wieser, Markus A. Keller, Rinse K. Weersma, Konrad Aden, Philip Rosenstiel, Richard S. Blumberg, Arthur Kaser, Herbert Tilg, Timon E. Adolph

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. Methods: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)–specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. Results: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1−/−IEC and Gpx4+/−IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. Conclusions: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.

Original languageEnglish (US)
Pages (from-to)1690-1704
Number of pages15
JournalGastroenterology
Volume162
Issue number6
DOIs
StatePublished - May 2022

Keywords

  • Endoplasmic Reticulum Stress
  • Glutathione Peroxidase 4
  • X-Box–Binding Protein 1
  • ω-3 Polyunsaturated Fatty Acids
  • ω-6 Polyunsaturated Fatty Acids

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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