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 Sprung, Qitao 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
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Gastroenterology (New York, N.Y. 1943)
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<h4>Background & aims</h4>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 IBD remains elusive. Here, we aimed at delineating how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, impacts gut inflammation and disease course. We hypothesized that the unfolded protein response and anti-oxidative activity of Glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs.<h4>Methods</h4>We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in two 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 findings to human CD epithelial organoids and correlated PUFA intake, estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in two independent CD cohorts.<h4>Results</h4>PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1<sup>-/-IEC</sup> and in Gpx4<sup>+/-IEC</sup> mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor IRE1α by toll-like receptor 2 (TLR2) sensing of oxygen 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.<h4>Conclusion</h4>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.