Year of publication:
2022
Volume:
-
Issue:
-
Issn:
0016-5085
Journal title abbreviated:
GASTROENTEROLOGY
Journal title long:
Gastroenterology (New York, N.Y. 1943)
Impact factor:
33.883
Pubmed:
Abstract:
<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.