| First Author | Schwärzler J | Year | 2022 |
| Journal | Gastroenterology | Volume | 162 |
| Issue | 6 | Pages | 1690-1704 |
| PubMed ID | 35031299 | Mgi Jnum | J:324251 |
| Mgi Id | MGI:7266221 | Doi | 10.1053/j.gastro.2022.01.004 |
| Citation | Schwarzler J, et al. (2022) PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease. Gastroenterology 162(6):1690-1704 |
| abstractText | 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. omega-3 and omega-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1alpha (IRE1alpha) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1alpha activity governed PUFA-induced chemokine production and enteritis. In active human CD, omega-3 and omega-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. |
