TY - JOUR
T1 - PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease
AU - Schwärzler, Julian
AU - Mayr, Lisa
AU - Vich Vila, Arnau
AU - Grabherr, Felix
AU - Niederreiter, Lukas
AU - Philipp, Maureen
AU - Grander, Christoph
AU - Meyer, Moritz
AU - Jukic, Almina
AU - Tröger, Simone
AU - Enrich, Barbara
AU - Przysiecki, Nicole
AU - Tschurtschenthaler, Markus
AU - Sommer, Felix
AU - Kronberger, Irmgard
AU - Koch, Jakob
AU - Hilbe, Richard
AU - Hess, Michael W.
AU - Oberhuber, Georg
AU - Sprung, Susanne
AU - Ran, Qitao
AU - Koch, Robert
AU - Effenberger, Maria
AU - Kaneider, Nicole C.
AU - Wieser, Verena
AU - Keller, Markus A.
AU - Weersma, Rinse K.
AU - Aden, Konrad
AU - Rosenstiel, Philip
AU - Blumberg, Richard S.
AU - Kaser, Arthur
AU - Tilg, Herbert
AU - Adolph, Timon E.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
KW - Endoplasmic Reticulum Stress
KW - Glutathione Peroxidase 4
KW - X-Box–Binding Protein 1
KW - ω-3 Polyunsaturated Fatty Acids
KW - ω-6 Polyunsaturated Fatty Acids
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UR - http://www.scopus.com/inward/citedby.url?scp=85126287761&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2022.01.004
DO - 10.1053/j.gastro.2022.01.004
M3 - Article
C2 - 35031299
AN - SCOPUS:85126287761
SN - 0016-5085
VL - 162
SP - 1690
EP - 1704
JO - Gastroenterology
JF - Gastroenterology
IS - 6
ER -