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

Gastroenterology. 2022 May;162(6):1690-1704. doi: 10.1053/j.gastro.2022.01.004. Epub 2022 Jan 12.


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.

Keywords: Endoplasmic Reticulum Stress; Glutathione Peroxidase 4; X-Box–Binding Protein 1; ω-3 Polyunsaturated Fatty Acids; ω-6 Polyunsaturated Fatty Acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crohn Disease* / drug therapy
  • Endoribonucleases
  • Enteritis* / chemically induced
  • Enteritis* / drug therapy
  • Fatty Acids, Omega-3*
  • Fatty Acids, Unsaturated
  • Humans
  • Inflammation / drug therapy
  • Mice
  • Protein Serine-Threonine Kinases
  • Toll-Like Receptor 2


  • Fatty Acids, Omega-3
  • Fatty Acids, Unsaturated
  • Toll-Like Receptor 2
  • Protein Serine-Threonine Kinases
  • Endoribonucleases