期刊
GASTROENTEROLOGY
卷 162, 期 6, 页码 1690-1704出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2022.01.004
关键词
Glutathione Peroxidase 4; X-Box-Binding Protein 1; omega-3 Polyunsaturated Fatty Acids; omega-6 Polyunsaturated Fatty Acids; Endoplasmic Reticulum Stress
资金
- European Research Council [101039320]
- Austrian Science Fund [FWF P33070]
- European Crohn's and Colitis Organisation
- Excellence Initiative (Competence Centers for Excellent Technologies) of the Austrian Research Promotion Agency FFG: Research Center of Excellence in Vascular Ageing Tyrol
- VASCage - BMVIT [843536]
- BMWFW
- Wirtschaftsagentur Wien
- Standortagentur Tirol
- Austrian Society of Gastroenterology and Hepatology
- IMI2 grant ImmUniverse
- BMBF [01ZX1915A]
- Seerave Foundation
- TIMID project - PPP allowance by Top Sector Life Sciences and Health [LSHM18057-SGF]
- SGF
- Takeda Pharmaceuticals
- National Institutes of Health [NIH NIDDK R01DK088199]
- Medical University of Innsbruck [2020-01-017]
- Tiroler Wissenschaftsforderung
- [SO1141/101]
- [FOR5042]
- [CRC1182]
- [395357507]
- European Research Council (ERC) [101039320] Funding Source: European Research Council (ERC)
This study provides evidence that excessive intake of polyunsaturated fatty acids (PUFAs) in a Western diet can induce gut inflammation and worsen the course of Crohn's disease (CD). The findings suggest a potential role for targeted nutritional therapy.
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 1 alpha (IRE1 alpha) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1 alpha 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.
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