多不饱和脂肪酸或加重克罗恩病
创作:Bingbing 审核:Bingbing 02月01日
  • 添加多不饱和脂肪酸(PUFA)的西式饮食强力诱导了内质网应激,驱动了Xbp1−/−IEC 和Gpx4+/−IEC小鼠的小肠炎;
  • ω-3和ω-6 PUFA通过Toll样受体2(TLR2)激活小肠上皮细胞内质网感受器IRE1α,TLR2调控的IRE1α活性控制PUFA诱导的趋化因子产生与肠炎;
  • 在活动期克罗恩病(CD)患者中,ω-3和ω-6 PUFA驱动小肠上皮细胞趋化因子的表达,血浆中呈现相应的炎症压力特征;
  • CD患者中,PUFA摄入量与临床和生化疾病活性有关。
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Bingbing
克罗恩病(CD)与西式生活习惯有关。本文重点关注西式饮食中的PUFA与CD的相关性。研究结果显示,PUFA可能引发代谢性肠炎,进而加重CD。
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Gastroenterology [IF:33.883]

PUFA-induced metabolic enteritis as a fuel for Crohn‘s disease

PUFA诱导的代谢性小肠炎加重克罗恩病

10.1053/j.gastro.2022.01.004

01-11, Article

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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 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.
Methods: 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.
Results: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1−/−IEC and in Gpx4+/−IEC 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.
Conclusion: 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.

First Authors:
Julian Schwärzler,Lisa Mayr,Arnau Vich Vila

Correspondence Authors:
Timon E Adolph

All Authors:
Julian Schwärzler,Lisa Mayr,Arnau Vich Vila,Felix Grabherr,Lukas Niederreiter,Maureen Philipp,Christoph Grander,Moritz Meyer,Almina Jukic,Simone Tröger,Barbara Enrich,Nicole Przysiecki,Markus Tschurtschenthaler,Felix Sommer,Irmgard Kronberger,Jakob Koch,Richard Hilbe,Michael W Hess,Georg Oberhuber,Susanne Sprung,Qitao Ran,Robert Koch,Maria Effenberger,Nicole C Kaneider,Verena Wieser,Markus A Keller,Rinse K Weersma,Konrad Aden,Philip Rosenstiel,Richard S Blumberg,Arthur Kaser,Herbert Tilg,Timon E Adolph

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