Dietary-derived ω-3 and ω-6 polyunsaturated fatty acids induce metabolic enteritis as a fuel of Crohn’s disease

Introduction The incidence of Crohn’s disease (CD) has increased drastically in recent years, which is mainly explained by environmental factors and changes in our diet. A Western-style diet, characterized by increased consumption of sugars and fats such as polyunsaturated fatty acids (PUFAs), triggers inflammation in metabolically active tissues, termed metabolic inflammation However, a non-toxic dietary component driving gut inflammation hasn’t been identified yet. Here, we demonstrate how ω-3 and ω-6 PUFAs fuel intestinal inflammation and assessed the implication of PUFA-consumption on human CD.

Methods An intestinal epithelial cell (IEC) line (termed MODE-K) was used for in vitro experiments. Gpx4^+/-IEC, Xbp1^-/-IEC and Ern1^-/-IEC /Gpx4^+/-IEC (IRE1α-knockout) mice were fed a Western diet enriched with ω-3 and ω-6 PUFAs for three months. In a CD cohort comprising 160 patients the relation between PUFA-intake (estimated by a dietary questionnaire) and the clinical disease course over an observation period of ~5 years was assessed.

Results ω-3 and ω-6 PUFAs trigger chemokine production in IECs and drive intestinal inflammation in mice, which is limited by the anti-oxidative enzyme Glutathione peroxidase 4 (GPX4) and X-box binding protein 1 (XBP1). PUFAs are incorporated into cellular membranes at the endoplasmic reticulum (ER), where they are targeted for oxidation. This causes ER stress and induction of the unfolded protein response (UPR) in IECs, which is similarly observed in PUFA-induced enteritis. Activation of the UPR and specifically IRE1α drives enteritis dependent on JNK-signalling. In CD, ~50 % of patients display a serum signature comprising lipid peroxidation, ER stress and chemokines. Furthermore, dietary PUFA-intake correlates with longitudinal disease activity and severity.

Conclusions We demonstrate how PUFAs fuel gut inflammation mimicking metabolic inflammation by analysing IECs, transgenic mice, and a CD patient cohort. As such, we identify a non-toxic dietary constituent as driver of inflammation in human CD, providing a basis for targeted nutritional therapy.

Publication History

Article published online:
01 September 2021