Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease

Abstract

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western lifestyle. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.

Ferroptosis: molecular mechanisms and health implications

“…72,186 The heterozygous knockout of GPX4 in intestinal epithelial cells increases the inflammatory bowel disease (IBD) in mice caused by a PUFA-rich Western diet (containing 10% fish oil with omega-3 and omega-6 PUFAs). 59 The inhibition of ferroptosis by liproxstatin-1 and rosiglitazone (an ACSL4 inhibitor) also reduces intestinal I/R injury. 92 It remains to be seen whether chronic inflammation mediated by ferroptosis is related to colon cancer.…”

Oxidative Damage and Antioxidant Defense in Ferroptosis

“…et al, 2018;Hirata et al, 2019), although oxytosis has long been considered to be the main mode leading to neuronal cell damage caused by glutamate toxicity (Tan et al, 2001). Inflammation mediated by ferroptotic cell death can promote pancreatitis (Liu et al, 2020d), liver fibrosis (Tsurusaki et al, 2019;Zeng et al, 2020), chronic obstructive pulmonary disease (COPD) (Park et al, 2019;Wang and Tang, 2019;Yoshida et al, 2019), inflammatory bowel disease (Mayr et al, 2020), and preeclampsia (Zhang et al, 2020). In addition, inhibiting ferroptosis can prevent I/R damage to various tissues, especially liver, kidney, brain, and heart (Linkermann et al, 2014;Skouta et al, 2014;Martin-Sanchez et al, 2017;Muller et al, 2017;Fang et al, 2019).…”

Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia‐reperfusion

“…8 Knockout or inactivation of GPX4 loses the capacity of inhibiting the lethal lipid peroxidation in phospholipid bilayers and resulted in cell death. [9][10][11] Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), could be catalyzed and esterified to produce oxidized phosphatidylethanolamines (PE) during ferroptosis. [12][13][14] However, the specific mechanism of how lipid peroxidation contributes to ferroptotic damage is yet to be understood.…”

“…The execution of ferroptosis depends on the overwhelming lipid peroxidation produced enzymatically or non‐enzymatically, which could be reduced by a lipid repair enzyme called glutathione peroxidase 4 (GPX4) 8 . Knockout or inactivation of GPX4 loses the capacity of inhibiting the lethal lipid peroxidation in phospholipid bilayers and resulted in cell death 9‐11 . Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), could be catalyzed and esterified to produce oxidized phosphatidylethanolamines (PE) during ferroptosis 12‐14 .…”