Polyunsaturated fatty acids in a Western diet trigger TLR2-dependent Crohn’s-like enteritis in mice

Introduction Westernisation of diet is suspected to contribute to a rising incidence of inflammatory bowel diseases across the globe, while specific macronutrients that would trigger gut inflammation remain largely elusive. We recently demonstrated that Crohn’s disease (CD) patients exhibit impaired activity of the antioxidative enzyme glutathione peroxidase 4 (GPX4) specifically in intestinal epithelial cells. Mice lacking one allele of Gpx4 in the intestinal epithelium develop a Crohn’s-like enteritis after dietary challenge with a Western diet enriched with polyunsaturated fatty acids (PUFA). Here, we illustrate how PUFAs evoke gut inflammation in the context of impaired epithelial GPX4 activity.

Methods We studied immortalized intestinal epithelial cells (IECs), namely MODE-K IECs, with reduced Gpx4 expression or genetically impaired enzymatic GPX4 activity. To translate the identified mechanism to mice, we generated double mutant mice that lack one allele of Gpx4 in IECs and both alleles of toll-like receptor 2 and exposed these mice (and respective controls) to a PUFA-enriched Western diet for 3 months. Gut inflammation was analysed biochemically and histologically.

Results GPX4 enzymatic activity restricts PUFA-induced lipid peroxidation and accumulation of oxygen specific epitopes (i.e. stress related by-products). Lipid peroxidation and oxygen specific epitopes triggered toll-like receptor 2 activation and downstream MAPK signalling, which drives the production of chemokines in GPX4-deficient IECs upon ω-3 and ω-6 PUFA exposure. Likewise, TLR2 co-deletion in Gpx4^+/-IECs mice protected against Crohn’s-like gut inflammation evoked by a PUFA-enriched Western diet, similar to pharmacologic inhibition of MAPK signalling or blockade of the IL-8 pathway.

Conclusion We identify a mechanism of PUFA-induced gut inflammation in mammals, highlighting a pivotal role for GPX4-restricted lipid peroxidation as driver of TLR2 activity in intestinal epithelial cells. Our findings may set the basis for targeted nutritional therapy in CD.

Publication History

Article published online:
01 September 2021