Epithelial RXRa activity induced by Westernization of diet instigates enteritis in Crohn's disease

Westernization of diet, partly characterised by excess of long-chain fatty acids, provides a risk for developing Crohn's disease (CD), and perturbs the function of specialized intestinal epithelium termed Paneth cells. The lack of a cellular and molecular framework of lipid sensing in intestinal inflammation poses a constraint to understanding detrimental effects of Western diets. Here, we report how Paneth cell sensing of lipid excess in a Western diet is translated into CD-like intestinal inflammation. Small intestinal transcriptional profiling of CD patients from three independent cohorts identified increased activity of the transcription factor retinoid x receptor alpha (RXRa) specifically in intestinal epithelium. Intestinal epithelial RXRa activity was induced by polyunsaturated fatty acid (PUFA) excess in a Western diet in mice with CD-like enteritis. PUFA-induced RXRa activity in Paneth cells governed chronic transmural enteritis by enabling the expression of the interleukin 8 homologue CXCL1. Blockade of PUFA-induced RXRa activity by 9-cis retinoic acid ameliorated CXCL1 production and enteritis, and patients receiving isotretinoin therapy (a precursor for 9-cis retinoic acid) displayed reduced odds of developing CD. Collectively, we identify Paneth cells as gatekeepers of lipid stress that exploit RXRa to sense and translate PUFA excess into enteritis, which could be targeted to prevent or treat CD. Overall design: Bulk RNA-seq profiling of siGpx4 (n=3) vs siCtrl MODE-K IECs (n=3) stimulated with arachidonic acid (AA) for 8 hours or with the omega-3 PUFA docosahexaenoic acid (DHA), and single-cell RNA-seq profiling of WT (n=3) and Gpx4+/-IEC mice (n=4) fed with a PUFA enriched Western diet for 3 months.