Metabolic stress sensing by epithelial RXRα links westernization of diet with Crohn’s disease

Westernization of diet, partly characterized by long-chain fatty acid excess, perturbs intestinal immune responses in Crohn's disease (CD). The cellular and molecular framework of lipid sensing in intestinal inflammation remains enigmatic. By small intestinal transcriptional profiling of CD, we identified increased transcriptional activity of retinoid X receptor alpha (RXRα) specifically in intestinal epithelial cells (IECs). Transcriptional RXRα activity was induced in IECs of mice by ω-3 and ω-6 polyunsaturated fatty acid (PUFA) excess in a Western diet. PUFA-induced RXRα activity in Paneth cells governed chronic transmural enteritis by enabling the expression of CXCL1. Oral exposure to isotretinoin ameliorated PUFA-induced metabolic enteritis in two mouse models, and isotretinoin therapy reduced the odds of developing CD in an analysis of electronic health care records from 170,597 patients. Collectively, we identify RXRα in Paneth cells as a metabolic stress sensor that enables enteritis, providing novel perspectives for the prevention and treatment of CD.