Free fatty acid receptor 4 deletion attenuates colitis by modulating Treg Cells via ZBED6-IL33 pathway

BACKGROUND: Inflammatory bowel disease (IBD) has complex genetic and environmental aspects, and free fatty acid receptors (FFARs) may bridge genetic and dietary aspects. FFAR4 is highly expressed in the intestine and acts primarily as the receptor of long-chain fatty acids, which are major components of the human diet. It is unclear what role, if any, FFAR4 may play in IBD. METHODS: Mouse and human colitis samples, mice with complete FFAR4 knockout, intestine-specific FFAR4 knockout and FFAR4 overexpression and cell culture were used. RNA-sequencing analysis and flow cytometry were performed to examine the mechanisms. FINDINGS: The results showed that FFAR4 expression was upregulated in colitis tissues and that the loss of intestinal FFAR4 ameliorated colitis, whereas intestinal FFAR4 overexpression exacerbated the disease. We identified intestinal epithelial cell deletion of FFAR4 by upregulating ZBED6, which in turn induced L33 transcription, and L33 elevated Treg cell numbers, ameliorating colitis. INTERPRETATION: FFAR4 deletion attenuates colitis by modulating Treg cells via the ZBED6-IL33 pathway. FUNDING: National Natural Science Foundation of China, Innovation and Application Project of Medical and Public Health Technology of Wuxi Science and Technology, Fundamental Research Funds for the Central Universities and the Fund of Wuxi Healthcare Commission.