Wuxi School of Medicine, Jiangnan University, Wuxi, China; Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, China.
School of Food Science and Technology, Jiangnan University, Wuxi, China.
EBioMedicine. 2022 Jun;80:104060. doi: 10.1016/j.ebiom.2022.104060. Epub 2022 May 16.
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.
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.
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.
FFAR4 deletion attenuates colitis by modulating Treg cells via the ZBED6-IL33 pathway.
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.
炎症性肠病（IBD）具有复杂的遗传和环境方面，游离脂肪酸受体（FFARs）可能连接遗传和饮食方面。FFAR4 在肠道中高度表达，主要作为长链脂肪酸的受体，长链脂肪酸是人类饮食的主要成分。FFAR4 在 IBD 中可能发挥什么作用尚不清楚。
使用鼠和人结肠炎样本、完全 FFAR4 敲除小鼠、肠道特异性 FFAR4 敲除和 FFAR4 过表达小鼠以及细胞培养物进行研究。进行 RNA 测序分析和流式细胞术以检查机制。
结果表明，FFAR4 表达在上皮细胞中上调，肠道 FFAR4 的缺失可改善结肠炎，而肠道 FFAR4 的过表达则加剧了疾病。我们通过上调 ZBED6 鉴定了 FFAR4 在肠上皮细胞中的缺失，ZBED6 反过来诱导 L33 转录，L33 增加了 Treg 细胞数量，从而改善了结肠炎。
FFAR4 缺失通过 ZBED6-IL33 途径调节 Treg 细胞来减轻结肠炎。
国家自然科学基金、无锡科技医学和公共卫生技术创新应用项目、中央高校基本科研业务费基金和无锡市卫生健康委员会基金。
