The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States.
Division of Pediatric Surgery, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, United States.
Am J Physiol Gastrointest Liver Physiol. 2024 Aug 1;327(2):G175-G187. doi: 10.1152/ajpgi.00063.2024. Epub 2024 Jun 11.
Accumulating literature suggests that the farnesoid-X receptor (FXR), a nuclear bile acid receptor best known for its role in bile acid homeostasis, is also a potent context-dependent regulator of inflammation. FXR may thus be relevant to several intestinal disease states including inflammatory bowel disease, necrotizing enterocolitis, and sepsis. In this study, we tested the effects of FXR deletion on acute murine intestinal inflammation. We found that FXR knockout (KO) mice were protected from intestinal injury and barrier dysfunction induced by lipopolysaccharide (LPS) injection, dithizone (DI)/, and cecal ligation/puncture models. In the LPS model, RNA sequencing and qPCR analysis showed that this protection correlated with substantial reduction in LPS-induced proinflammatory gene expression, including lower tissue levels of , , and . Examining functional effects on the epithelium, we found that LPS-induced tight junctional disruption as assessed by internalization of ZO-1 and occludin was ameliorated in FXR KO animals. Taken together, these data suggest a role for FXR in the intestinal barrier during inflammatory injury. Intestinal barrier failure is a hallmark in gut-origin sepsis. We demonstrate that the intestinal barriers of farnesoid-X receptor (FXR) knockout (KO) animals are protected from inflammatory insult using multiple models of acute intestinal inflammation. This protection is due to decreased inflammatory cytokine production and maintenance of tight junctional architecture seen within the KO animals. This is the first report of FXR deletion being protective to the intestinal barrier.
越来越多的文献表明，法尼醇 X 受体（FXR）是一种核胆汁酸受体，以其在胆汁酸稳态中的作用而闻名，它也是炎症的一种强有力的、依赖于背景的调节因子。因此，FXR 可能与几种肠道疾病状态有关，包括炎症性肠病、坏死性小肠结肠炎和脓毒症。在这项研究中，我们测试了 FXR 缺失对急性肠道炎症的影响。我们发现，FXR 敲除（KO）小鼠对脂多糖（LPS）注射、二硫代氨基甲酸盐（DI）/和盲肠结扎/穿刺模型诱导的肠道损伤和屏障功能障碍具有保护作用。在 LPS 模型中，RNA 测序和 qPCR 分析表明，这种保护与 LPS 诱导的促炎基因表达的显著减少相关，包括组织水平降低的 、 和 。研究对上皮细胞的功能影响，我们发现 LPS 诱导的紧密连接破坏（通过 ZO-1 和 occludin 的内化来评估）在 FXR KO 动物中得到改善。综上所述，这些数据表明 FXR 在炎症损伤期间在肠道屏障中发挥作用。肠道屏障衰竭是肠道起源性脓毒症的一个标志。我们证明，使用多种急性肠道炎症模型，法尼醇 X 受体（FXR）敲除（KO）动物的肠道屏障免受炎症损伤。这种保护是由于 KO 动物中炎症细胞因子产生减少和紧密连接结构的维持。这是第一个报道 FXR 缺失对肠道屏障具有保护作用的报告。
