FXR deletion attenuates intestinal barrier dysfunction in murine acute intestinal inflammation.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI:10.1152/ajpgi.00063.2024
MaKayla L O'Guinn, David A Handler, Jonathan J Hsieh, Michael U Mallicote, Karina Feliciano, Christopher P Gayer
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Abstract

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)/Klebsiella, 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 Il1a, Il1b, and Tnf. 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.NEW & NOTEWORTHY 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.

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FXR缺失可减轻小鼠急性肠炎的肠屏障功能障碍
不断积累的文献表明,法尼类固醇-X 受体(FXR)是一种核胆汁酸受体,因其在胆汁酸平衡中的作用而最为人熟知,它也是炎症的一种有效的环境依赖性调节因子。因此,FXR 可能与炎症性肠病、坏死性小肠结肠炎和败血症等多种肠道疾病相关。在这项研究中,我们测试了 FXR 缺失对小鼠急性肠道炎症的影响。我们发现,FXR 基因敲除(KO)小鼠对 LPS 注射、双硫仑/克雷伯氏菌和盲肠结扎/穿刺模型诱发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大幅减少有关,包括较低的组织 Il1a、Il1b 和 Tnf 水平。在研究对上皮细胞的功能性影响时,我们发现 FXR KO 动物体内 ZO-1 和闭塞素的内化可评估 LPS 诱导的紧密连接破坏。综上所述,这些数据表明 FXR 在炎症损伤期间对肠屏障的作用。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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