Department of Gastroenterology and Hepatology, UMC Utrecht, The Netherlands.
Gut. 2011 Apr;60(4):463-72. doi: 10.1136/gut.2010.212159. Epub 2011 Jan 17.
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models.
Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types.
INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD.
FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.
炎症性肠病（IBD）的特征是慢性肠道炎症，这是由于黏膜免疫系统失调和肠道上皮屏障功能受损所致。核法尼醇 X 受体（FXR）是一种胆汁盐受体，最近被认为与肠道抗菌防御和屏障功能有关。本研究旨在通过体内和体外补充模型来研究 FXR 激动剂治疗肠道炎症的潜在作用。
使用葡聚糖硫酸钠诱导野生型（WT）和 Fxr 基因敲除（KO）小鼠结肠炎，并用三硝基苯磺酸诱导 WT 小鼠结肠炎。用载体或 FXR 激动剂 INT-747 处理小鼠，每天评估结肠炎症状。用 INT-747 处理鼠结肠和肠上皮样细胞（Caco-2/HT29），进行上皮通透性测定和细胞因子表达分析。通过 ELISA 法检测各种人免疫细胞类型中炎性细胞因子的分泌。
用 INT-747 处理的 WT 小鼠可预防 DSS 和 TNBS 诱导的结肠炎，表现在体重减轻、上皮通透性、直肠出血、结肠缩短、溃疡、炎症细胞浸润和杯状细胞丢失等方面有显著改善。此外，WT 小鼠和分化的肠上皮样细胞中 Fxr 的激活下调了关键促炎细胞因子的表达，并维持了上皮屏障功能。INT-747 可显著减少激活的人外周血单核细胞、纯化的 CD14 单核细胞和树突状细胞以及 IBD 患者的黏膜固有层单核细胞中肿瘤坏死因子-α的分泌。
FXR 的激活可预防化学诱导的肠道炎症，改善结肠炎症状，抑制上皮通透性，并减少杯状细胞丢失。此外，FXR 的激活可抑制体内（在鼠结肠黏膜中）和体外（在不同免疫细胞群中）的促炎细胞因子的产生。这些发现为探索 FXR 激动剂作为治疗 IBD 的新策略提供了依据。
