Clinical Pharmacology, Department of Medicine, Western University, 339 Windermere Rd, London, ON, N6A 5A5, Canada.
Gastroenterology, Department of Medicine, Western University, 339 Windermere Rd, London, ON, N6A 5A5, Canada.
Sci Rep. 2020 Feb 5;10(1):1866. doi: 10.1038/s41598-020-58644-w.
Bile acids are endogenous ligands of nuclear receptors pregnane X (PXR) and farnesoid X (FXR). PXR and FXR regulate pathways that are impaired in inflammatory bowel disease (IBD). Decreases in PXR and FXR activity are documented in IBD; however reasons for this are unknown. We aimed to assess the effect of Crohn's disease (CD) on the plasma bile acid composition in vivo and the resultant impact on PXR and FXR activation. A cross-sectional study evaluated the plasma concentrations of 12 bile acids in addition to 4β-hydroxycholesterol (4βOHC), an in vivo probe of the PXR target-gene cytochrome 3A4 (CYP3A4) and the FXR target-gene, fibroblast growth factor (FGF) 19 in individuals with (n = 74) and without (n = 71) CD. An in vitro model was used to assess the impact of CD-specific changes in the plasma bile acid composition on PXR and FXR activation. Decreases in glycochenodeoxycholic acid, taurocholic acid and lithocholic acid were seen in CD with increases in glycodeoxycholic acid and glycocholic acid relative to the total plasma bile acid profile. In vitro, increasing concentrations of bile acids applied in the same ratio as seen in the study cohorts resulted in decreased activation of both PXR and FXR in the CD model. In vivo, plasma 4βOHC (CD = 18.68 ng/ml ± 13.02 ng/ml, non-CD = 46.38 ng/ml ± 40.70 ng/ml, p ≤ 0.0001) and FGF19 (CD = 0.276 pg/L ± 0.189 pg/L, non-CD = 0.485 pg/L ± 0.42 pg/L, p = 0.0002) concentrations were lower in CD versus controls. Ultimately, CD-specific changes in the plasma bile acid composition lead to reduced activation of FXR and PXR target genes in vitro and in vivo.
胆汁酸是核受体孕烷 X（PXR）和法尼醇 X（FXR）的内源性配体。PXR 和 FXR 调节炎症性肠病（IBD）受损的途径。IBD 中 PXR 和 FXR 活性降低已有记载；然而，其原因尚不清楚。我们旨在评估克罗恩病（CD）对体内胆汁酸组成的影响，以及对 PXR 和 FXR 激活的影响。一项横断面研究评估了 12 种胆汁酸以及 4β-羟胆固醇（4βOHC）在有（n=74）和没有（n=71）CD 的个体中的血浆浓度，4βOHC 是 PXR 靶基因细胞色素 3A4（CYP3A4）和 FXR 靶基因成纤维细胞生长因子（FGF）19 的体内探针。体外模型用于评估 CD 特异性改变血浆胆汁酸组成对 PXR 和 FXR 激活的影响。与总血浆胆汁酸谱相比，CD 中甘氨鹅脱氧胆酸、牛磺胆酸和石胆酸减少，而甘脱氧胆酸和甘胆酸增加。在体外，以研究队列中所见的相同比例应用胆汁酸浓度增加导致 CD 模型中 PXR 和 FXR 的激活降低。在体内，与非 CD 相比，血浆 4βOHC（CD=18.68ng/ml±13.02ng/ml，非 CD=46.38ng/ml±40.70ng/ml，p≤0.0001）和 FGF19（CD=0.276pg/L±0.189pg/L，非 CD=0.485pg/L±0.42pg/L，p=0.0002）浓度在 CD 中较低。最终，CD 特异性改变血浆胆汁酸组成导致体外和体内 FXR 和 PXR 靶基因的激活降低。
