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. 2020 Feb 5;10(1):1866.
doi: 10.1038/s41598-020-58644-w.

"VSports最新版本" Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn's disease

Aze Wilson  1   2   3 , Ahmed Almousa  4 , Wendy A Teft  4 , Richard B Kim  4   5
Affiliations

"V体育2025版" Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn's disease

"VSports最新版本" Aze Wilson et al. Sci Rep. .

Abstract (VSports注册入口)

Bile acids are endogenous ligands of nuclear receptors pregnane X (PXR) and farnesoid X (FXR) VSports手机版. 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. .

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The ratio of the plasma concentration of conjugated to unconjugated bile acids stratified by cohort (control, active CD, inactive CD). The 95%CI is represented by the vertical T-line. *p < 0.05; **p < 0.01; ***p < 0.001. Crohn’s disease, CD.
Figure 2
Figure 2
Effect of known bile acid agonists on CYP3A4-pGL3 basic reporter (light grey bars) or BSEP-pGL3 basic reporter (dark grey bars) activity in HepG2 cells co-transfected with hPXR or hFXR respectively or a vector control. In addition to 0.1%DMSO, one of DCA, LCA, or GDCA (10 µM) were incubated with cells for 24 hours as positive controls to validate the PXR-CYP3A4. Similarly, one of GCDCA, LCA or CDCA (10 µM) was incubated with cells for 24 hours as positive controls to validate the FXR-BSEP. Data are presented relative to the vector control. Data are presented as mean ± SEM. Three independent experiments were performed for each model. Deoxycholic acid, DCA; lithocholic acid, LCA; glycodeoxycholic acid, GDCA; glycochenodeoxycholic acid, GCDCA; lithocholic acid, LCA; chenodeoxycholic acid, CDCA; Crohn’s disease, CD; dimethyl sulfoxide, DMSO; pregnane X receptor, PXR; farnesoid X receptor, FXR; cytochrome p450, CYP; bile salt export pump, BSEP; pGL3, luciferase; hepatocarcinoma, Hep; human, h; standard error of the mean, SEM.
Figure 3
Figure 3
Effect of patient-derived plasma bile acid profiles on CYP3A4-pGL3 basic reporter (white bars) or BSEP-pGL3 (grey bars) basic reporter activity in HepG2 cells co-transfected with hPXR or hFXR respectively or a vector control. Bile acid profiles in increasing concentrations (Panel A, 25 µM; Panel B, 50 µM; Panel C, 75 µM) representative of inactive or active CD or a healthy population were incubated with cells for 24 hours. Data are presented relative to the vector control. Data are presented as mean ± SEM. Different letters represent statistically significant differences among groups. Three independent experiments were performed for each model. Crohn’s disease, CD; pregnane X receptor, PXR; cytochrome p450, CYP; farnesoid X receptor, FXR; bile salt export pump, BSEP; pGL3, luciferase; hepatocarcinoma, Hep; human, h; standard error of the mean, SEM.
Figure 4
Figure 4
The mean 4βOHC plasma concentrations for subjects with active and inactive Crohn’s disease (CD) as well as non-CD controls. Median values (thick horizontal line), 25th and 75th percentile values (box outline), minimum and maximum values (whiskers), and outlier values (circles). *p < 0.05; **p < 0.01; ***p < 0.001. 4β-hydroxycholesterol, 4βOHC.
Figure 5
Figure 5
The mean FGF19 plasma concentrations for subjects with active and inactive Crohn’s disease (CD) as well as non-CD controls. Median values (thick horizontal line), 25th and 75th percentile values (box outline), minimum and maximum values (whiskers), and outlier values (circles). *p < 0.05; **p < 0.01; ***p < 0.001. Fibroblast growth factor 19, FGF19.
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