Abstract
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.
Highlights
Bile acids are a collection of dynamic “acidic steroids”, produced by the liver[1]
Limited data exploring the link between inflammatory bowel disease (IBD) pathogenesis and nuclear receptors suggest that PXR and FXR activity are repressed in IBD, providing a plausible mechanism for the dysregulation of such processes[20,21,22,23]
Significant differences in the composition of the bile acid profile were seen based on presence or absence of Crohn’s disease (CD)
Summary
Bile acids are a collection of dynamic “acidic steroids”, produced by the liver[1]. In health, physiologic concentrations of bile acids differ amongst the various compartments with the highest concentrations seen in the gallbladder (300 mmol/L) with decreasing concentrations in the hepatic canaliculi (20–50 mmol/L) and intestine (10 mmol/L)[2]. The role of bile acids in vivo extends beyond simple lipid absorption and metabolism and encompasses several key physiologic processes paramount to humans These include regulation of xenobiotic exposure and drug metabolism, inflammatory pathways, and intestinal barrier function, mediated mainly through master regulators and transcription factors known as nuclear receptors[3,4,5,6]. PXR, known as the steroid and xenobiotic-sensing nuclear receptor, plays an important role in the “detoxification” of the human body[3] It is activated by a variety of endogenous and exogenous compounds, including bile acids. Differences in bile acid synthesis or metabolism may be an underappreciated determinant of nuclear receptor signaling in IBD and may play a role in intestinal inflammation as alluded to by Pavlidis et al (2015) in a comprehensive review of the topic[26]. We sought to assess the effect of CD presence and activity on the plasma bile acid profile in vivo and the resultant impact on the activation of PXR and FXR target genes in vitro and in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
