Abstract
BackgroundInfectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis.MethodsExperimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs.ResultsIn wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology.ConclusionWe found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon.
Highlights
Acute pancreatitis (AP) is the acute inflammation of the pancreas, and is mostly caused by gallstones or alcohol abuse [1]
Because of its role in intestinal barrier function, i.e. prevention of bacterial translocation and modulation of inflammation, we hypothesized that farnesoid X receptor (FXR) might play an important role in AP
Failure of the intestinal barrier plays an important role in human acute pancreatitis, because it facilitates bacterial translocation which can lead to infectious complications
Summary
Acute pancreatitis (AP) is the acute inflammation of the pancreas, and is mostly caused by gallstones or alcohol abuse [1]. Failure of the intestinal barrier function plays a critical role, as it allows for bacterial translocation, facilitating such infectious complications [5,6,7,8]. The intracellular bile salt receptor farnesoid X receptor (FXR) is mainly expressed in ileum and liver, and to some extent in other organs, such as the pancreas [9], with little information available on its function in the latter organ. Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-kB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. A genetic association study in 387 acute pancreatitis patients and 853
Sign-in/Register to view highlights & summary 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.
