Background and aim: Intestinal failure-associated liver disease (IFALD) is a clinical challenge. The pathophysiology is multifactorial and remains poorly understood. Disturbed recirculation of bile salts, e.g. due to loss of bile via an enterocutaneous fistula, is considered a major contributing factor. We hypothesize that impaired signaling via the bile salt receptor FXR underlies the development of IFALD. The aim of this study was to investigate whether activation of FXR improves liver homeostasis during chronic loss of bile in rats.
Methods: To study consequences of chronic loss of bile, rats underwent external biliary drainage (EBD) or sham surgery for seven days, and the prophylactic potential of the FXR agonist INT-747 was assessed.
Results: EBD for 7 days resulted in liver test abnormalities and histological liver damage. Expression of the intestinal FXR target gene Fgf15 was undetectable after EBD, and this was accompanied by an anticipated increase in hepatic Cyp7a1 expression, indicating increased bile salt synthesis. Treatment with INT-747 improved serum biochemistry, reduced loss of bile fluid in drained rats and prevented development of drainage-associated histological liver injury.
Conclusions: EBD results in extensive hepatobiliary injury and cholestasis. These data suggest that FXR activation might be a novel therapy in preventing liver dysfunction in patients with intestinal failure.
Relevance for patients: This study demonstrates that chronic loss of bile causes liver injury in rats. Abrogated recycling of bile salts impairing of enterohepatic bile salt/FXR signaling underlies these pathological changes, as administration of FXR agonist INT747 prevents biliary drainage-induced liver damage. Pharmacological activation of FXR might be a therapeutic strategy to treat disorders accompanied by a perturbed enterohepatic circulation such as intestinal failure-associated liver disease.
1 Department of Surgery, Maastricht University Medical Center, Maastricht University, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands
2 Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, the Netherlands
3 Department of Pathology, Maastricht University Medical Center, Maastricht, the Netherlands
4 Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands
5 Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
6 Institute for Liver and Digestive Health, University College London, London, United Kingdom
7 Department of Visceral- and Transplantation Surgery, RWTH Aachen University, Germany
Steven Olde Damink, MD, MSc, PhD
Department of Surgery, Maastricht University Medical Center, PO BOX 5800, 6202 AZ Maastricht, the Netherlands
Tel: +31 43 3881463; Fax: +31 43 3877878
Rowan van Golen
Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands