Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial.

Background The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. Objective We evaluated effect of glepaglutide, a long-acting glucagon-like peptide-2 analog, on bile acid synthesis, the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS. Design In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to two of three treatment arms (0.1, 1 and 10 mg) with daily subcutaneous injections of glepaglutide for three weeks. The wash-out period between the two treatment periods was four to eight weeks. Measurements were performed at baseline and at the end of each treatment period and included: Postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids and liver biochemistry. Results Compared to baseline, the median (IQR) postprandial response (AUC0-2h ) of FGF19 increased by 150 h×ng/L (41, 195;P = 0.001) and C4 decreased by 82 h×μg/L (-169, -28;P = 0.010) in the 10 mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. Conclusions Glepaglutide may stimulate the bile acid-FXR-FGF19 axis leading to increased plasma concentrations of FGF19. Thereby glepaglutide may ameliorate the accelerated de-novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease. This article is protected by copyright. All rights reserved.