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

Abstract

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. 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).

METHOD:

In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 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 with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) 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.

CONCLUSION:

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.

• Authors: Mark Krogh Hvistendahl, Rahim Mohammad Naimi, Svend Høime Hansen, Jens Frederik Rehfeld, Hannelouise Kissow, Jens Pedersen, Lars Ove Dragsted, David Peick Sonne, Filip Krag Knop, Palle Bekker Jeppesen
• Journal: JPEN. Journal of parenteral and enteral nutrition (JPEN J Parenter Enteral Nutr) Vol. 46 Issue 4 Pg. 923-935 (05 2022) ISSN: 1941-2444 [Electronic] United States
• PMID: 34287979 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Society for Parenteral and Enteral Nutrition.

Chemical References

• Bile Acids and Salts
• Glucagon-Like Peptide 2
• Fibroblast Growth Factors

Topics

• Bile Acids and Salts (metabolism)
• Fibroblast Growth Factors (metabolism)
• Glucagon-Like Peptide 2 (pharmacology)
• Humans
• Liver
• Short Bowel Syndrome (pathology)