Emma C.E. Meessen1, Soumia Majait2, Ümran Ay3,4, Steven W. Olde Damink3,4,, Johannes A. Romijn5, Jens J. Holst6,7, Bolette Hartmann6,7, Folkert Kuipers8,9 , Max Nieuwdorp10, Frank G. Schaap3,4, Albert K. Groen10, E. Marleen Kemper 2,10 and Maarten R. Soeters1*

1Department of Endocrinology and Metabolism, Amsterdam University Medical Centres, Amsterdam, The Netherlands. 2Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. 3Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, The Netherlands. 4Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Germany. 5Department of Internal Medicine, Amsterdam University Medical Centres – location AMC, University of Amsterdam, Amsterdam, The Netherlands. 6Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 7Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 8Department of Paediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 9European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 10Department of (Experimental) Vascular Medicine, Amsterdam University Medical Centres – location AMC, University of Amsterdam, Amsterdam, The Netherlands.

E-mail address: e.c.meessen@amsterdamumc.nl

Background: Bile acids play vital roles in control of lipid-, glucose-, and energy metabolism by activating Takeda G protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR), the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation, e.g. of chenodeoxycholic acid (CDCA) for gallstone dissolution, has been reported to have adverse effects.

Methods: In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in two groups of each 10 healthy lean men respectively.

Results: GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids CDCA and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid-, glucose-, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events.

Discussion/Conclusion: GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose- and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.