Glycodeoxycholic Acid Inhibits Primary Bile Acid Synthesis With Minor Effects on Glucose and Lipid Homeostasis in Humans

Abstract

Background: Bile acids play vital roles in control of lipid, glucose, and energy metabolism by activating Takeda G protein-coupled receptor 5 and Farnesoid X receptor, 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 (eg, of chenodeoxycholic acid for gallstone dissolution) has been reported to have adverse effects.

Study design: 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 2 groups of each 10 healthy lean men, respectively.

Main findings: GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids chenodeoxycholic acid 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.

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.

Keywords: Farnesoid X receptor; Takeda G protein-coupled receptor 5; bile acids; glucagon-like peptide 1; glycodeoxycholic acid; humans; metabolic diseases.

Figure 1.

Flowchart of study inclusion and exclusion. Overview of the included and excluded participants and the assignment to GDCA administration via regular or slow-release capsules.

Figure 2.

Postprandial bile acid, FGF19, and C4 responses measured at baseline, day 15, and day 31 after the start of GDCA administration in regular (A, B and C) and slow-release capsules (D, E and F). Data are presented as mean ± SEM. *P ≤ .05, **P < .01, ***P < .001 at day 15 assessed with mixed-effect models for TBA and FGF19 at day 31 assessed with mixed-effect models and post hoc multiple comparisons (baseline vs day 15), or with 1-way repeated measures ANOVA/Friedman test post hoc analysis for C4. †P ≤ .05, ††P < .01, †††P < .001 at day 31 assessed with mixed-effect models and post hoc multiple comparisons (baseline vs day 31) for TBA and FGF19 or with 1-way repeated measures ANOVA/Friedman test for C4. Abbreviations: C4, 7a-hydroxy-4-cholesten-3-one; FGF19, fibroblast growth factor 19; TBA, total bile acids.

Figure 3.

Effects of GDCA administration on postprandial glucose, insulin, and GLP-1. Postprandial glucose, insulin, and GLP-1 responses measured at days 15 and 31 after the start of GDCA administration. Data are presented as mean ± SEM. †P ≤ .05, at day 31 assessed with mixed-effect models and post hoc multiple comparisons (baseline vs day 31). Abbreviations: GDCA, glycodeoxycholic acid; GLP-1, glucagon-like peptide-1.