Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder

Abstract

Background: Ghrelin may influence several alcohol-related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD).

Methods: We used serum samples from a randomized, crossover, double-blind, placebo-controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3 µg/kg) followed by continuous infusion (16.9 ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self-administration (IV-ASA) session and the second experiment included an IV alcohol clamp (IV-AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session.

Results: In both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV-ASA q-value = 0.0003 and IV-AC q < 0.0001), corticosterone (IV-ASA q = 0.0202 and IV-AC q < 0.0001), and glycochenodeoxycholic acid (IV-ASA q = 0.0375 and IV-AC q = 0.0013). In the IV-ASA experiment, ghrelin infusion increased levels of cortisone (q = 0.0352) and fatty acids 18:1 (q = 0.0406) and 18:3 (q = 0.0320). Moreover, in the IV-AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q < 0.0001) and phenylalanine (q = 0.0458).

Conclusion: IV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine-conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol.

Keywords: alcohol use disorder; bile acids; corticosteroids; ghrelin; metabolomics.

Conflict of interest statement

Conflicts of interest

OK and AK are co-owners of Afekta Technologies Ltd., a company providing metabolomics analysis services. The other authors do not report any conflict of interest relevant to this work.

© 2021 Research Society on Alcoholism. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Figures

Figure 1:. Study flow of intravenous alcohol self-administration and intravenous alcohol clamp experiments.

Simplified schematic view of the study showing the crossover design and the serum sampling time-points used in the metabolomics analysis. A minimum of a 3-day washout period occurred between each session. During each session, after sampling for pre-drug baseline, a 10-minute loading dose of intravenous acyl-ghrelin (3 μg/kg) or placebo was administered. This dose was followed by a continuous infusion of acyl-ghrelin (16.9 ng/kg/min) or placebo. Abbreviations: BrAC=Breath Alcohol Concentration; IV=Intravenous; IV-ASA=IV Alcohol Self-Administration; IV-A=IV Alcohol Clamp; LD=Loading Dose.

Figure 2:. Intravenous ghrelin administration alters the circulating metabolite profile.

Serum metabolite profiles were analyzed from repeated serum samples collected during each of the four sessions (see Figure 1). When comparing area under the curve values using linear mixed-effect models, significant differences between ghrelin and placebo infusions were seen in both the intravenous (IV) alcohol self-administration (ASA) experiment and the IV alcohol clamp (AC) experiment in levels of cortisol (FRD corrected q-value = 0.0003, and