The baseline microbiome and GABA level in stool influences alcohol consumption in a zonisamide clinical trial in adults with AUD
Development and severity of alcohol use disorder (AUD) has been linked to variations in gut microbiota and their associated metabolites in both animal and human studies. However, the involvement of the gut microbiome in alcohol consumption of individuals with AUD undergoing treatment remains unclear. To address this, stool samples (n=48) were collected at screening (baseline) and trial completion from a single site of a multi-site double-blind, placebo-controlled trial of Zonisamide, an FDA approved anticonvulsant shown to reduce alcohol consumption in individuals with AUD. GGT and PEth levels were measured both at baseline and trial completion along with alcohol consumption reporting throughout the 16-week trial period. Stool microbiome was analyzed via 16S rRNA sequencing and metabolome via untargeted LC-MS. Both sex (p = 0.003) and psychotropic medication usage (p = 0.025) are associated with baseline microbiome composition. Genus-level relative abundance of 12 genera at baseline was correlated (rho>0.3, p < 0.05) to percent drinking reduction, baseline and endpoint alcohol consumption, and changes in alcohol-associated biomarkers over the course of treatment. Overall microbiome community structure at baseline differed between high and low responders (67-100% and 0-33% drinking reduction, respectively) (p = 0.03). A positive relationship between baseline GABA levels and percent drinking reduction (R=0.43, p < 0.05) was identified by microbiome function prediction and confirmed by ELISA and metabolomics. Predicted microbiome function and metabolomics additionally implicate tryptophan metabolism and Akkermansia relative abundance in low drinking reduction. These findings highlight importance of baseline microbiome in influencing alcohol consumption in AUD patients undergoing zonisamide treatment.