Baseline gut microbiome and metabolites are correlated with alcohol consumption in a zonisamide clinical trial of heavy drinking alcoholic civilians

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 in individuals with AUD. Alcohol consumption, gamma-glutamyl transferase (GGT), and phosphatidylethanol (PEth)levels were measured both at baseline and endpoint of 16-week trial period. Fecal 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. The relative abundance of 12 genera at baseline was correlated with percent drinking reduction, baseline and endpoint alcohol consumption, and changes in GGT and PeTH over the course of treatment (p.adj < 0.05). 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 fecal 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 analysis have found that tryptophan metabolic pathways are over-represented in low responders. These findings highlight importance of baseline microbiome and metabolites in alcohol consumption in AUD patients undergoing zonisamide treatment.