Short-chain fatty acid valerate reduces voluntary alcohol intake in male mice

作者：Suresh Bokoliya, Jordan T. Russell, Yair Dorsett, Hunter A. Panier, Vijender Singh, Lauren Daddi, Hanshu Yuan, Liv R. Dedon, Zhongmao Liu, Yuqi Zhou, Zefang Min, Jessica R. Barson, Jonathan Covault, Jason A. Bubier, Yanjiao Zhou · 发表于：Microbiome · 年份：2024 · DOI：10.1186/s40168-024-01829-6 · 被引用次数：15 · 研究领域：GABA and Rice Research、Gut microbiota and health、Neurotransmitter Receptor Influence on Behavior

BACKGROUND: Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied. RESULTS: Here, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acid short-chain fatty acid with a similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S micr...