A human microbiota-associated translational mouse model reveals sex-specific responses to cannabidiol and cannabigerol

Cannabidiol (CBD) and cannabigerol (CBG) are non-psychoactive phytocannabinoids with therapeutic potential, yet their effects on host physiology and interactions with the gut microbiome remain poorly defined. Here, we used a translational mouse model colonized with human-associated microbiotas to investigate the effects of oral CBD and CBG intervention on microbial composition, endocannabinoid signaling, and intestinal protein expression. While neither phytocannabinoids altered overall gut microbiome diversity, both induced sex-specific shifts in bacterial taxa associated with mucin utilization and short-chain fatty acid production. Circulating concentrations of CBD were higher than those of CBG, and females exhibited higher plasma phytocannabinoid concentrations than males. Males treated with CBD had elevated anandamide (AEA) levels, potentially reflecting inhibition of fatty acid amide hydrolase, consistent with upregulation of serine protease inhibitors observed in ileal proteomes. Females also accumulated more subcutaneous adipose tissue with both CBD and CBG treatment resulting in greater total CBD storage in this depot. Collectively, these findings suggest sex-specific interactions between phytocannabinoids, the endocannabinoid system, and the gut microbiome, underscoring the importance of considering biological sex in cannabinoid research and informing personalized therapeutic strategies.