Sex-specific effects of synbiotic exposure in mice on addictive-like behavioural alterations induced by chronic alcohol intake are associated with changes in specific gut bacterial taxa and tryptophan metabolism

Chronic alcohol intake has been shown to disrupt gut microbiota homeostasis, but whether microbiota modulation could prevent behavioural alterations associated with chronic alcohol intake still remains unknown. We investigated the effects of a synbiotic mixture on the development of alcohol-related addictive behaviour in female and male mice, and evaluated whether these effects were associated with changes in bacterial species abundance, short chain fatty acids, tryptophan metabolism and neurotransmitter levels in plasma, prefrontal cortex (PFC) and hippocampus (HPC). Chronic intermittent exposure to alcohol during 21 days induced escalation of intake in both female and male mice. Following alcohol deprivation, relapse-like behaviour was observed in both sexes, but anxiogenic and cognitive deficits were present only in females. Synbiotic intake reduced escalation behaviour in females and males, and prevented relapse and the anxiogenic-like state and cognitive deficits observed in females. Alcohol induced differential alterations in microbial diversity and abundance in both sexes. In females, synbiotic exposure abrogated the alterations provoked by alcohol in Prevotellaceae UCG-001 and Ruminococcaceae UCG-014 abundance and Lachnospiraceae NK 4A136 abundance was reduced mostly in mice exposed to synbiotic. In males, synbiotic exposure restored the changes induced by alcohol in Akkermansia and Muribaculum uncultured bacterium abundance. Tryptophan metabolites in plasma, PFC and HPC, and tissue concentrations of serotonin and GABA in the PFC and the HPC following alcohol withdrawal were correlated with bacterial abundance and behavioural alterations in a sex-dependent manner. These results suggest that a dietary intervention to reduce gut dysbiosis during chronic alcohol intake, may impact differently the functionality of the gut-brain-axis in females and males.