Abstract
Chronic alcohol intake has been shown to disrupt gut microbiota homeostasis, but whether microbiota modulation could prevent behavioral alterations associated with chronic alcohol intake remains unknown. We investigated the effects of synbiotic dietary supplementation on the development of alcohol-related addictive behavior 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 the prefrontal cortex and hippocampus. Chronic intermittent exposure to alcohol during 20 days induced escalation of intake in both female and male mice. Following alcohol deprivation, relapse-like behavior was observed in both sexes, but anxiogenic and cognitive deficits were present only in females. Synbiotic treatment reduced escalation and relapse to alcohol intake in females and males. In addition, the anxiogenic-like state and cognitive deficits observed in females following alcohol deprivation were abolished in mice exposed to synbiotic. 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. In males, synbiotic exposure restored the changes induced by alcohol in Akkermansia and Muribaculum uncultured bacterium abundance. Following alcohol withdrawal, tryptophan metabolites, noradrenaline, dopamine, and γ-aminobutyric acid concentrations in the prefrontal cortex and the hippocampus were correlated with bacterial abundance and behavioral alterations in a sex-dependent manner. These results suggested that a dietary intervention with a synbiotic to reduce gut dysbiosis during chronic alcohol intake may impact differently the gut-brain-axis in females and males.
Highlights
According to the WHO [1], alcohol misuse causes ∼3 million deaths every year, and the public health burden of associated mental and behavioral disorders is very high [2]
We found that synbiotic dietary supplementation during chronic intermittent alcohol drinking reduced escalation and relapse-like behaviors in mice of both sexes
These results suggest that modulation of gut microbiota through synbiotic exposure may be beneficial for averting alcohol-related addictive behaviors
Summary
According to the WHO [1], alcohol misuse causes ∼3 million deaths every year, and the public health burden of associated mental and behavioral disorders is very high [2]. The prevalence of frequent binges in younger women is increasing to resemble those of men [4, 5] These data underscore the relevance of including both sexes in studies aimed at investigating the biological factors contributing to the development of alcohol use disorders, and to finding new treatment avenues to prevent the alcohol-related addictive process and the associated neuropathological consequences. Several species of bacteria including Bifidobacterium and Lactobacillus have been shown to produce acetate, butyrate, isobutyrate, and propionate that have neuroactive properties [12]. Some of these bacteria can produce neurotransmitters such as γ-aminobutyric acid (GABA), serotonin (5-HT), dopamine (DA), and noradrenaline (NA) [13], which play key roles in the pathophysiology of several CNS diseases, including anxiety, depression, and addiction [14, 15]. Gut microbes metabolize their energy resources via the tryptophan (Tryp) pathway, which regulates the availability of circulating 5-HT and kynurenine (Kyn), known neuroactive metabolites involved in the pathophysiology of several CNS diseases [16, 17]
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