Gut–microbiota–brain axis in the vulnerability to psychosis in adulthood after repeated cannabis exposure during adolescence

Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212–2 during adolescence. Repeated administration of WIN55,212–2 (2 mg/kg/day) during adolescence (P35–P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212–2 exposure during adolescence. Therefore, it is likely that gut–microbiota–microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.