Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders

•Shank3 KO displays differential abundance of several microbial general and species.•GABA receptor expression correlates with L. reuteri abundance.•L. reuteri modifies social and repetitive behaviors in Shank3 KO mice.•L. reuteri modifies GABA receptor expression and oxytocin expression in Shank3 KO mice. Recent studies have determined that the microbiome has direct effects on behavior, and may be dysregulated in neurodevelopmental conditions. Considering that neurodevelopmental conditions, such as autism, have a strong genetic etiology, it is necessary to understand if genes associated with neurodevelopmental disorders, such as Shank3, can influence the gut microbiome, and if probiotics can be a therapeutic tool. In this study, we have identified dysregulation of several genera and species of bacteria in the gut and colon of both male and female Shank3 KO mice. L. reuteri, a species with decreased relative abundance in the Shank3 KO mice, positively correlated with the expression of gamma-Aminobutyric acid (GABA) receptor subunits in the brain. Treatment of Shank3 KO mice with L. reuteri induced an attenuation of unsocial behavior specifically in male Shank3 mice, and a decrease in repetitive behaviors in both male and female Shank3 KO mice. In addition, L. reuteri treatment affected GABA receptor gene expression and protein levels in multiple brain regions. This study identifies bacterial species that are sensitive to an autism-related mutation, and further suggests a therapeutic potential for probiotic treatment.