Microbiota and social behavior alterations in a mouse model of down syndrome: Modulation by a synbiotic treatment

Sex differences in the composition and functionality of gut microbiota are an emerging field of interest in neurodevelopmental disorders, as they may help in understanding the phenotypic disparities between males and females. This study aimed to characterize sex-related specific alterations in gut microbiota composition in a mouse model of Down syndrome (Ts65Dn mice, TS mice) through the sequencing of the PCR-amplified 16S ribosomal DNA fraction. Moreover, it intended to examine whether the modulation of gut microbiota by the administration of a synbiotic (SYN) treatment would be beneficial for the behavioral alterations observed in male and female TS mice. Our results show that male, but not female, TS mice exhibit alterations in beta diversity compared to their wild-type (WT) littermates. Sex-dependent differences are also observed in the relative abundance of the classes Bacilli and Clostridia. Administering the SYN effectively counteracts hypersociability in females, and normalizes the overall abundance of Bacilli, specifically by increasing Lactobacillaceae. On the contrary, it rescues emotional recognition deficits in male TS mice and increases the relative abundance of the families Lactobacillaceae, Streptococcaceae and Atopobiaceae. In addition, a metagenome KEGG analysis of differentially enriched pathways shows relevant changes in the cofactor biosynthesis and the amino acid synthesis categories. Finally, following SYN treatment, both male and female TS mice exhibit a robust increase in propionic acid levels compared to WT littermates. These findings suggest sex-specific mechanisms that could link gut microbiota composition with behavior in TS mice, and underscore the potential of targeted gut microbiota interventions to modulate social abnormalities in neurodevelopmental disorders.