Semaglutide attenuates autistic-like behaviors in BTBR mice through the shaping of gut microbiota.

Abstract

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental condition characterized by deficits in social communication and the presence of repetitive behaviors. The significance of the gut-brain axis in the pathogenesis of ASD often points to a relationship with gut dysbiosis and metabolic disruptions in affected individuals. This study investigates the potential of the glucagon-like peptide-1 receptor agonist, semaglutide, to modulate gut microbiota, metabolic pathways, and neurodevelopmental outcomes using the BTBR T(+) Itpr3(tf)/J (BTBR) mouse model of ASD. Our findings indicate that administration of semaglutide during an early neurodevelopmental stage leads to significant improvements in social behavior, cognitive function, and repetitive behaviors in BTBR mice. This therapeutic effect is associated with the restoration of gut microbiota, as demonstrated by fecal microbiota transplantation from C57BL/6 J controls and semaglutide-treated BTBR mice, which ameliorated the ASD behaviors in BTBR mice. Metabolomic profiling identified adrenic acid (AdA) as a crucial mediator; AdA levels in BTBR mice were lower but returned to normal following semaglutide treatment. Additionally, RNA sequencing revealed that hippocampal neurogenesis is associated with semaglutide treatment, and AdA supplementation restored social behaviors and hippocampal neurogenesis. These results highlight the critical role of the gut microbiota-brain axis in the therapeutic effects of semaglutide on ASD and suggest that targeting this axis alongside AdA may represent a promising strategy for ASD.