Xylitol ameliorates ASD-like behavior in Chd8+/- mice via modulations of the gut microbiome, neurotransmitters, and dendritic spine morphology.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with complex etiology involving gut-brain axis interactions. It remains elusive how prebiotics modulate this axis to alleviate ASD symptoms. This study aimed to investigate whether xylitol, a potential prebiotic, improves behavioral and neural deficits in Chd8+/- mice, a genetic model of ASD, and to explore the associated roles of the gut microbiome, neurotransmitters and synaptic morphology in these effects. We found that Chd8+/- mice exhibited disrupted gut microbiota and imbalanced levels of key neuromodulators including indole-3-lactic acid (ILA), asparagine (Asn) and glycine (Gly), as well as reduced dendritic spine density and maturity in the mPFC and hippocampal CA1 regions and diminished c-Fos activation in response to social stimuli. Xylitol supplementation significantly ameliorated social deficits, restored microbial composition and neurotransmitter metabolite profiles, and rescued synaptic maturation and neuronal activity in these mice. These findings suggest that xylitol may act via the gut-brain axis to reverse ASD-like phenotypes, although direct causal evidence remains to be established. Nonetheless, this work supports the potential of xylitol as a dietary intervention for ASD.