Probiotics derived sodium benzoate improves social behavior of offspring exposed in the maternal immune activation through regulation of histone lysine benzoylation in astrocytes

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition increasingly linked to microbiota-gut-brain axis dysregulation, yet the causal microbial mediators and molecular mechanisms remain elusive. Based on our previously published ASD cohort, we discovered that depletion of Lactobacillus species in children with ASD correlates with exacerbated gastrointestinal symptoms and social deficits. Maternal immune activation (MIA) during pregnancy has been established as a critical environmental risk factor for ASD. Furthermore, in the MIA-induced ASD mouse model, we demonstrated that supplementation with Lactiplantibacillus plantarum, or its derived sodium benzoate (NaB), mitigates gut dysbiosis, alleviates deficits of social behavior, glutamate-glutamine levels, and neuronal activity in autistic mice. Single-cell RNA sequencing revealed that NaB restored the genes expression, like Cxcl16, in astrocytes of autistic mice, which is linked to glutamate metabolic activity between neurons and astrocytes. Further, we demonstrated that astrocytes-specific Cxcl16 knock-in hippocampus bypassed microbiota effects to restore social memory in autistic mice. Recent investigations have established NaB as key mediator of histone lysine benzoylation (Kbz), primarily through its role in generating benzoyl-CoA, the essential substrate for this epigenetic modification. Mechanistically, through integrating RNA-seq and Cut & Tag analysis, our findings revealed that NaB boosts Cxcl16 gene expression in astrocytes, possibly by increasing H3K27 benzoylation binding at enhancer regions. This highlights the therapeutic potential of probiotics-derived NaB for ASD and uncovers a novel epigenetic mechanism within the microbiota-gut-brain axis.