Targeted fecal microbiota transplantation ameliorates autism-like behaviors via gut-brain axis and excitatory/inhibitory balance restoration in a propionic acid mouse model.

Abstract

Autism spectrum disorder (ASD) is characterized by social interaction deficits, repetitive behaviors, and restricted interests. Emerging evidence suggests a role for the gut microbiota in ASD pathophysiology, with fecal microbiota transplantation (FMT) emerging as a potential therapeutic strategy. This study investigated the effects of targeted FMT using processed fecal suspensions from rigorously screened healthy human donors, selected by 16S rRNA sequencing for high Lactobacillus abundance, on a propionic acid (PPA)-induced ASD mouse model. PPA-exposed mice exhibited ASD-like behaviors, including anxiety, repetitive grooming, and social interaction deficits, along with alterations in gut microbiota composition, SCFA levels, and neurotransmitter profiles. Donor selection based on 16S rRNA gene sequencing revealed that FMT from donors with high Lactobacillus abundance was more effective in improving social interaction deficits compared to donors with lower Lactobacillus levels. Targeted FMT intervention restored gut microbiota diversity and enriched beneficial taxa, such as Lactobacillus, Roseburia, and Blautia. Furthermore, targeted FMT reduced PPA levels in both feces and the prefrontal cortex (PFC), and normalized the Glu/GABA ratio in the PFC, suggesting a restoration of E/I balance. Electrophysiological recordings confirmed that FMT corrected the E/I imbalance in PFC pyramidal neurons by reducing sEPSC frequency and increasing sIPSC frequency. These findings demonstrate that FMT can ameliorate ASD-like behaviors in a PPA-induced mouse model by modulating gut microbiota and restoring E/I balance in the brain. Our study provides foundational evidence for the potential of targeted FMT as a therapeutic strategy for ASD, highlighting the importance of donor selection based on gut microbiota composition.