Gut Microbiota and Brain-Resident CD4 T Cells Shape Behavioral Outcomes in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormal social interactions, repetitive behaviors, and anxiety-like symptoms. While emerging evidence suggest a gut-brain axis in the etiology of ASD, the underlying mechanisms remain unclear. To dissect this axis, we developed a germ-free (GF) BTBR mouse model for ASD. Remarkably, the absence of gut microbiota prevented ASD-associated behaviors, concurrent with a reduced population and inflammatory phenotype of brain-resident T cells. CD4 T cell depletion in BTBR mice mitigated ASD behaviors and neuroinflammation. We identified several microbes and metabolites, particularly those relevant to the glutamate/GABA ratio and 3-hydroxyglutaric acid, as critical drivers of ASD. Using an in silico metabolite prediction model, we identified Limosilactobacillus reuteri IMB015 (IMB015) as a probiotic candidate. Administration of IMB015 reduced the glutamate/GABA ratio and neuroinflammation, resulting in improved behaviors. These findings suggest a gut-immune-brain axis in which the gut microbiota and its metabolites can modulate brain-resident immune cells and ASD-associated behaviors.