Sarkis Mazmanian

– Abstract –

Influence of the Gut Microbiome on Autism Spectrum Disorder

Commensal bacteria influence a variety of complex behaviors, including social, emotional and anxiety-like behaviors, and contribute to brain development in mice and neuronal activation in humans. However, specific connections between the gut and the brain that impact neurologic function remain poorly described. Autism spectrum disorder (ASD) is a neurodevelopmental disease that affects 1 million children and their families, and is characterized by 3 cardinal symptoms: repetitive and stereotyped behaviors, impaired communication, and abnormal social interactions. The incidence of autism has increased at an alarming rate in recent decades, suggesting a possible role for the environment and making ASD one of the most significant medical and social burdens of our time. Intriguingly, studies report that children with autism exhibit dysbiosis of the gut microbiome. Using a validated mouse model that displays the 3 core symptoms of ASD, we show that animals with behavioral deficits also display an altered gut microbiome and increased intestinal permeability, similar to features reported in humans. Remarkably, treatment with a specific member of the human microbiome reduces ASD-related anxiety and improves communicative, stereotyped and sensorimotor abnormalities. Consistent with the role of gut microbes in regulating intestinal permeability and metabolic homeostasis, we show that probiotic treatment corrects altered metabolite profiles of “autistic” mice. In a proof-of concept test, we reveal that injection of one identified metabolite into naïve mice is sufficient to induce anxiety-like behavior. Further, we demonstrate that transplant of gut microbiota from children with ASD into mice is sufficient to transfer core behaviors of autism. These data suggest that microbiome-regulated metabolomic changes contribute to behavioral abnormalities. We propose the provocative concept that ASD may be, at its core, a disease of the gut that manifests in altered behaviors partially mediated by bacterial metabolites.