Congenitally underdeveloped intestine drives autism-related gut microbiota and behavior.

Autism spectrum disorder (ASD) is a neurological and developmental disorder accompanied by gut dysbiosis and gastrointestinal symptoms in most cases. However, the development of the autism-related gut microbiota and its relationship with intestinal dysfunction in ASD remain unclear. Using a valproic acid (VPA)-induced ASD mouse model, we showed a congenitally immature intestine of VPA-exposed mice accompanied by prominent oxidative stress and inflammation. Of note, the gut microbiota composition of VPA-exposed mice resembled that of control mice within 24 h after birth; however, their gut microbiota compositions differed on postnatal days 7 and 21. Oral administration of superoxide dismutase (SOD) to attenuate intestinal oxidative stress either before weaning or during juvenile restored the autism-associated gut microbiota, leading to the amelioration of autism-related behaviors. These findings collectively suggest the congenitally underdeveloped intestine as an early driving force shaping the autism-associated gut microbiota and host neurodevelopment through enhancing oxidative stress.