Microbiota-Indole 3-Propionic Acid-Brain Axis Mediates Abnormal Synaptic Pruning of Hippocampal Microglia and Susceptibility to ASD in IUGR Offsprings

Autism Spectrum disorder (ASD) has been associated with intrauterine growth retardation (IUGR), but the underlying mechanisms are unclear. We found that the IUGR rat model induced by prenatal caffeine exposure (PCE) showed ASD-like manifestations, accompanied by altered gut microbiota and reduced production of indole 3-propionic acid (IPA), a microbiota-specific metabolite and a ligand of aryl hydrocarbon receptor (AHR). IUGR children also had a reduced serum IPA level consistent with the animal model. We demonstrated that the dysregulated IPA/AHR/NF-kB signaling caused by disturbed gut microbiota mediated the hippocampal microglia hyperactivation and neuronal synapse over-pruning in the PCE-induced IUGR rats. Moreover, postnatal IPA supplementation restored the ASD-like manifestations and the underlying hippocampal lesions in the IUGR rats. This study suggests that the microbiota-IPA-brain axis regulats the ASD susceptibility in PCE-induced IUGR offsprings, and supplementation of microbiota-derived IPA might be a promising interventional strategy for ASD with a fetal origin.