Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring

Microbiome. 2023 Nov 7;11(1):245. doi: 10.1186/s40168-023-01656-1.


Background: Autism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear.

Results: We found that the IUGR rat model induced by prenatal caffeine exposure (PCE) showed ASD-like symptoms, 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-κB 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 symptoms and the underlying hippocampal lesions in the IUGR rats.

Conclusions: This study suggests that the microbiota-IPA-brain axis regulates ASD susceptibility in PCE-induced IUGR offspring, and supplementation of microbiota-derived IPA might be a promising interventional strategy for ASD with a fetal origin. Video Abstract.

Keywords: Autism spectrum disorder; Gut microbiota; Indole 3-propionic acid; Intrauterine growth restriction; Microglia synaptic pruning.

Publication types

  • Video-Audio Media
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder*
  • Brain
  • Caffeine / toxicity
  • Female
  • Fetal Growth Retardation / chemically induced
  • Gastrointestinal Microbiome* / physiology
  • Hippocampus
  • Microglia
  • Neuronal Plasticity
  • Pregnancy
  • Rats


  • Caffeine
  • propionic acid