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

• Published in: Microbiome 2023-11, Vol.11 (1), p.1-245, Article 245
• Main Authors: Wang, Tingting, Chen, Beidi, Luo, Mingcui, Xie, Lulu, Lu, Mengxi, Lu, Xiaoqian, Zhang, Shuai, Wei, Liyi, Zhou, Xinli, Yao, Baozhen, Wang, Hui, Xu, Dan
• Format: Article
• Language: English
• Subjects: Animal models; Autism; Autism spectrum disorder; Birth weight; Caffeine; Disease; Females; Fetuses; Gut microbiota; Health care; Hippocampus; Indole 3-propionic acid; Intestinal microflora; Intrauterine growth restriction; Metabolism; Metabolites; Microbiota; Microglia; Microglia synaptic pruning; Nervous system; Neurons; NF-κB protein; Offspring; Pathogenesis; Pregnancy; Prenatal experience; Propionic acid; Womens health
• ISSN: 2049-2618; 2049-2618
• DOI: 10.1186/s40168-023-01656-1

BackgroundAutism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear.ResultsWe 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.ConclusionsThis 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