Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring.
Autism spectrum disorder
Gut microbiota
Indole 3-propionic acid
Intrauterine growth restriction
Microglia synaptic pruning
Journal
Microbiome
ISSN: 2049-2618
Titre abrégé: Microbiome
Pays: England
ID NLM: 101615147
Informations de publication
Date de publication:
07 11 2023
07 11 2023
Historique:
received:
08
09
2022
accepted:
23
08
2023
medline:
8
11
2023
pubmed:
7
11
2023
entrez:
7
11
2023
Statut:
epublish
Résumé
Autism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37932832
doi: 10.1186/s40168-023-01656-1
pii: 10.1186/s40168-023-01656-1
pmc: PMC10629055
doi:
Substances chimiques
Caffeine
3G6A5W338E
propionic acid
JHU490RVYR
Types de publication
Video-Audio Media
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
245Informations de copyright
© 2023. The Author(s).
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