Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring
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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.
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Indole-3-propionic acid, one of the primary tryptophan metabolites produced by the gut microbiota, has been suggested to influence ASD susceptibility in offspring.
“Nonetheless, indole-3-propionic acid (IPA), one of the primary tryptophan metabolites produced by the gut microbiota, has been suggested to influence ASD susceptibility in offspring.”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [70]
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References 96 · Cited by 118
Research works printed but not linked: 1
- [90]Zhao ZH Xin FZ Xue YQ Hu ZM Han YM Ma FG Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats Exp Mol Med 2019 51 103 10.1038/s12276-019-0304-5 PMC6802644 31506421 · DOI
- Authors
- Wang, T., Chen, B., Luo, M., Xie, L., Lu, M., Lu, X., Zhang, S., Wei, L., Zhou, X., Yao, B., Wang, H., & Xu, D.
- Affiliations
- Wuhan University (CN)
- Peking University Third Hospital (CN)
- Renmin Hospital of Wuhan University (CN)
- Corresponding author
- Xu, Dan
- Venue
- Microbiome
- Published
- 2023-11-07
- Volume
- 11
- Issue
- 1
- Pages
- 245-245
- ISSN
- 2049-2618 (ISSN-L)
- PMC
- PMC10629055
- OpenAlex
- W4388440585
- Cited by
- 118
- References
- 96
- Citations by year
- 2026: 56 · 2025: 46 · 2024: 16
- FWCI
- 17.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Microbiome (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (No. 82030111, No. 82122071)
- National Key R&D Program of China (No. 2020YFA0803900)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- autism spectrum disorder, fetal growth restriction, gut microbiota, indole-3-propionic acid, aryl hydrocarbon receptor, NF-κB signaling, hippocampal microglia, synaptic pruning, prenatal caffeine exposure, microbiota-brain axis
- MeSH terms
- Autism Spectrum Disorder, Gastrointestinal Microbiome, Animals, Brain, Caffeine, Female, Fetal Growth Retardation, Hippocampus, Neuronal Plasticity, Pregnancy, Propionates, Microglia, Rats
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