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.
Tingting Wang  #  1 ,  Beidi Chen  #  2 ,  Mingcui Luo  1 ,  Lulu Xie  3 ,  Mengxi Lu  1 ,  Xiaoqian Lu  4 ,  Shuai Zhang  1 ,  Liyi Wei  1 ,  Xinli Zhou  4 ,  Baozhen Yao  3 ,  Hui Wang  4  5 ,  Dan Xu  6  7
Affiliations
  • 1. Department of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 2. Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, 100191, China.
  • 3. Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan, 430071, China.
  • 4. Department of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China.
  • 5. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
  • 6. Department of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. [email protected].
  • 7. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. [email protected].
  • # Contributed equally.
PMID: 37932832 DOI: 10.1186/s40168-023-01656-1
Abstract

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.
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