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微生物群-吲哚 3-丙酸-脑轴介导宫内发育迟缓后代中海马小胶质细胞异常突触修剪和易患 ASD。

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

机构信息

Department of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.

Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, 100191, China.

出版信息

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

DOI:10.1186/s40168-023-01656-1
PMID:37932832
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10629055/
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.

摘要

背景

自闭症谱系障碍（ASD）与宫内生长受限（IUGR）有关，但潜在机制尚不清楚。

结果

我们发现，产前咖啡因暴露（PCE）诱导的 IUGR 大鼠模型表现出类似 ASD 的症状，伴随着肠道微生物群的改变和吲哚 3-丙酸（IPA）的产生减少，IPA 是一种特定于微生物群的代谢物和芳香烃受体（AHR）的配体。IUGR 儿童的血清 IPA 水平也降低，与动物模型一致。我们证明，肠道微生物群失调引起的 IPA/AHR/NF-κB 信号通路紊乱介导了 PCE 诱导的 IUGR 大鼠中海马小胶质细胞过度激活和神经元突触过度修剪。此外，产后 IPA 补充恢复了 IUGR 大鼠的 ASD 样症状和潜在的海马损伤。

结论

本研究表明，微生物群-IPA-大脑轴调节了 PCE 诱导的 IUGR 后代的 ASD 易感性，补充微生物群衍生的 IPA 可能是一种有前途的具有胎儿起源的 ASD 干预策略。视频摘要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/05016a0811b2/40168_2023_1656_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/58e0ac315f47/40168_2023_1656_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/08972b8a2010/40168_2023_1656_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/5e5372644f35/40168_2023_1656_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/d3e5efde9608/40168_2023_1656_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/dabbb148cda9/40168_2023_1656_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/dea1ea732653/40168_2023_1656_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/05016a0811b2/40168_2023_1656_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/58e0ac315f47/40168_2023_1656_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/08972b8a2010/40168_2023_1656_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/5e5372644f35/40168_2023_1656_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/d3e5efde9608/40168_2023_1656_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/dabbb148cda9/40168_2023_1656_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/dea1ea732653/40168_2023_1656_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7af5/10629055/05016a0811b2/40168_2023_1656_Fig7_HTML.jpg

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