Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring
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 mic...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
|
| Series: | Microbiome |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40168-023-01656-1 |
| _version_ | 1797630096089022464 |
|---|---|
| author | Tingting Wang Beidi Chen Mingcui Luo Lulu Xie Mengxi Lu Xiaoqian Lu Shuai Zhang Liyi Wei Xinli Zhou Baozhen Yao Hui Wang Dan Xu |
| author_facet | Tingting Wang Beidi Chen Mingcui Luo Lulu Xie Mengxi Lu Xiaoqian Lu Shuai Zhang Liyi Wei Xinli Zhou Baozhen Yao Hui Wang Dan Xu |
| author_sort | Tingting Wang |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-03-11T11:02:05Z |
| format | Article |
| id | doaj.art-4f24a8572ebe4103bc106bbe88f90a07 |
| institution | Directory Open Access Journal |
| issn | 2049-2618 |
| language | English |
| last_indexed | 2024-03-11T11:02:05Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj.art-4f24a8572ebe4103bc106bbe88f90a072023-11-12T12:24:20ZengBMCMicrobiome2049-26182023-11-0111112310.1186/s40168-023-01656-1Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspringTingting Wang0Beidi Chen1Mingcui Luo2Lulu Xie3Mengxi Lu4Xiaoqian Lu5Shuai Zhang6Liyi Wei7Xinli Zhou8Baozhen Yao9Hui Wang10Dan Xu11Department of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan UniversityDepartment of Rheumatology and Immunology, Peking University Third HospitalDepartment of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan UniversityDepartment of Pediatrics, Renmin Hospital of Wuhan UniversityDepartment of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan UniversityDepartment of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan UniversityDepartment of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan UniversityDepartment of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Pediatrics, Renmin Hospital of Wuhan UniversityDepartment of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan UniversityAbstract 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 Abstracthttps://doi.org/10.1186/s40168-023-01656-1Intrauterine growth restrictionAutism spectrum disorderGut microbiotaIndole 3-propionic acidMicroglia synaptic pruning |
| spellingShingle | Tingting Wang Beidi Chen Mingcui Luo Lulu Xie Mengxi Lu Xiaoqian Lu Shuai Zhang Liyi Wei Xinli Zhou Baozhen Yao Hui Wang Dan Xu Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring Microbiome Intrauterine growth restriction Autism spectrum disorder Gut microbiota Indole 3-propionic acid Microglia synaptic pruning |
| title | Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring |
| title_full | Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring |
| title_fullStr | Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring |
| title_full_unstemmed | Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring |
| title_short | Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring |
| title_sort | microbiota indole 3 propionic acid brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to asd in iugr offspring |
| topic | Intrauterine growth restriction Autism spectrum disorder Gut microbiota Indole 3-propionic acid Microglia synaptic pruning |
| url | https://doi.org/10.1186/s40168-023-01656-1 |
| work_keys_str_mv | AT tingtingwang microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT beidichen microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT mingcuiluo microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT luluxie microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT mengxilu microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT xiaoqianlu microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT shuaizhang microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT liyiwei microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT xinlizhou microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT baozhenyao microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT huiwang microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring AT danxu microbiotaindole3propionicacidbrainaxismediatesabnormalsynapticpruningofhippocampalmicrogliaandsusceptibilitytoasdiniugroffspring |