Jiang, Jian;
Wang, Dilong;
Jiang, Youheng;
Yang, Xiuyan;
Sun, Runfeng;
Chang, Jinlong;
Zhu, Wenhui;
... Li, Ningning; + view all
(2024)
The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model.
Microbiome
, 12
, Article 66. 10.1186/s40168-024-01755-7.
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Abstract
Background: Microdeletion of the human chromosomal region 16p11.2 (16p11.2+/−) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and efective treatments for 16p11.2+/− syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabo‑ lites in the context of 16p11.2+/− are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural defcits associated with 16p11.2+/−, as well as the underlying molecular mechanisms. // Results: Mice with the 16p11.2+/− showed dysbiosis of the gut microbiota and a signifcant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited signifcant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA efectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive defcits of the mice. Remarkably, IPA treatment signifcantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, with‑ out afecting the transcription and translation of the Mapk3 gene. // Conclusions: Our study reveals that 16p11.2+/− leads to a decline in gut metabolite IPA levels; however, IPA supple‑ mentation notably reverses the behavioral and neural phenotypes of 16p11.2+/− mice. These fndings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory defcit disorders, such as 16p11.2 microdeletion syndrome.
| Type: | Article |
|---|---|
| Title: | The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s40168-024-01755-7 |
| Publisher version: | http://dx.doi.org/10.1186/s40168-024-01755-7 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Keywords: | Autism; Social deficits; Gut microbiota metabolite; Indole-3-propionic acid; Mapk3; GABA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10190060 |
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