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

Jiang，Jian1; Wang，Dilong1,2; Jiang，Youheng1; Yang，Xiuyan1; Sun，Runfeng3; Chang，Jinlong1; Zhu，Wenhui1; Yao，Peijia1; Song，Kun4; Chang，Shuwen5; Wang，Hong5; Zhou，Lei3; Zhang，Xue Song6; Li，Huiliang7; Li，Ningning1,8,9

2024-12-01

10.1186/s40168-024-01755-7

Microbiome   影响因子和分区

2049-2618

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 effective 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 metabolites 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 deficits 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 significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant 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 effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting 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 supplementation notably reverses the behavioral and neural phenotypes of 16p11.2 mice. These findings 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 deficit disorders, such as 16p11.2 microdeletion syndrome.

Autism GABA Gut microbiota metabolite Indole-3-propionic acid Mapk3 Social deficits

SCI

英语

其他

2-s2.0-85188811134

Scopus

1.Tomas Lindahl Nobel Laureate Laboratory,The Seventh Affiliated Hospital,Sun Yat-Sen University,Shenzhen,China
2.Department of Pediatrics,Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University,Guangzhou,China
3.Institute of Molecular Physiology,Shenzhen Bay Laboratory,Shenzhen,China
4.Brain Research Centre,Department of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen,China
5.The Brain Cognition and Brain Disease Institute (BCBDI),Shenzhen-Hong Kong Institute of Brain Science Shenzhen Fundamental Research Institutions,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China
6.Center for Advanced Biotechnology and Medicine,Rutgers University,Piscataway,United States
7.Wolfson Institute for Biomedical Research,Division of Medicine,Faculty of Medical Sciences,University College London,London,United Kingdom
8.China-UK Institute for Frontier Science,Shenzhen,China
9.Department of Anesthesiology,The Afliated Hospital of Youjiang Medical University for Nationalities,Baise,China

Jiang，Jian,Wang，Dilong,Jiang，Youheng,et al. 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[J]. Microbiome,2024,12(1).

Jiang，Jian.,Wang，Dilong.,Jiang，Youheng.,Yang，Xiuyan.,Sun，Runfeng.,...&Li，Ningning.(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(1).

Jiang，Jian,et al."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 12.1(2024).