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

Background Microdeletion of the 16p11.2 region of the human chromosome is a prevalent genetic factor for autism spectrum disorder (ASD) and other neurodevelopmental disorders, but its pathogenic mechanism remains unclear, and effective treatments for 16p11.2 microdeletion 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. However, the functional roles of microbial metabolites in the context of 16p11.2 microdeletion 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 pathological deficits associated with 16p11.2 microdeletion, as well as the underlying molecular mechanisms. Results Mice with the 16p11.2 microdeletion (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 impairments, and abnormal activation of hippocampal dentate gyrus neurons, which was accompanied by an imbalance of inhibitory synaptic transmission in this region. However, oral supplementation of IPA significantly mitigated these alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA administration 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 reveal that 16p11.2+/− leads to a decline in gut metabolite IPA levels, and that supplementation with IPA can reverse the associated histological and electrophysiological changes and behavioral defects in 16p11.2+/− mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and presents a promising treatment treatment strategy for social and cognitive deficit disorders, such as 16p11.2 microdeletion syndrome.