Changes to gut amino acid transporters and microbiome associated with increased E/I ratio in Chd8+/\u2212 mouse model of ASD-like behavior

You Yu,Chang Liu,Bing Zhang,Fangqing Zhao,Yongxi Huang,Peifeng Ji,Shuang-Jiang Liu,Ning Wang,Zhenqiang Zuo

doi:10.1038/s41467-022-28746-2

Abstract

Autism spectrum disorder (ASD), a group of neurodevelopmental disorders characterized by social communication deficits and stereotyped behaviors, may be associated with changes to the gut microbiota. However, how gut commensal bacteria modulate brain function in ASD remains unclear. Here, we used chromodomain helicase DNA-binding protein 8 (CHD8) haploinsufficient mice as a model of ASD to elucidate the pathways through which the host and gut microbiota interact with each other. We found that increased levels of amino acid transporters in the intestines of the mouse model of ASD contribute to the high level of serum glutamine and the increased excitation/inhibition (E/I) ratio in the brain. In addition, elevated α-defensin levels in the haploinsufficient mice resulted in dysregulation of the gut microbiota characterized by a reduced abundance of Bacteroides. Furthermore, supplementation with Bacteroides uniformis improved the ASD-like behaviors and restored the E/I ratio in the brain by decreasing intestinal amino acid transport and the serum glutamine levels. Our study demonstrates associations between changes in the gut microbiota and amino acid transporters, and ASD-like behavioral and electrophysiology phenotypes, in a mouse model.

Highlights

Autism spectrum disorder (ASD), a group of neurodevelopmental disorders characterized by social communication deficits and stereotyped behaviors, may be associated with changes to the gut microbiota
S-benzyl-Lcysteine did not significantly affect the Chd8+/− mouse body weight, whole brain weight or cerebrum weight (Supplementary Fig. 7f). These results indicated that the restoration of the ASDlike phenotypes in the Chd8+/− mice by B. uniformis may be achieved by suppressing the expression of their intestinal amino acid transporters
Our study focused on analyzing the mutual interactions between the host and the gut microbiota in the development of ASD and our results support a role of intestinal amino acid transporters in the regulation of host neural activities by the gut microbiota in a mouse model of ASD-like behavior (Fig. 7)

Summary

Introduction

Autism spectrum disorder (ASD), a group of neurodevelopmental disorders characterized by social communication deficits and stereotyped behaviors, may be associated with changes to the gut microbiota. Supplementation with Bacteroides uniformis improved the ASD-like behaviors and restored the E/I ratio in the brain by decreasing intestinal amino acid transport and the serum glutamine levels. Our study demonstrates associations between changes in the gut microbiota and amino acid transporters, and ASD-like behavioral and electrophysiology phenotypes, in a mouse model. The gut microbiota has been shown to modulate the neural function and central nervous system (CNS)-related behaviors in physiological and pathological conditions[9]. In both people with ASD and animal models, gut microbiota dysbiosis has been reported[10,11], and probiotics may alleviate the symptoms[12]. Increased intestinal amino acid transport contributes to the increased excitation/ inhibition (E/I) ratio with the increased glutamate levels in the brain, and the gut microbiota can restore the E/I imbalance in the brain by decreasing intestinal amino acid transport

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