Sodium butyrate facilitates CRHR2 expression to alleviate HPA axis hyperactivity in autism-like rats induced by prenatal lipopolysaccharides through histone deacetylase inhibition

作者全名："Wang, Xinyuan; Sun, Zhujun; Yang, Ting; Lin, Fang; Ye, Shasha; Yan, Junyan; Li, Tingyu; Chen, Jie"

作者地址："[Wang, Xinyuan; Sun, Zhujun; Yang, Ting; Lin, Fang; Ye, Shasha; Yan, Junyan; Li, Tingyu; Chen, Jie] Chongqing Med Univ, Chongqing Key Lab Childhood Nutr & Hlth, Childrens Hosp, Chongqing, Peoples R China; [Wang, Xinyuan; Sun, Zhujun; Yang, Ting; Lin, Fang; Ye, Shasha; Yan, Junyan; Li, Tingyu; Chen, Jie] Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China"

通信作者："Chen, J (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Childhood Nutr & Hlth, Childrens Hosp, Chongqing, Peoples R China.; Chen, J (通讯作者)，Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China."

来源：MSYSTEMS

ESI学科分类：MICROBIOLOGY

WOS号：WOS:001023841600001

JCR分区：Q1

影响因子：5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：short chain fatty acids; glucocorticoid; HPA axis; autism; social behavior; histone deacetylases

摘要："Short-chain fatty acids (SCFAs, especially butyric acid) have been demonstrated to play a promising role in the development of autism spectrum disorders (ASD). Recently, the hypothalamic-pituitary-adrenal (HPA) axis is also suggested to increase the risk of ASD. However, the mechanism underlying SCFAs and HPA axis in ASD development remains unknown. Here, we show that children with ASD exhibited lower SCFA concentrations and higher cortisol levels, which were recaptured in prenatal lipopolysaccharide (LPS)-exposed rat model of ASD. These offspring also showed decreased SCFA-producing bacteria and histone acetylation activity as well as impaired corticotropin-releasing hormone receptor 2 (CRHR2) expression. Sodium butyrate (NaB), which can act as histone deacetylases inhibitors, significantly increased histone acetylation at the CRHR2 promoter in vitro and normalized the corticosterone as well as CRHR2 expression level in vivo. Behavioral assays indicated ameliorative effects of NaB on anxiety and social deficit in LPS-exposed offspring. Our results imply that NaB treatment can improve ASD-like symptoms via epigenetic regulation of the HPA axis in offspring; thus, it may provide new insight into the SCFA treatment of neurodevelopmental disorders like ASD. IMPORTANCEGrowing evidence suggests that microbiota can affect brain function and behavior through the ""microbiome-gut-brain'' axis, but its mechanism remains poorly understood. Here, we show that both children with autism and LPS-exposed rat model of autism exhibited lower SCFA concentrations and overactivation of HPA axis. SCFA-producing bacteria, Lactobacillus, might be the key differential microbiota between the control and LPS-exposed offspring. Interestingly, NaB treatment contributed to the regulation of HPA axis (such as corticosterone as well as CRHR2) and improvement of anxiety and social deficit behaviors in LPS-exposed offspring. The potential underlying mechanism of the ameliorative effect of NaB may be mediated via increasing histone acetylation to the CRHR2 promoter. These results enhance our understanding of the relationship between the SCFAs and the HPA axis in the development of ASD. And gut microbiota-derived SCFAs may serve as a potential therapeutic agent to neurodevelopmental disorders like ASD. Growing evidence suggests that microbiota can affect brain function and behavior through the ""microbiome-gut-brain'' axis, but its mechanism remains poorly understood. Here, we show that both children with autism and LPS-exposed rat model of autism exhibited lower SCFA concentrations and overactivation of HPA axis. SCFA-producing bacteria, Lactobacillus, might be the key differential microbiota between the control and LPS-exposed offspring. Interestingly, NaB treatment contributed to the regulation of HPA axis (such as corticosterone as well as CRHR2) and improvement of anxiety and social deficit behaviors in LPS-exposed offspring. The potential underlying mechanism of the ameliorative effect of NaB may be mediated via increasing histone acetylation to the CRHR2 promoter. These results enhance our understanding of the relationship between the SCFAs and the HPA axis in the development of ASD. And gut microbiota-derived SCFAs may serve as a potential therapeutic agent to neurodevelopmental disorders like ASD."

基金机构："National Natural Science Foundation of China [81770526, 31971089, 82372592]"

基金资助正文："ACKNOWLEDGMENTS We thank all of the families and children who participated in the study. This work was supported by the National Natural Science Foundation of China (81770526, 31971089, 82372592) from Professor J.C."