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

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 remain unknown. Here we show that ASD children exhibited lower SCFAs 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, which can act as histone deacetylases (HDACs) 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 sodium butyrate on anxiety and social deficit in LPS-exposed offspring. Our results imply that sodium butyrate treatment can improve ASD-like symptoms via epigenetic regulation of the HPA axis in offspring, thus it may provide new insight into the SCFAs treatment of neurodevelopmental disorders like ASD.