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

Abstract

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. IMPORTANCE 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.

Oxytocin and corticotropin‐releasing hormone exaggerate nucleus tractus solitarii neuronal and synaptic activity following chronic intermittent hypoxia

“…The membrane was washed 3 × 5 min in TBS‐T and then incubated in either rabbit anti‐OTR (1:300, Abcam (Waltham, MA, USA), ab217212, overnight, ) or rabbit anti‐CRHR2 (1:1000, Abcam, ab236982, 3 nights) antibodies in TBS‐T with 5% milk at 4°C on a shaker. Antibody specificity has been previously confirmed (Wang et al., 2023; Wei et al., 2023). Following a TBS‐T wash (3 × 5 min) the membrane was incubated in donkey anti‐rabbit antibody conjugated to peroxidase (1:5000, Jackson ImmunoResearch) for 2 h on a shaker at room temperature.…”

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

“…In addition, recently, increased activation of the HPA axis was suggested to play an important role in ASD-like social behaviors ( Jacobson, 2014 ; Rusch et al, 2023 ). As CRHR2 is one of the receptors for the hormones involved in the HPA axis, decreased CRHR2 expression levels in the hypothalamus were recently suggested to increase the risk of ASD ( Wang X. et al, 2023 ). Interestingly, the current data revealed that an intronic CRHR2 variant (rs7793837), which mostly causes mutations in the CRHR2 protein, was significantly associated with a positive impact on the total active moiety level in the plasma of children with ASD.…”

Linking stress with urocortin in rats

“…Increased Urocortin"s after chronic variable stress is in accordance with the findings of [ 26 , 27 ] where stress induces neurodegenerative process with in the limbic system and hippocampus which causes more detrimental effects by high production of glucocorticoids which leads to the production of free radicals in the neurons because of oxidative stress [ 26 , 27 ]. It has been postulated that glucocorticoids regulate CRF transcription via a cAMP-responsive element (CRE) present in the promoter of the CRF-gene [ 28 ] Since CRE is also present in the promoter of the mouse UCN1 gene it might be a target for glucocorticoids to regulate UCN1-gene expression [ 29 ]. On the other hand, the expression of UCN2 in the mouse hypothalamus and brainstem appears to be controlled by glucocorticoids via a glucocorticoid-responsive element (GRE) in the Ucn2-gene promoter were reported [ 30 , 31 ].…”