Histone acetylation and mitochondrial function contribute importantly to neural differentiation, which is critically associated with neurodevelopmental disorders such as Down Syndrome (DS). However, whether and how histone acetylation regulates mitochondrial function and further affects neural differentiation has not been well described. In this study, when treated with retinoid acid (RA), the human neuroblastoma SH-SY5Y cell line was used as a neural differentiation model. We found that the acetylation of histone H3, especially H3 lysine 14 acetylation (H3K14ac), and mitochondrial function, including biogenesis and electron transport chain, were enhanced during neural differentiation. Specific inhibition of histone acetyltransferases (HATs) induced neural differentiation deficits, accompanied by downregulation of mitochondrial function. Furthermore, RA receptors (RARs) interacting with HATs were involved in the increased H3K14ac and the enhanced mitochondrial function during the neural differentiation process. Finally, receptor-interacting protein 140 (RIP140), a co-repressor of RARs, was also involved in regulating histone acetylation. RIP140 overexpression inhibited histone acetylation and mediated negative feedback on target genes which are involved in RA signaling. These findings evidenced that when interacting with RARs which had been negatively regulated by RIP140, RA promoted neural differentiation by promoting H3K14ac and enhanced mitochondrial function. This provides a molecular foundation for further investigations into abnormal neural development.

Cognitive impairment is a significant health problem worldwide, closely associated with the status of gut microbiota. Our recent research has revealed the Blautia faecis and Blautia massiliensis exhibit opposing associations with cognitive function in children with Down syndrome clinically characterized by cognitive dysfunction. However, the role and mechanisms of Blautia faecis and Blautia massiliensis in cognitive function remain unknown. Therefore, we gavaged C57BL/6 male mice with commercially available Blautia faecis and Blautia massiliensis for 3 weeks and assessed cognitive function using the novel object recognition and Y-maze test. Blautia faecis administration impaired cognitive performance, whereas Blautia massiliensis treatment improved it, with these effects observed predominantly in the absence of antibiotic pretreatment. Furthermore, we observed that administration of Blautia faecis increased the number of microglia, resulting in a twofold increase in cell count relative to WT control. Hippocampal pro-inflammatory cytokines were significantly upregulated in the Blautia faecis group, while Blautia massiliensis suppressed these neuroinflammatory responses. Notably, Blautia massiliensis produces approximately six times more acetate than Blautia faecis . Consequently, our findings indicate that Blautia massiliensis enhances cognitive function whereas Blautia faecis impairs it, and we speculate that differential acetate production may contribute to these opposing effects.