Gut microbiota regulates hepatic ischemia-reperfusion injury-induced cognitive dysfunction via the HDAC2-ACSS2 axis in mice

Abstract Hepatic inflow occlusion is a common procedure in liver surgery aimed at reducing intraoperative bleeding and improving surgical visualization. However, as a complication, hepatic ischemia-reperfusion injury (HIRI) resulting from this procedure is inevitable. Research has confirmed that cognitive dysfunction induced by HIRI is closely related to dysbiosis of the gut microbiota. To investigate the mechanisms underlying this complication, gut microbiota transplantation, HDAC2-ACSS2 axis detection, and LC/MS short-chain fatty acid detection were employed. Results showed a significant decrease in ACSS2 expression in the hippocampus of mice with hepatic ischemia-reperfusion injury, highlighting impaired acetate metabolism in this region. Moreover, both the phenotype of cognitive impairment and the dysregulation of the HDAC2-ACSS2 axis could be transferred to germ-free mice through fecal microbial transplantation. Enzyme-linked immunosorbent assay also revealed reduced Acetyl-coenzyme A (acetyl-CoA) levels in the hippocampus. These findings suggest that acetate metabolism is impaired in the hippocampus of HIRI-induced cognitive impairment mice and related to dysbiosis, leading to compromised histone acetylation. Keywords： hepatic ischemia, reperfusion injury, cognitive dysfunction, gut microbiota, HDAC2-ACSS2 axi