Intestinal Dysbacteriosis Contributes to Persistent Cognitive Impairment after Resolution of Acute Liver Failure

Abstract

Regulating the gut microbiota alleviates hepatic encephalopathy (HE). Whether it is imperative to withhold treatment for microbial imbalance after liver functional recovery remains unclear. The aim of this work was to elucidate the alterations in cognitive behavior, liver function, synaptic transmission, and brain metabolites in acute liver failure (ALF) mice before and after hepatic function recovery. Towards this end, thioacetamide was injected intraperitoneally to establish an ALF mouse model, which induced HE. Hierarchical clustering analysis indicated that while the liver functions normalized, cognitive dysfunction and intestinal dysbacteriosis occurred in the ALF mice 14 days after thioacetamide injection. In addition, fecal microbiota transplantation from the ALF mice with liver function recovery induced liver injury and cognitive impairment. Alterations in synaptic transmission were found in the ALF mice with liver function improvement, and the correlations between the gut bacteria and synaptic transmission in the cortex were significant. Finally, apparent alterations in the brain metabolic profiles of the ALF mice were detected after liver function improvement by performing ¹H nuclear magnetic resonance spectroscopy, suggesting a risk of HE. These results showed that intestinal dysbacteriosis in ALF mice with liver function recovery is sufficient to induce liver injury and cognitive impairment. This indicates that continuous care may be necessary for monitoring microbial imbalance even in patients with ALF-induced HE whose liver function has recovered significantly.