AbstractAimsPatients with acute liver injury (ALI) can develop cognitive dysfunction (CD). The study investigated the role of gut microbiota and cerebral metabolism in ALI mice with and without CD.MethodsMale C57BL/6 mice that received thioacetamide were classified into ALI mice with (susceptible) or without (unsusceptible) CD‐like phenotypes by hierarchical cluster analysis of behavior. The role of gut microbiota was investigated by 16S ribosomal RNA gene sequencing and feces microbiota transplantation (FMT).1H‐[13C] NMR and electrophysiology were used to detect the changes in cerebral neurotransmitter metabolic and synaptic transition in neurons or astrocytes.ResultsApromixlay 55% (11/20) of mice developed CD and FMT from the susceptible group transmitted CD to gut microbiota‐depleted mice.Alloprevotellawas enriched in the susceptible group. GABA production was decreased in the frontal cortex, while hippocampal glutamine was increased in the susceptible group. AlteredEscherichia. ShigellaandAlloprevotellawere correlated with behaviors and cerebral metabolic kinetics and identified as good predictors of ALI‐induced CD. The frequencies of both miniature inhibitory and excitatory postsynaptic currents in hippocampal CA1 and prefrontal cortex were decreased in the susceptible group.ConclusionAltered transmitter metabolism and synaptic transmission in the hippocampus and prefrontal cortex and gut microbiota disturbance may lead to ALI‐induced CD.