BackgroundSalidroside (Sal), the main component of a famous herbRhodiola rosea L, enhances memory performance and reduces fatigue. Therefore, this study assessed the effect ofSalon memory impairment induced by a long-term intake of ethanol (EtOH) in rats and investigated its relevant mechanisms using gut microbiota metagenomic analysis and hippocampal transcriptomic analysis.MethodsEighteen male SD rats were divided into the normal control group (CON group), EtOH model group (Model group), andSaltreatment group (Salgroup). The rats in the Model andSalgroups intragastrically (i.g.) received 2 g/kg EtOH for 30 consecutive days, whereas the CON group was given an equal volume of distilled water. Meanwhile, the rats in theSalgroup were administered i.g. 30 mg/kgSal60 min after EtOH intake. All rats were tested in the eight-arm maze for their memory function every 3 days. On the 30th day, metagenomic analyses of gut microbiota and transcriptomic analyses of the hippocampus were performed.ResultsCompared with the Model group,Saltreatment reduced the total time to complete the eight-arm maze task, decreased the number of arm entries, and abated the working memory error that was significant from the 9th day. Additionally,Salintervention improved the gut microbiota composition, such as the increased abundance ofActinobacteriaandBifidobacterium, which was related to the metabolism of amino acids and terpenoid carbohydrate, endocrine function, and signal transduction by neurotransmitters. In the hippocampus, the EtOH intake differentially expressed 68 genes (54 genes increased, whereas 14 genes decreased), compared with the CON group, whereasSalintervention affected these changes: 15 genes increased whereas 11 genes decreased. And, enrichment analyses revealed these genes were related to the structural components of the ribosome, mRNA splicing process, protein translation, mitochondria function, and immunological reaction. Finally, a correlation analysis found the memory impairment was positively correlated with the abnormal upregulation ofTomm7but negatively correlated with decreased abundance of gutAlistipes_indistinctus,Lactobacillus_taiwanensis,Lactobacillus_paragasseri, andLactobacillus johnsonii.ConclusionSalimproved memory impairment caused by long-term EtOH intake in rats, which may be related to its regulation of gut dysbiosis and hippocampal dysfunction.