Chronic alcoholic encephalopathy (CAE) is a condition induced by alcohol consumption, with a huge demand for research on its prevention and treatment drugs. Puerarin, the principal active compound found in Pueraria lobata, has been traditionally utilized in ethnopharmacology to mitigate alcoholic brain injury and rectify imbalances in intestinal flora. The study was aimed to investigate the mechanism by which puerarin exerts its anti-CAE effect. The CAE mice model induced by alcohol were treated with oral administration of puerarin. First, the effects of puerarin on cognitive function, motor ability, and hippocampal tissue pathology along with the expression of TLR4, Myd88, NF-κB, IL-1β, and IL-6 of brain and fecal LPS were investigated. Finally, the composition of the gut microbiome of fecal and TJs (Claudin-1 and Occludin) in the intestine and colon, focusing on the production and transporter of LPS, were measured. The findings revealed that puerarin administration significantly ameliorated motor deficits, anxiety-like behaviors, and cognitive impairments in CAE mice. Histopathological analysis revealed puerarin reduced hippocampal damage and decreased Iba1 immunoreactivity, indicating attenuated neuroinflammation. Puerarin treatment downregulated the protein expression of IL-1β, IL-6, TLR4, Myd88, and NF-κB in brain. Notably, puerarin restored intestinal barrier integrity by upregulating Claudin-1 and Occludin expression. Intestinal flora analysis demonstrated that puerarin treatment increased the abundance of beneficial bacteria (e.g., norank_f_Eubacterium_coprostanoligenes_group) while reducing pathogenic bacteria (e.g., Escherichia-Shigella). The study showed that puerarin exerts a treatment CAE effect, which may be related to modulation of the "microbiota-gut-brain axis" LPS/TLR4/NF-κB inflammatory pathway.
