Vanillin alleviates circadian disruption-induced cognitive impairment: involvement of gut microbiota alterations and tryptophan metabolism.

Circadian disruption (CD) is an important risk factor for cognitive impairment and neurodegenerative diseases, potentially through disturbances in tryptophan (TRP) metabolism. This study investigated the protective effects of orally administered vanillin in a mouse model of CD. CD impaired spatial learning and recognition memory, whereas vanillin improved cognitive performance and corrected abnormal changes in TRP-related metabolites, including tryptophan, kynurenine (KYN), and kynurenic acid (KYNA). Vanillin also modulated the composition and diversity of the gut microbiota, enhanced intestinal barrier function, and improved immune homeostasis. Immunofluorescence staining and western blot analysis further showed that vanillin regulated hippocampal proteins associated with neuronal and synaptic function and reduced astrocyte activation. These findings suggest that vanillin alleviates CD-induced cognitive impairment, accompanied by alterations in gut microbiota composition, TRP-kynurenine metabolism, intestinal barrier function, and neuroinflammatory responses.