Umbelliferone Alleviates Sleep Deprivation Induced Cognitive Impairment through the Modulation of Gut Microbiota

Sleep deprivation (SD) is a major contributor to cognitive impairment, often accompanied by central neuroinflammation and gut microbiota dysbiosis. The tryptophan (TRP) pathway, activated via indoleamine 2,3-dioxygenase (IDO), serves as a critical link between immune activation and neuronal damage. Umbelliferone (UMB), a naturally occurring coumarin compound, possesses anti-inflammatory, antioxidant, and microbiota-modulating properties. A cognitive impairment model induced by SD was established to evaluate the effects of UMB on the central nervous system. Our findings showed that UMB treatment significantly improved learning and memory performance in mice subjected to sleep deprivation, restored gut microbiota composition, and levels of short-chain fatty acids (SCFAs), inhibited IDO expression, and rebalanced TRP-KYN metabolism. Additionally, UMB reduced pro-inflammatory cell release and oxidative stress, suppressed astrocyte and microglial activation, and upregulated synaptic protein PSD-95. It suggested that UMB may exert neuroprotective effects by modulating the gut–brain metabolic axis and alleviating neuroinflammation and synaptic dysfunction.