| Summary: | Sleep deprivation (SD) induces cognitive impairment associated with gut microbiota dysbiosis, making it crucial to explore natural remedies targeting the microbiota–gut–brain axis. This study aims to investigate whether <i>Ficus pandurata</i> var. <i>angustifolia</i> W.C. Cheng (a traditional medicine–food plant rich in flavonoids) can mitigate cognitive impairment caused by SD by modulating the gut microbiota. The sleep-deprived mouse model was established using the multiple platform water environment method. This study investigated the effects of <i>F. pandurata</i> var. <i>angustifolia</i> flavonoids (FCFs) via behavioral tests, 16S rRNA sequencing, and biochemical analyses to assess cognitive function, gut microbiota, and related pathways. FCF alleviated SD-induced cognitive deficits, reversed gut microbiota dysbiosis (increased beneficial bacteria like <i>Lactobacillus</i>, reduced harmful ones like <i>Desulfovibrio</i>), promoted short-chain fatty acids production, improved colonic histopathology and intestinal barrier function, reduced serum lipopolysaccharide, inhibited glial cell activation and TLR4/NF-κB signaling, and regulated neurotransmitters. In conclusion, FCF ameliorates SD-induced cognitive impairment through regulating gut microbiota, enhancing intestinal barrier, and suppressing neuroinflammation via the microbiota–gut–brain axis, providing a theoretical basis for its application.
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