Chronic sleep deprivation (SD) induces systemic inflammation and significantly increases the risk of neuropsychiatric disorders, including anxiety. Our previous findings demonstrated that Lactobacillus kisonensis (L. kisonensis)-fermented red quinoa (RQF) was enriched with polyphenols possessing anti-inflammatory potential. However, whether RQF confers neuroprotection against SD-induced injury remains unexplored. This study therefore examined this effect and underlying mechanisms in a murine model of chronic SD. C57BL/6 J mice were subjected to SD (20 h/d for 4 weeks) using an SD apparatus and simultaneously administered RQF supernatant daily via oral gavage (20 mL/kg·body weight, containing 5 × 108 CFU/mL L. kisonensis). Our results showed that RQF treatment elevated central entries, visit time, and distance in the open field test, as well as time spent in open arms in the elevated plus maze test, suggesting reduced anxiety-like behavior. RQF also preserved hippocampal synaptic ultrastructure, as observed by transmission electron microscopy. Mechanistically, RQF partially modulated the mRNA expression of circadian rhythm genes (Bmal1, Clock, Per, Cry) in the liver, brain, and colon, while upregulating antioxidant enzyme genes (Cat, Gpx, Sod) and suppressing pro-inflammatory cytokines (Tnf-α, Il-6, Il-1β). Moreover, RQF upregulated tight junction proteins (ZO-1, Ocln, Cldn1) and reduced serum LPS levels, collectively indicating improved intestinal barrier integrity. Furthermore, RQF increased gut microbiota diversity, reduced the relative abundance of the pro-inflammatory genus Faecalibaculum, and enriched short-chain fatty acids (SCFA)-producing genera, including Muribaculum and Duncaniella. Targeted SCFA analysis confirmed that RQF significantly elevated fecal isobutyric, isovaleric, and caproic acids, and upregulated the mRNA expression of SCFA receptors (Ffar2, Ffar3), the downstream target Npy, and Hdac3. In conclusion, RQF supplementation alleviates SD-induced anxiety-like behavior and inflammation, an effect associated with gut-brain axis modulation. These findings suggest that fermented red quinoa may represent a promising dietary strategy against sleep deprivation-induced neurobehavioral deficits.
