In modern society, Circadian Rhythm Disruption (CRD), a pathological state where the internal biological clock is mismatched with the external environment, is a significant risk factor for cognitive impairment. This disruption can mediate cognitive damage through the gut-brain axis, with shift work and irregular schedules being two common triggers. Consequently, nutritional interventions for CRD-induced cognitive impairment are of great interest. However, the molecular regulatory mechanisms of natural food components, such as Dendrobium officinale stem polysaccharides (DOP) from Yandang Mountain, remain to be elucidated. Accordingly, this study investigated whether DOP ameliorates cognitive dysfunction in a CRD mouse model via the gut-brain axis. Integrated multi-omics and behavioral assessments demonstrated that DOP significantly restored spatial working memory and intestinal barrier integrity. Mechanistically, DOP enriched butyrate-producing genera (e.g., Butyricicoccus ) and elevated fecal butyrate levels, which coincided with suppressed systemic inflammation and upregulated brain-derived neurotrophic factor (BDNF). Furthermore, computational causal inference proposed a putative “Butyrate-Hdac2-Bdnf” axis, suggesting butyrate modulates synaptic plasticity potentially by inhibiting the epigenetic regulator histone deacetylase 2 (Hdac2). Pharmacokinetic predictions further characterized DOP as a gut-restricted prebiotic scaffold acting through metabolite biotransformation rather than direct absorption. Collectively, these findings highlight DOP as a promising prebiotic intervention for mitigating circadian-related cognitive impairment. • Dendrobium officinale polysaccharide mitigates cognitive decline from circadian disruption. • Enriches butyrate-producers and restores key short-chain fatty acid production. • Links gut metabolites to the brain's CREB and neurotrophic factor signaling.
Wang et al. (Sun,) studied this question.