Polygonatum cyrtonema Polysaccharides Alleviate Sleep Deprivation-Induced Behavioral Disorders via Gut Microbiota-Dependent Regulation of the Butyrate-HDAC3 Signaling Axis

Abstract

This study aimed to determine whether Polygonatum cyrtonema polysaccharides (PCP) protect against sleep deprivation (SD)-induced neurobehavioral disorders via gut microbiota and epigenetic regulation. PCP was characterized as a structurally stable, glucose-rich heteropolysaccharide. Intervention with PCP significantly alleviated anxiety- and despair-like behaviors, yielding a 42.7% improvement in open-arm exploration time during the EPM test compared to the SD group. Mechanistically, PCP preserved intestinal and blood–brain barrier integrity, suppressed microglial activation, and repaired hippocampal synapses. Microbial profiling revealed that PCP reshaped the gut microbiota by enriching butyrate-producing taxa, leading to a 1.3-fold elevation in fecal butyrate levels. This metabolic shift suppressed hippocampal HDAC3 activity and drove a 60.8% increase in BDNF expression. Notably, these neuroprotective effects were completely abolished in microbiota-depleted mice. Overall, PCP relies on a microbiota-driven cascade of butyrate production and subsequent epigenetic regulation to maintain gut-brain homeostasis.