<i>Panacis Quinquefolii Radix</i> Polysaccharides Alleviate Depressive‐Like Behaviors in Chronic Unpredictable Mild Stress‐Induced Mice by Suppressing Complement <scp>C1Q</scp> / <scp>C3</scp> ‐Mediated Microglial Synaptic Pruning and Modulating Gut

AIMS: Panax quinquefolius Radix (American ginseng) is a medicinal herb used for its neuroprotective and tonic effects. However, the antidepressant potential of its polysaccharide components is not well studied. This research aimed to investigate the antidepressant effects of XYS1, a polysaccharide from American ginseng, focusing on mechanisms related to the complement system and the gut-brain axis. METHODS: A chronic unpredictable mild stress (CUMS) mouse model was used to induce depressive behaviors. Mice were treated with XYS1 via oral gavage, followed by assessments of behavior, molecular changes, and gut microbiota. RESULTS: XYS1 treatment significantly alleviated depression-like behaviors in CUMS mice, as demonstrated by reduced immobility time in the TST and FST, and increased sucrose preference and body weight. Mechanistically, XYS1 attenuated complement system activation by downregulating C1Q expression in microglia and C3 expression in astrocytes, not only in the hippocampal CA1 region but also in the mPFC and PVN, as well as in the colon. Furthermore, XYS1 inhibited microglial activation and associated synaptic phagocytosis, preserved glutamatergic neuron density, restored excitatory synapse density, and reversed CUMS-induced gut microbiota dysbiosis by enriching Bacillota and reducing Bacteroidota abundance. Additionally, XYS1 effectively mitigated both colonic and systemic inflammation, reducing pro-inflammatory cytokines TNF-α and IL-1β and complement components C1Q and C3, while restoring anti-inflammatory IL-10 levels, thereby modulating the gut-brain axis. CONCLUSIONS: XYS1 exerts antidepressant effects by modulating the C1Q/C3 complement pathway, inhibiting microglial-mediated synaptic pruning, and restoring gut microbiota homeostasis.