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

Mar 31, 2026CNS neuroscience & therapeutics

Plant Polysaccharides Reduce Depression-Like Behavior in Stressed Mice by Limiting Immune Cell Synapse Removal and Changing Gut Bacteria

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Abstract

XYS1 treatment significantly alleviated depression-like behaviors in mice subjected to chronic unpredictable mild stress.

XYS1 reduced immobility time in the tail suspension test and forced swim test, indicating improved mood.
Increased sucrose preference and body weight suggest enhanced motivation and overall well-being following XYS1 treatment.
XYS1 downregulated complement protein C1Q in microglia and C3 in astrocytes, impacting brain regions involved in mood regulation.
The treatment inhibited microglial activation and preserved the density of glutamatergic neurons and excitatory synapses.
XYS1 also restored gut microbiota balance by increasing Bacillota and decreasing Bacteroidota abundance.
Reduction of pro-inflammatory cytokines and restoration of anti-inflammatory cytokine IL-10 were observed, indicating modulation of inflammation.

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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.

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

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