Paeonia lactiflora Pall. Polysaccharide alleviates depression in CUMS mice by inhibiting the NLRP3/ASC/Caspase-1 signaling pathway and affecting the composition of their intestinal flora

Paeonia lactiflora Pall. (PL) has been commonly used to de-stressing the liver and relieve depression in traditional Chinese medicine for over a thousand years. Recently, it has been widely used in studies on anti-depressant, anti-inflammatory and regulation of intestinal flora. However, the polysaccharide component has received less attention than the saponin component of PL.This study aimed to elucidate the effects of Paeonia lactiflora polysaccharide (PLP) on depressive behavior in mice in a chronic unpredictable mild stress (CUMS) model and its possible action mechanisms.A model of chronic depression induced by the CUMS approach. Behavioral experiments were used to assess the success of the CUMS model and the therapeutic impact of PLP. Then the extent of damage to the colonic mucosa was assessed by H&E staining; the extent of neuronal damage was assessed by Nissler staining. Inflammatory factor expression was assessed at different sites in the mouse by enzyme-linked immunoassay (Elisa). The alterations of faecal microflora were detected by 16S rRNA gene sequencing. In the colonic tissues, NLRP3, ASC and Caspase-1 mRNA and protein levels detected by quantitative real-time PCR (qRT-PCR) and Western blot(WB).PLP can improve depressive behavior in CUMS mice, and colonic mucosal and neuronal damage. Elisa assay showed that PLP could reduce interleukin-1β (IL-1β), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) levels, and increase 5-Hydroxytryptamine(5-HT) levels in CUMS mice. 16S sequencing analysis showed that PLP could regulate the intestinal flora of CUMS mice and increase their species richness. In addition, PLP significantly inhibited NLRP3/ASC/Caspase-1 signalling pathways activation in the colonic tissues of CUMS mice.PLP modulates depression-related intestinal ecological dysregulation, increases species richness, and inhibits inflammatory factors levels and NLRP3 inflammasome activation to reduce colonic mucosal and neurons damage, thereby improving depression-like behavior and neurotransmitter release in CUMS mice.