Polysaccharides from Polygonatum cyrtonema Hua prevent depression-like behaviors in mice with chronic unpredictable mild stress through refining gut microbiota-lipopolysaccharide-paraventricular nucleus signal axis

As natural polysaccharide cannot directly pass the blood-brain barrier, it is of potential importance to investigate the systemic anti-depression mechanisms of polysaccharides (PSP) from <i>Polygonatum cyrtonema</i> Hua, a well-known herbal medicine with the anti-depressant activity. Here, we explored the underlying mechanisms of effects of PSP on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice from the perspective of the microbiota-gut-brain axis. The results demonstrated that PSP intervention for 14 days significantly improved CUMS-induced depressive-like behaviors. Interestingly, PSP treatment increased the relative abundance of <i>Muribaculaceae</i>, <i>Dubosiella</i> and <i>Lactobacillus</i> and decreased the relative abundance of <i>Akkermansia</i>, <i>Helicobacter</i> and <i>Clostridium_methylpentosum</i> in the colon of CUMS mice. Meanwhile, PSP blocked CUMS-induced impairment of intestinal barrier function, inhibited the levels of corticosterone and lipopolysaccharide (LPS), and increased the level of 5-hydroxytryptamine in the serum. Importantly, PSP treatment prevented abnormal neuronal activation and altered local field potential (LFP) in the paraventricular nucleus of CUMS mice, especially the decrease of power spectral density in delta and theta frequency bands. Finally, the results of LFP and c-fos staining after multiple repetitions of LPS injection showed consistencies with CUMS. Taken together, our study indicates that PSP ameliorates depression-like behavior likely via modulating the gut microbiota-lipopolysaccharide-paraventricular nucleus signal axis.