Paeoniflorin ameliorates depressive behaviours by modulating microbiota–gut–brain axis functions

Background Major depressive disorder (MDD), characterised by persistent anhedonia and elevated suicide risk, represents a global mental health challenge. Recent studies suggest a link between gut–brain axis dysfunction and depression. The natural compound paeoniflorin demonstrates clinically relevant antidepressant effects, yet its underlying neurobiological mechanisms remain elusive.Aims This study aims to examine how paeoniflorin alleviates depression-like behaviours in rats subjected to chronic unpredictable mild stress (CUMS) by modulating the function of gut–brain axis, and explore the connections between gut microbiota, metabolites and MDD.Methods Depression-like behaviours in rats were induced by CUMS, and the antidepressant effect of paeoniflorin was assessed using behavioural tests. The composition and function of the intestinal microbiota were analysed using 16S rRNA sequencing, and metabolomic analysis was performed on serum, hippocampus, jejunum and faecal samples. Enzyme-linked immunosorbent assay and hematoxylin and eosin staining were used to detect the levels of inflammatory factors and cortisol, as well as the infiltration of inflammatory cells in the jejunum of rats after cohousing. Long-term potentiation assays and Golgi staining were used to detect dendritic spine density and synaptic plasticity, respectively.Results Paeoniflorin significantly alleviated depression-like behaviours and cognitive deficits in CUMS rats. 16S rRNA sequencing revealed that paeoniflorin improved the abundance and diversity of the gut microbiota in CUMS rats. Enrichment of differential metabolites in the brain, intestine, faeces and serum revealed a primary accumulation in the amino acid metabolism pathway. We further observed a correlation between the relative abundance of microbial communities and metabolites. Cohousing experiments verified that microbial metabolites of paeoniflorin can reduce neuroinflammation and improve synaptic plasticity.Conclusions Disruptions in gut microbiota and its metabolites impair gut–brain interactions. Paeoniflorin’s neuroprotective and antidepressant effects are mediated through the modulation of the function of the gut–brain axis.