Shouhui Tongbian Capsule Is Associated with Antidepressant-Like Effects and Gut-Brain Axis-Related Biological Improvements in Mouse Models of Depression

Major depressive disorder (MDD) is a global health challenge with complex etiology. The gut-brain axis, particularly neuroinflammation and synaptic dysfunction, has emerged as a critical therapeutic target. Shouhui Tongbian Capsule (SHTB), a clinically used Chinese patent medicine for constipation, has shown potential in modulating gut microbiota and alleviating comorbid mood symptoms, yet its systemic antidepressant mechanisms remain unexplored. This study aimed to evaluate the antidepressant-like effects of SHTB in mouse models and characterize accompanying gut- and brain-related biological changes. Network pharmacology was used to assess whether reported SHTB constituents were relevant to depression-related gene networks. Subsequent in vivo validation was conducted in lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS) mouse models of depression. Behavioral phenotypes, neuroinflammation, hippocampal neuronal and synaptic integrity, intestinal barrier function, and mRNA expression of selected predicted targets were evaluated. Exploratory network analysis indicated potential associations between reported SHTB constituents and depression-related gene networks, providing a preliminary rationale for animal experiments. In vivo, SHTB administration was associated with significant improvements in depressive- and anxiety-like behaviors in both LPS and CUMS-induced mouse models of depression. These behavioral effects were accompanied by attenuation of neuroinflammatory responses, preservation of hippocampal neuronal and synaptic features, maintenance of intestinal barrier integrity, and altered hippocampal expression of several neurotransmitter-related genes. SHTB showed significant antidepressant-like effects accompanied by gut-brain axis-related biological improvements. This study provides a novel, multi-evidence rationale for repurposing SHTB as a promising multi-target therapeutic agent for MDD, mediated via the gut-brain axis. • SHTB attenuates LPS-induced depressive and anxiety-like behaviors in mice • SHTB reverses CUMS-induced depressive-like and anxiety-like behaviors in mice • SHTB alleviated LPS-induced neuroinflammation and neuronal loss in the hippocampus • SHTB rescues synaptic loss in LPS-induced depressive mice • SHTB ameliorates gut barrier dysfunction of colon tissue driven by LPS