Shugan granule contributes to the improvement of depression-like behaviors in chronic restraint stress-stimulated rats by altering gut microbiota

Abstract

Aim: The investigation aims to evaluate the potential effect of Shugan Granule (SGKL) on the gut, brain, and behaviors in rats exposed to chronic restraint stress (CRS). Methods: The fecal microbiota and metabolite changes were studied in rats exposed to CRS and treated with SGKL (0.1 mg/kg/day). Depressive behaviors of these rats were determined through an open-field experiment, forced swimming test, sucrose preference, and weighing. Moreover, LPS-stimulated microglia and CRS-stimulated rats were treated with SGKL to investigate the regulation between SGKL and the PI3K/Akt/pathway, which is inhibited by LY294002, a PI3K inhibitor. Results: (i) SGKL improved the altered behaviors in CRS-stimulated rats; (ii) SGKL ameliorated the CRS-induced neuronal degeneration and tangled nerve fiber and also contributed to the recovery of intestinal barrier injury in these rats; (iii) SGKL inhibited the hippocampus elevations of TNF-α, IL-1β, and IL-6 in response to CRS modeling; (iv) based on the principal coordinates analysis (PCoA), SGKL altered α-diversity indices and shifted β-diversity in CRS-stimulated rats; (v) at the genus level, SGKL decreased the CRS-enhanced abundance of Bacteroides; (vi) Butyricimonas and Candidatus Arthromitus were enriched in SGKL-treated rats; (vii) altered gut microbiota and metabolites were correlated with behaviors, inflammation, and PI3K/Akt/mTOR pathway; (viii) SGKL increased the LPS-decreased phosphorylation of the PI3K/Akt/mTOR pathway in microglia and inhibited the LPS-induced microglial activation; (ix) PI3K/Akt/mTOR pathway inactivation reversed the SGKL effects in CRS rats. Conclusion: SGKL targets the PI3K/Akt/mTOR pathway by altering gut microbiota and metabolites, which ameliorates altered behavior and inflammation in the hippocampus.