The anti-depressive role of the Pei Yuan Kai Yu formula in cerebral small vessel disease based on gut microbiota

Lixuan Yang¹Yutian Ao¹Yannan Li¹Baoan Dai¹Junnan Li²Wenzhe Duan¹Kaiqiang Dong¹Zhenyun Han³Rongjuan Guo^4*

• ¹Beijing University of Chinese Medicine, Beijing, Beijing Municipality, China
• ²Johns Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, United States
• ³Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
• ⁴Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China

This study investigated the antidepressant effect of Pei Yuan Kai Yu formula (PY) on rats with cerebral small vessel disease (CSVD) comorbid with depression. To mimic this condition, Dahl/SS rats were fed a diet containing 8% NaCl and were subjected to chronic unpredictable mild stress (CUMS) stimulation for four weeks. PY (1.407 g/kg/day) was administered intragastrically to evaluate its role in CSVD with depression. Pseudo germ-free rats were colonized with gut microbiota from highsalt-fed rats exposed to CUMS, followed by PY administration. In rats with CSVD and depression, PY significantly increased body weight; alleviated depression-like behaviors; and decreased the levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in both serum and hippocampus. Additionally, PY reversed inflammationinduced nerve damage; reduced the overexpression of microglia in the hippocampus; decreased the levels of hippocampal VEGF and MMP-9, and increased the levels of hippocampal occludin, ZO-1, and claudin-5. Moreover, PY improved the composition of gut microbiota and enhanced microbial diversity. PY induced characteristic changes in the microbiome, which were associated with inflammation, endothelial dysfunction, and depressive-like behaviors. These significant metabolites were identified and were found closely related to inflammation, endothelial cell dysfunction, and depression-like behaviors. In conclusion, PY acts as an antidepressant to slow down the progression of CSVD by inhibiting microglial activation, reducing inflammation and ameliorating endothelial dysfunction. It exerts its effect, at least in part, by enhancing microbiota-mediated metabolism in vivo.