Butyrate emerges as a crucial effector of Zhi-Zi-Chi decoctions to ameliorate depression via multiple pathways of brain-gut axis

Abstract Background: Gut microbiota has emerged as a crucial target of gut-brain axis to influence brain and behavior and also has been closely connected with depression. Zhi-Zi-Chi decoctions (ZZCD), as a classic oral formula in clinic prescribed to clear heat and relieve restlessness traditionally, is widely applied in depression treatment nowadays. However, the underlying mechanism in the antidepressant activity of ZZCD remains largely unknown. Our previous study revealed that isoflavones, the bioactive constituents of Semen Sojae Praeparatum, benefited health by regulating the gut microbiota, which introduced the gut microbiota into understanding the mechanism of Traditional Chinese Medicine (TCM). Hence, in the present study, we aimed to investigate the antidepressant mechanism of ZZCD by focusing on the gut microbiota. Results: A classic depression model of chronic mild unpredictable stress (CUMS) was established in rats based on the results of behavioral tests and hippocampal histomorphology. 16S rRNA sequencing analysis indicated that ZZCD could increase short-chain fatty acid-producing and anti-inflammatory bacteria and reduce inflammatory and tryptophan-metabolizing bacteria, which reflected the changes of short-chain fatty acids (SCFAs), inflammation and tryptophan metabolism from the perspective of the gut microbiota. Furthermore, ZZCD reversed the alterations of BDNF, TNF-α, pro-inflammatory cytokines and neurotransmitters in the gut, blood and brain along the brain-gut axis and restored the decrease of butyrate in cecal content caused by CUMS. Then, butyrate was utilized to validate its ameliorative effect on pathological characteristics of depressive rats. Conclusions: Taken together, these results show that ZZCD exhibits antidepressant effect through modulating gut microbiota to facilitate the production of butyrate, which further regulate anti-inflammation, neurotransmitters, endocrine and BDNF along the gut-brain axis. Hence, this study fills the gap of the antidepressive mechanism of ZZCD in the light of the brain-gut axis and established a multi-targets and multi-levels platform eventually for further research into the mechanism of other TCM efficacy.