Liu Jialin, Fang Yichao, Cui Lixun, Wang Zhongzhao, Luo Yusha, Gao Congcong, Ge Wen, Huang Taohong, Wen Jun, Zhou Tingting
School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Biomed Pharmacother. 2022 May;149:112861. doi: 10.1016/j.biopha.2022.112861. Epub 2022 Mar 23.
Gut microbiota has emerged as a crucial target of gut-brain axis to influence depression. Zhi-Zi-Chi decoctions (ZZCD), as a classic oral formula in clinic, is widely applied in depression treatment nowadays. However, the underlying mechanism in the antidepressant activity of ZZCD remains unknown. 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. 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. 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.
肠道微生物群已成为肠-脑轴影响抑郁症的关键靶点。栀子豉汤作为临床上经典的口服方剂，如今广泛应用于抑郁症治疗。然而，栀子豉汤抗抑郁活性的潜在机制仍不清楚。基于行为测试和海马组织形态学结果，在大鼠中建立了经典的慢性轻度不可预测应激（CUMS）抑郁症模型。16S rRNA测序分析表明，栀子豉汤可增加产生短链脂肪酸和抗炎的细菌，并减少炎症和色氨酸代谢细菌。此外，栀子豉汤逆转了沿着脑-肠轴在肠道、血液和大脑中脑源性神经营养因子（BDNF）、肿瘤坏死因子-α（TNF-α）、促炎细胞因子和神经递质的改变，并恢复了由CUMS引起的盲肠内容物中丁酸盐的减少。然后，利用丁酸盐来验证其对抑郁大鼠病理特征的改善作用。综上所述，这些结果表明，栀子豉汤通过调节肠道微生物群促进丁酸盐的产生而发挥抗抑郁作用，丁酸盐进而沿着肠-脑轴调节抗炎、神经递质、内分泌和BDNF。因此，本研究填补了栀子豉汤在脑-肠轴方面抗抑郁机制的空白，并最终建立了一个多靶点、多层次的平台，用于进一步研究其他中药疗效的机制。
