Jiang Zheng-Meng, Wang Fang-Fang, Zhao Yuan-Yuan, Lu Lin-Feng, Jiang Xiao-Yu, Huang Tian-Qing, Lin Yang, Guo Long, Weng Ze-Bin, Liu E-Hu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China.
Phytomedicine. 2024 Sep;132:155847. doi: 10.1016/j.phymed.2024.155847. Epub 2024 Jul 3.
Gut microbiota dysbiosis significantly contributes to progression of depression. Hypericum perforatum L. (HPL) is traditionally used in Europe for treating depression. However, its mechanism remains largely underexplored.
This study aims to investigate the pivotal gut microbiota species and microbial signaling metabolites associated with the antidepressant effects of HPL.
Fecal microbiota transplantation was used to assess whether HPL mitigates depression through alterations in gut microbiota. Microbiota and metabolic profiling of control, chronic restraint stress (CRS)-induced depression, and HPL-treated CRS mice were examined using 16S rRNA gene sequencing and metabolomics analysis. The influence of gut microbiota on HPL's antidepressant effects was assessed by metabolite and bacterial intervention experiments.
HPL significantly alleviated depression symptoms in a manner dependent on gut microbiota and restored gut microbial composition by enriching Akkermansia muciniphila (AKK). Metabolomic analysis indicated that HPL regulated tryptophan metabolism, reducing kynurenine (KYN) levels derived from microbiota and increasing 5-hydroxytryptophan (5-HTP) levels. Notably, supplementation with KYN activated the NFκB-NLRP2-Caspase1-IL1β pathway and increased proinflammatory IL1β in the hippocampus of mice with depression. Interestingly, mono-colonization with AKK notably increased 5-hydroxytryptamine (5-HT) and decreased KYN levels, ameliorating depression symptoms through modulation of the NFκB-NLRP2-Caspase1-IL1β pathway.
The promising therapeutic role of HPL in treating depression is primarily attributed to its regulation of the NFκB-NLRP2-Caspase1-IL1β pathway, specifically by targeting AKK and tryptophan metabolites.
肠道微生物群失调显著促进抑郁症的进展。贯叶连翘在欧洲传统上用于治疗抑郁症。然而，其作用机制在很大程度上仍未得到充分探索。
本研究旨在调查与贯叶连翘抗抑郁作用相关的关键肠道微生物物种和微生物信号代谢物。
采用粪便微生物群移植来评估贯叶连翘是否通过改变肠道微生物群来减轻抑郁症。使用16S rRNA基因测序和代谢组学分析对对照、慢性束缚应激（CRS）诱导的抑郁症以及贯叶连翘治疗的CRS小鼠的微生物群和代谢谱进行检测。通过代谢物和细菌干预实验评估肠道微生物群对贯叶连翘抗抑郁作用的影响。
贯叶连翘以依赖肠道微生物群的方式显著减轻抑郁症状，并通过富集嗜黏蛋白阿克曼氏菌（AKK）恢复肠道微生物组成。代谢组学分析表明，贯叶连翘调节色氨酸代谢，降低源自微生物群的犬尿氨酸（KYN）水平并提高5-羟色氨酸（5-HTP）水平。值得注意的是，补充KYN激活了NFκB-NLRP2-Caspase1-IL1β通路，并增加了抑郁症小鼠海马中促炎细胞因子IL1β的水平。有趣的是，单一定植AKK显著增加了5-羟色胺（5-HT）并降低了KYN水平，通过调节NFκB-NLRP2-Caspase1-IL1β通路改善了抑郁症状。
贯叶连翘在治疗抑郁症方面具有前景的治疗作用主要归因于其对NFκB-NLRP2-Caspase1-IL1β通路的调节，特别是通过靶向AKK和色氨酸代谢物。
