Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.
Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.
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微生物群-肠-脑轴参与慢性束缚应激：肠道和大脑中犬尿氨酸代谢途径的紊乱
DOI：
10.1080/19490976.2020.1869501
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发表时间：
2021-01
期刊：
影响因子：
12.2
通讯作者：
Gao R
中科院分区：
文献类型：
--
作者：
Deng Y;Zhou M;Wang J;Yao J;Yu J;Liu W;Wu L;Wang J;Gao R
新出现的证据表明，肠道微生物群可能与宿主大脑相互作用，并在神经精神疾病的发病机制中发挥关键作用。然而，抑郁症中微生物-肠-脑轴沿着相互作用的机制仍不清楚。本研究通过建立慢性束缚应激（CRS）小鼠模型，探讨色氨酸（Trp）神经传递在抑郁症肠道和中枢水平的代谢信号转导。结果表明，CRS小鼠表现出抑郁和焦虑样行为。此外，犬尿氨酸（Kyn）及其代谢产物，一个重要的色氨酸代谢途径，在大脑中被强烈激活。有趣的是，Kyn毒性信号在肠道中加剧，特别是在结肠中。吲哚胺2，3-双加氧酶（IDO）是一种负责Kyn代谢途径启动的限速酶，与对照小鼠相比，CRS小鼠的脑和肠道中的IDO显著上调，促进Trp代谢途径向Kyn信号转导的转移。此外，IDO抑制剂1-甲基色氨酸（1-MT）的给药部分挽救了CRS诱导的抑郁和焦虑样变化。此外，CRS介导的增强的肠道通透性允许有毒代谢物“泄漏”到血流中。CRS小鼠的微生物组谱显示出明显改变的分类组成，并且在脑中的肠杆菌属、副杆菌属和Kyn水平之间观察到负相关。通过西酞普兰治疗、IDO抑制剂和微生物群干预进一步验证了大脑和肠道之间的相互串扰，这抵消了CRS小鼠中的抑郁样行为、Kyn代谢信号传导和微生物群组成。同时，拟杆菌处理影响小鼠海马Trp代谢，表现为5-HT浓度升高以及5-HT/Trp比值升高。这些结果表明，长期的压力破坏了Kyn代谢和沿着肠-脑轴的内分泌功能，伴随着某些微生物群的稳态被破坏，这些微生物群共同促成了抑郁样行为的发展。
Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, kynurenine (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to “leak” into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed between Enterorhabdus, Parabacteroides and Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile, Parabacteroides treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior.
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作者：
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