本文是肠道菌群如厚壁菌门、拟杆菌门、放线菌门和变形菌门等，影响脑部的正常发育和功能调节等，在自闭症、焦虑症、抑郁症和其他疾病中发挥作用的基础科学研究论文。
(Translated by Baidu: )
Nature: Intestinal microbiota metabolites can affect brain activity and lead to anxious behavior! Anxiety can originate from gut microbiota
This article is a fundamental scientific research paper on gut microbiota such as Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, which affect normal brain development and functional regulation, and play a role in autism, anxiety, depression, and other diseases.
（百度翻訳： ）
Nature：腸内微生物代謝物は脳活動に影響を与え、不安行動を引き起こす！不安は腸内細菌群に由来する可能性がある
本文は腸管菌群、例えば厚肉菌門、擬桿菌門、放線菌門と変形菌門など、脳の正常な発育と機能調節などに影響し、自閉症、焦慮症、うつ病とその他の疾病の中で作用する基礎科学研究論文である。
BioArt
2022/03/07
论文
论文标题：A gut-derived metabolite alters brain activity and anxiety behaviour in mice
作者：Needham, Brittany D., Funabashi, Masanori, Adame, Mark D., Wang, Zhuo, Boktor, Joseph C., Haney, Jillian, Wu, Wei-Li, Rabut, Claire, Ladinsky, Mark S., Hwang, Son-Jong, Guo, Yumei, Zhu, Qiyun, Griffiths, Jessica A., Knight, Rob, Bjorkman, Pamela J., Shapiro, Mikhail G., Geschwind, Daniel H., Holschneider, Daniel P., Fischbach, Michael A., Mazmanian, Sarkis K.
期刊：Nature
发表时间：2022/02/14
数字识别码：10.1038/s41586-022-04396-8
摘要：Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut–brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte–neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9,10,11,12,13,14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.
数十年来，科学家在关于自闭症的研究中取得了一些引人注目的成果。大约3/4的自闭症患者同时伴有某些胃肠功能异常，这一现象促使科学家们探究肠道微生物与自闭症之间的潜在联系。近期研究表明，自闭症患者的肠道菌群与对照组有显著差异，但微生物具体如何与自闭症互相作用，微生物究竟是自闭症的一个触发器还是防护盾，依旧是未解之谜。加州理工学院的微生物学家萨尔基斯·马兹曼尼亚（Sarkis Mazmanian）一直致力于探究肠道菌群与自闭症的关系，因其在肠道菌群方面的工作，他在2012年获得了麦克阿瑟奖（MacArthur Fellows Program or MacArthur Fellowship，俗称“天才奖”，被视为美国跨领域最高奖项之一）。目前，马兹曼尼亚和他的同事们已经确定了一个可能介导肠道菌群和自闭症相互作用的关联物，即由肠道细菌产生的名为4-乙基苯酚硫酸盐（4-ethylphenyl sulphate, 4EPS）的化学物质。他们发现，有自闭症症状的小鼠，血液中的4EPS水平比对照组小鼠高出40多倍；给小鼠注射4EPS后，会出现类似自闭症的症状【4】。马兹曼尼亚认为“在小鼠模型中除掉产生4EPS的源头，自闭症症状便会消失，调整肠道细菌可能是治疗自闭症的一项可行的措施，”。但4EPS水平与大脑之间的关系尚不明确。
2022年2月14日，Sarkis K. Mazmanian团队在Nature杂志上在线发表了题为A gut-derived metabolite alters brain activity and anxiety behaviour in mice的文章，揭示了4EPS与大脑相互作用的机制。研究人员发现酪氨酸可以被肠道微生物群代谢成4EP，随后4EP在宿主磺基转移酶（SULT1A1）的作用下生成4EPS；4EPS进入小鼠大脑，影响特定大脑区域的激活和连接，并破坏大脑中少突胶质细胞的成熟和髓鞘形成模式，进而调控小鼠的大脑活动和焦虑样行为。
虽然4EP或4EPS（之后统称为4EP(S)）可能对各种器官都有影响，但该研究中，作者重点关注的是大脑。通过功能超声成像（functional ultrasound imaging, fUSi）评估4EP+和4EP−小鼠的全脑功能连接差异：与4EP−小鼠相比，4EP+小鼠内信号传导模式的相关性发生改变，主要发生在海马（hippocampus）、丘脑（thalamus）、杏仁核（amygdala）、下丘脑（hypothalamus）、梨状体（piriform）和皮层（cortex），提示4EPS的升高与小鼠大脑各区域间异常的功能连接有关。随后作者通过葡萄糖摄取实验比较了大脑的神经活动：4EP(S)与下丘脑亚区（前部、外侧和室旁核）、杏仁核（前部、基底外侧、中央和皮层）和终纹床核（bed nucleus of the stria terminalis, BNST），以及丘脑室旁核（paraventricular nucleus of the thalamus, PVT）的葡萄糖摄取增加有关。这些数据表明，4EP会导致多个大脑区域的功能连接和活动改变，包括几个与边缘系统相关的区域。
1. Sharon, G. et al. Specialized metabolites from the microbiome in health and disease. Cell Metab. 20, 719–730 (2014).
2. Vuong, H. E., Yano, J. M., Fung, T. C. & Hsiao, E. Y. The microbiome and host behavior. Annu. Rev. Neurosci. 40, 21–49 (2017).
3. Huang, F. & Wu, X. Brain neurotransmitter modulation by gut microbiota in anxiety and depression. Front. Cell Dev. Biol. 9, 649103 (2021).
4. Needham, B. D. et al. Plasma and fecal metabolite profiles in autism spectrum disorder. Biol. Psychiatry 89, 451–462 (2020).
5. Chamkha, M., Garcia, J. L. & Labat, M. Metabolism of cinnamic acids by some Clostridiales and emendation of the descriptions of Clostridium aerotolerans, Clostridium celerecrescens and Clostridium xylanolyticum. Int. J. Syst. Evol. Microbiol. 51, 2105–2111 (2001).
6. Santamaría, L., Reverón, I., Felipe, F. L. D., et al. Ethylphenol Formation by Lactobacillus plantarum: identification of the enzyme involved in the reduction of vinylphenols. Appl. Environ. Microbiol. 84, e01064-18 (2018).
