美国加州理工学院Sarkis K. Mazmanian、Brittany D. Needham等研究人员合作发现，一种源自肠道的代谢物可改变小鼠的大脑活动和焦虑行为。2022年2月14日，《自然》杂志在线发表了这项成果。

研究人员表示，来自环境的感觉和分子输入的整合塑造了动物行为。暴露于环境分子的一个主要部位是胃肠道，其中的饮食成分被微生物群化学转化，肠道衍生的代谢物被传播到所有器官，包括大脑。在小鼠中，肠道微生物群影响行为，调节肠道和大脑中的神经递质生产，并影响大脑发育和髓鞘化形成。介导肠道-大脑相互作用的机制仍然定义不清，尽管它们广泛涉及体液或神经元连接。研究人员曾报道，在非典型神经发育的小鼠模型中，微生物代谢物4-乙基苯基硫酸盐（4EPS）的水平增加。

研究人员确定了肠道微生物组的生物合成基因，这些基因介导了饮食中的酪氨酸向4-乙基苯酚（4EP）的转化，并通过生物工程使小鼠的肠道细菌选择性地产生4EPS。4EPS进入大脑并与区域特定活动和功能连接的变化有关。基因表达特征显示了大脑中少突胶质细胞功能的改变，4EPS损害了小鼠的少突胶质细胞成熟，并减少了少突胶质细胞与神经元在体外脑培养物中的相互作用。被4EPS细菌定植的小鼠表现出神经元轴突的髓鞘化减少。大脑中髓鞘化动态的改变与行为结果有关。因此，研究人员观察到暴露于4EPS的小鼠表现出焦虑样的行为，而促进少突胶质细胞分化的药物治疗可防止4EPS的行为影响。这些发现表明，一种来自肠道的分子通过影响少突胶质细胞的功能和大脑中的髓鞘形成来影响了小鼠的复杂行为。

附：英文原文

Title: A gut-derived metabolite alters brain activity and anxiety behaviour in mice

Author: 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.

Issue&Volume: 2022-02-14

Abstract: 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.

DOI: 10.1038/s41586-022-04396-8

Source: https://www.nature.com/articles/s41586-022-04396-8