PNAS：如何把肠道细菌改造成一种监测肠道环境的刺激因素

肠道是一个黑暗和隐秘的世界。我们通常只知道当它出现严重错误会发生什么。但我们肠道里有着成千上万的微生物，根据他们的天性，完全定位它们，然后告诉我们自己内部发生了什么事情。哈佛医学院的Pamela A. Silver正在训练它们做到这一点。她的团队正在把大肠埃希氏菌(E. coli)改造成探测活小鼠肠道内的一种环境刺激因素，并且以非侵入式的方式记录并报告这种刺激因素。

Pamela A. Silver及其同事试图改造肠道细菌大肠埃希氏菌(E. coli)的一个遗传系统，从而能够在一个活系统内部进行环境监测。

这组作者把来自通常感染大肠埃希氏菌(E. coli)的细菌病毒——λ噬菌体的cI/Cro遗传开关引入到了大肠埃希氏菌(E. coli)的基因组中。当这种经过改造的大肠埃希氏菌(E. coli)在体外培养并且暴露在失去活性的抗生素去水四环素中的时候，这种化学物质触发了这种噬菌体基因开始制造Cro蛋白。在没有去水四环素的情况下，这种细菌的噬菌体基因产生了cl蛋白。

这组作者把这个遗传开关系统转移给了从小鼠肠道中分离出来的适应小鼠肠道的大肠埃希氏菌(E. coli)菌株，然后让小鼠服下这种经过改造的大肠埃希氏菌(E. coli)。

对小鼠粪便样本的分析证实了这种经过改造的细菌在小鼠肠道立足并且正在制造cl蛋白。在让这些小鼠服用去水四环素之后，从粪便样本中收集的大肠埃希氏菌(E. coli)主要制造Cro蛋白，这提示这个遗传开关因为暴露在去水四环素中而被触发了，这类似于在体外观察到的情况。这组作者说，这些结果证明了一个遗传报告系统可以在一个活体生物内部稳定运行，让针对复杂内部环境的非侵入式探测成为可能。

原文摘要：

Programmable bacteria detect and record an environmental signal in the mammalian gut

Jonathan W. Kotula, S. Jordan Kerns, Lev A. Shaket, Layla Siraj, James J. Collins,Jeffrey C. Way and Pamela A. Silver

The mammalian gut is a dynamic community of symbiotic microbes that interact with the host to impact health, disease, and metabolism. We constructed engineered bacteria that survive in the mammalian gut and sense, remember, and report on their experiences. Based on previous genetic memory systems, we constructed a two-part system with a “trigger element” in which the lambda Cro gene is transcribed from a tetracycline-inducible promoter, and a “memory element” derived from the cI/Cro region of phage lambda. The memory element has an extremely stable cI state and a Cro state that is stable for many cell divisions. When Escherichia coli bearing the memory system are administered to mice treated with anhydrotetracycline, the recovered bacteria all have switched to the Cro state, whereas those administered to untreated mice remain in the cI state. The trigger and memory elements were transferred from E. coli K12 to a newly isolated murine E. coli strain; the stability and switching properties of the memory element were essentially identical in vitro and during passage through mice, but the engineered murine E. coli was more stably established in the mouse gut. This work lays a foundation for the use of synthetic genetic circuits as monitoring systems in complex, ill-defined environments, and may lead to the development of living diagnostics and therapeutics.

标签: 肠道环境 肠道细菌 大肠埃希氏菌

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