Riglar David T, Giessen Tobias W, Baym Michael, Kerns S Jordan, Niederhuber Matthew J, Bronson Roderick T, Kotula Jonathan W, Gerber Georg K, Way Jeffrey C, Silver Pamela A
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.
Nat Biotechnol. 2017 Jul;35(7):653-658. doi: 10.1038/nbt.3879. Epub 2017 May 29.
Bacteria can be engineered to function as diagnostics or therapeutics in the mammalian gut but commercial translation of technologies to accomplish this has been hindered by the susceptibility of synthetic genetic circuits to mutation and unpredictable function during extended gut colonization. Here, we report stable, engineered bacterial strains that maintain their function for 6 months in the mouse gut. We engineered a commensal murine Escherichia coli strain to detect tetrathionate, which is produced during inflammation. Using our engineered diagnostic strain, which retains memory of exposure in the gut for analysis by fecal testing, we detected tetrathionate in both infection-induced and genetic mouse models of inflammation over 6 months. The synthetic genetic circuits in the engineered strain were genetically stable and functioned as intended over time. The durable performance of these strains confirms the potential of engineered bacteria as living diagnostics.
细菌可被设计用于在哺乳动物肠道中发挥诊断或治疗功能，但将实现这一目标的技术进行商业转化却受到了阻碍，原因是合成基因回路在肠道长期定殖过程中容易发生突变且功能不可预测。在此，我们报告了稳定的工程菌株，它们在小鼠肠道中能维持6个月的功能。我们对一种共生的小鼠大肠杆菌菌株进行了工程改造，使其能够检测炎症期间产生的连四硫酸盐。利用我们的工程诊断菌株（该菌株能在肠道中保留暴露记忆，以便通过粪便检测进行分析），我们在6个月的时间里，在感染诱导和基因小鼠炎症模型中均检测到了连四硫酸盐。工程菌株中的合成基因回路具有遗传稳定性，并且随着时间推移能按预期发挥作用。这些菌株的持久性能证实了工程细菌作为活体诊断工具的潜力。
