4.8 Article

A designed whole-cell biosensor for live diagnosis of gut inflammation through nitrate sensing

Journal

BIOSENSORS & BIOELECTRONICS
Volume 168, Issue -, Pages -

Publisher

ELSEVIER ADVANCED TECHNOLOGY
DOI: 10.1016/j.bios.2020.112523

Keywords

Whole cell biosensor; Gut inflammation; Designer probiotic; Nitrate sensing; Thiosulfate sensing; Boolean AND gate

Funding

  1. Bio & Medical Technology Development Program [2018M3A 9H3024746]
  2. National Research Foundation - Ministry of Science and ICT of the Republic of Korea
  3. KRIBB Research Initiative Program
  4. National Research Council of Science & Technology (NST), Republic of Korea [KGM5402012] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Microbes reprogrammed using advanced genetic circuits are envisaged as emerging living diagnostics for a wide range of diseases and play key roles in regulating gut microbiota to treat disease-associated symptoms in a noninvasive manner. Here, we developed a designer probiotic Escherichia coli that senses and responds to nitrate, a biomarker of gut inflammation. To this end, we first employed the NarX-NarL two-component regulatory system in E. coli to construct a nitrate-responsive genetic circuit. Next, we optimized the nitrate biosensor for the best performance using measures of sensitivity and specificity. We then introduced this genetic circuit into a probiotic E. coli Nissle 1917. We demonstrated that the designed biosensor can sense elevated nitrate levels during gut inflammation in mice with native gut microbiota. Moreover, using Boolean AND gate, we generated a genetically encoded biosensor for simultaneous sensing of the thiosulfate and nitrate biomarkers, thus increasing the tool's specificity for diagnosing gut inflammation. The nitrate-responsive genetic circuit will enable new approaches for non-invasive diagnostics of inflammation-associated diseases.

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