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Variability of bacterial behavior in the mammalian gut captured using a growth-linked single-cell synthetic gene oscillator

View ORCID ProfileDavid T Riglar, David L Richmond, Laurent Potvin-Trottier, Andrew A Verdegaal, Alexander D Naydich, Somenath Bakshi, Emanuele Leoncini, Johan Paulsson, Pamela A Silver
doi: https://doi.org/10.1101/472720
David T Riglar
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston MA, USA
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  • ORCID record for David T Riglar
David L Richmond
3Image and Data Analysis Core, Harvard Medical School Boston MA, USA
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Laurent Potvin-Trottier
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
4Biology Department, Concordia University, Montreal QC, Canada
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Andrew A Verdegaal
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
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Alexander D Naydich
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston MA, USA
5Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge MA
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Somenath Bakshi
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
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Emanuele Leoncini
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
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Johan Paulsson
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
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Pamela A Silver
1Department of Systems Biology, Harvard Medical School, Boston MA, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston MA, USA
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Abstract

The dynamics of the bacterial population that comprises the gut microbiota plays key roles in overall mammalian health. However, a detailed understanding of bacterial growth within the gut is limited by the inherent complexity and inaccessibility of the gut environment. Here, we deploy an improved synthetic genetic oscillator to investigate dynamics of bacterial colonization and growth in the mammalian gut under both healthy and disease conditions. The synthetic oscillator, when introduced into both Escherichia coli and Salmonella Typhimurium maintains regular oscillations with a constant period in generations across growth conditions. We determine the phase of oscillation from individual bacteria using image analysis of resultant colonies and thereby infer the number of cell divisions elapsed. In doing so, we demonstrate robust functionality and controllability of the oscillator circuit’s activity during bacterial growth in vitro, in a simulated murine gut microfluidic environment, and in vivo within the mouse gut. We determine different dynamics of bacterial colonization and growth in the gut under normal and inflammatory conditions. Our results show that a precise genetic oscillator can function in a complex environment and reveal single cell behavior under diverse conditions where disease may create otherwise impossible-to-quantify variability in growth across the population.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 17, 2018.
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Variability of bacterial behavior in the mammalian gut captured using a growth-linked single-cell synthetic gene oscillator
David T Riglar, David L Richmond, Laurent Potvin-Trottier, Andrew A Verdegaal, Alexander D Naydich, Somenath Bakshi, Emanuele Leoncini, Johan Paulsson, Pamela A Silver
bioRxiv 472720; doi: https://doi.org/10.1101/472720
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Variability of bacterial behavior in the mammalian gut captured using a growth-linked single-cell synthetic gene oscillator
David T Riglar, David L Richmond, Laurent Potvin-Trottier, Andrew A Verdegaal, Alexander D Naydich, Somenath Bakshi, Emanuele Leoncini, Johan Paulsson, Pamela A Silver
bioRxiv 472720; doi: https://doi.org/10.1101/472720

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