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In situ reprogramming of gut bacteria by oral delivery

View ORCID ProfileBryan B. Hsu, View ORCID ProfileIsaac N. Plant, Lorena Lyon, Frances M. Anastassacos, Jeffrey C. Way, Pamela A. Silver
doi: https://doi.org/10.1101/2020.04.15.043232
Bryan B. Hsu
1Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24060, United States
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, United States
3Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 United States
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  • For correspondence: bhsu@vt.edu
Isaac N. Plant
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, United States
3Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 United States
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Lorena Lyon
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, United States
3Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 United States
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Frances M. Anastassacos
3Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 United States
4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States
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Jeffrey C. Way
3Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 United States
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Pamela A. Silver
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, United States
3Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 United States
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Abstract

Abundant links between the gut microbiota and human health indicate that the modification of bacterial function could be a powerful therapeutic strategy. The inaccessibility of the gut and inter-connections between gut bacteria and the host make it difficult to precisely target bacterial functions without disrupting the microbiota and/or host physiology. Herein we describe a multidisciplinary approach to modulate the expression of a specific bacterial gene within the gut by oral administration. We first demonstrate that an engineered temperate phage λ expressing a programmable dCas9 represses a targeted E. coli gene in the mammalian gut. To facilitate phage administration while minimizing disruption to host processes, we develop an aqueous-based encapsulation formulation with a microbiota-based release mechanism and show that it facilitates the oral delivery of phage in vivo. Finally we combine these technologies and show that bacterial gene expression in the mammalian gut can be precisely modified in situ with a single oral dose.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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 4.0 International license.
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Posted April 16, 2020.
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In situ reprogramming of gut bacteria by oral delivery
Bryan B. Hsu, Isaac N. Plant, Lorena Lyon, Frances M. Anastassacos, Jeffrey C. Way, Pamela A. Silver
bioRxiv 2020.04.15.043232; doi: https://doi.org/10.1101/2020.04.15.043232
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In situ reprogramming of gut bacteria by oral delivery
Bryan B. Hsu, Isaac N. Plant, Lorena Lyon, Frances M. Anastassacos, Jeffrey C. Way, Pamela A. Silver
bioRxiv 2020.04.15.043232; doi: https://doi.org/10.1101/2020.04.15.043232

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