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In situ reprogramming of gut bacteria by oral delivery

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dc.contributor.authorHsu, Bryan B.en
dc.contributor.authorPlant, Isaac N.en
dc.contributor.authorLyon, Lorenaen
dc.contributor.authorAnastassacos, Frances M.en
dc.contributor.authorWay, Jeffrey C.en
dc.contributor.authorSilver, Pamela A.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2021-02-02T20:33:21Zen
dc.date.available2021-02-02T20:33:21Zen
dc.date.issued2020-10-06en
dc.description.abstractAbundant links between the gut microbiota and human health indicate that 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 demonstrate that an engineered temperate phage lambda 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 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. It is difficult to precisely target bacterial populations in the mammalian gut. Here the authors use encapsulated phages to deliver dCas9 to E. coli in the mouse gut to modulate RFP expression.en
dc.description.notesWe are grateful to Dr. Georg Gerber for insightful discussions and Amanda Graveline, DVM, for her assistance and training for mouse experiments. We are also grateful to Calixto Saenz and the HMS Microfabrication Core Facility for assistance with the microfluidic devices. This work was supported by Defense Advanced Research Projects Agency Grant HR0011-15-C-0094, funds from the Wyss Institute for Biologically Inspired Engineering, the Bill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative (OPP1150555), and the Virginia Tech College of Science and Department of Biological Sciences. B.B.H. is grateful for support from the Rosenbloom Postdoctoral Fellowship.en
dc.description.sponsorshipDefense Advanced Research Projects AgencyUnited States Department of DefenseDefense Advanced Research Projects Agency (DARPA) [HR0011-15-C-0094]; Wyss Institute for Biologically Inspired Engineering; Bill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative [OPP1150555]; Virginia Tech College of Science and Department of Biological Sciences; Rosenbloom Postdoctoral Fellowshipen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41467-020-18614-2en
dc.identifier.issn2041-1723en
dc.identifier.issue1en
dc.identifier.other5030en
dc.identifier.pmid33024097en
dc.identifier.urihttp://hdl.handle.net/10919/102203en
dc.identifier.volume11en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleIn situ reprogramming of gut bacteria by oral deliveryen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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