Characterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip

M. Tyler Nelson (), Mark R. Charbonneau, Heidi G. Coia, Mary J. Castillo, Corey Holt, Eric S. Greenwood, Peter J. Robinson, Elaine A. Merrill, David Lubkowicz and Camilla A. Mauzy
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M. Tyler Nelson: Bioengineering Division, Wright-Patterson AFB
Mark R. Charbonneau: Synlogic Inc
Heidi G. Coia: Bioengineering Division, Wright-Patterson AFB
Mary J. Castillo: Synlogic Inc
Corey Holt: Bioengineering Division, Wright-Patterson AFB
Eric S. Greenwood: Bioengineering Division, Wright-Patterson AFB
Peter J. Robinson: Bioengineering Division, Wright-Patterson AFB
Elaine A. Merrill: Bioengineering Division, Wright-Patterson AFB
David Lubkowicz: Synlogic Inc
Camilla A. Mauzy: Bioengineering Division, Wright-Patterson AFB

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Engineered bacteria (synthetic biotics) represent a new class of therapeutics that leverage the tools of synthetic biology. Translational testing strategies are required to predict synthetic biotic function in the human body. Gut-on-a-chip microfluidics technology presents an opportunity to characterize strain function within a simulated human gastrointestinal tract. Here, we apply a human gut-chip model and a synthetic biotic designed for the treatment of phenylketonuria to demonstrate dose-dependent production of a strain-specific biomarker, to describe human tissue responses to the engineered strain, and to show reduced blood phenylalanine accumulation after administration of the engineered strain. Lastly, we show how in vitro gut-chip models can be used to construct mechanistic models of strain activity and recapitulate the behavior of the engineered strain in a non-human primate model. These data demonstrate that gut-chip models, together with mechanistic models, provide a framework to predict the function of candidate strains in vivo.

Date: 2021
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DOI: 10.1038/s41467-021-23072-5

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