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

Autor: Nelson MT; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA. mark.nelson.35@us.af.mil., Charbonneau MR; Synlogic Inc, Cambridge, MA, USA., Coia HG; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA.; National Research Council, The National Academies of Sciences, Engineering, and Medicine, Washington DC, USA., Castillo MJ; Synlogic Inc, Cambridge, MA, USA., Holt C; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA., Greenwood ES; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA.; Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA., Robinson PJ; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA.; The Henry M. Jackson Foundation, Bethesda, MD, USA., Merrill EA; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA., Lubkowicz D; Synlogic Inc, Cambridge, MA, USA., Mauzy CA; United States Air Force Research Laboratory, 711th Human Performance Wing, Airman Systems Directorate, Bioengineering Division, Wright-Patterson AFB, OH, Columbus, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 May 14; Vol. 12 (1), pp. 2805. Date of Electronic Publication: 2021 May 14.
DOI: 10.1038/s41467-021-23072-5
Abstrakt: 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.
Databáze: MEDLINE
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