Precision microbiome programming for therapeutic applications has been limited by challenges in achieving reproducible colonization of the colon. Previously, we used a porphyran prebiotic to create a synthetic niche to engraft engineered bacteria into diverse microbiota in mice. Here we extend that work with biocontainment that links essential gene expression to porphyran presence yielding a platform for controlled colonization and decolonization of humans with engineered Bacteroides. We engineered this chassis with a five-gene oxalate degradation pathway, creating a therapeutic candidate that reduces hyperoxaluria, a cause of kidney stones, in pre-clinical models. Our Phase 1/2a clinical trial demonstrates tunable and reversible engraftment in humans, shows promising oxalate reductions, highlights addressable challenges in this novel modality for therapeutics, and queries key questions in microbiome science.

Novome Biotechnologies is no longer operational. WRW, ZRN, ESS, JLS and WCD may receive future financial benefits from the licensing of intellectual property related to this work.

NCT04909723

This study was funded by Novome Biotechnologies Inc.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The central Institutional Review Board, Advarra, Inc., gave ethical approval for this work.

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Yes

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.