Controlled colonization of the human gut with a genetically engineered microbial medicine

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.