Reversible engraftment of an engineered microbe in the human gut

To develop effective microbial cell therapies, engineered bacteria should stably colonize the gut but also be effectively cleared after treatment. One strategy to enable exogenous bacteria to colonize the gut is by engineering them to use porphyran — a seaweed-derived polysaccharide — and then providing privileged nutrient access, which enables reliable engraftment but cannot be controllably reversed. Writing in Science, Whitaker et al. build on this strategy by engineering such bacteria to become dependent on porphyran for their survival. By putting the essential gene arginyl-tRNA synthetase under a porphyran-inducible promoter, they engineered bacteria to die when dietary porphyran is removed.

The authors used this strategy to develop a potential therapy for hyperoxaluria, a disease caused by overabsorption of dietary oxalate that often leads to kidney stones. They engineered a reversibly engrafting strain, called NB1000S, to carry an oxalate degradation pathway — which they first showed to reduce oxalate in urine by ~50% in rats — and applied it to humanized mice fed on a diet containing porphyran. After 4 weeks, removing porphyran cleared NB1000S in five of eight mice.