Persistent Physiological Change in a Host Using Engineered Native Bacteria

Engineered bacterial therapeutics have the potential to reverse disease by engrafting the gut lumen and providing a persistent beneficial effect on host physiology. However, attempts to functionally manipulate the gut microbiome of conventionally raised, wild-type (CR-WT) hosts have been largely unsuccessful. Here we show that specific and lasting functional changes in the gut microbiome can be achieved by isolating, modifying, and reintroducing native bacteria, thus allowing investigators to “knock in” individual functions into the gut microbiome. To demonstrate this approach, we isolated a native strain of Escherichia coli from stool cultures of CR-WT mice and modified it to express bile salt hydrolase (BSH), a bacterial enzyme that is theorized to affect host metabolism. Reintroduction of this strain by a single gavage induces perpetual, stable colonization of the entire gut, delivers the intended function, and affects host physiology. Furthermore, we demonstrate that tractable, native bacterial strains are easy to identify in humans and can be transformed to express a specific function. Thus, this approach to “knocking in” specific bacterial functions with engineered native bacteria allows for improved mechanistic studies of the role of the gut microbiome and makes individualized microbiome-mediated therapies with curative intent possible.