Scientists have designed a genome editing tool that can control the bacterial population in the Gut microbiome of living mice 1.

The tool – a kind of “base editor” – changed the target gene in more than 90% of casesEscherichia colicolony in the mouse intestine without the modified gene forming potentially harmful copies of itself. “We dreamed of being able to do this,” says Xavier Duportet, a synthetic biologist who co-founded Eligo Bioscience, a biotechnology company in Paris. The results were announced todayNaturepublished.

Several research teams have attempted to make genetic changes to gut bacteria in mice, but achieving this in the body has been challenging. 4, 3, 2. So far, base editors that swap one nucleotide base for another—for example, converting an A to a G—without breaking the DNA double strand have been unable to modify enough of the target bacterial population to be effective. This is because the vectors in which they were delivered only targeted receptors common in bacteria cultured in the laboratory.

Innovative delivery system

To overcome these hurdles, Duportet and his colleagues constructed a delivery vehicle using components of a bacteriophage - a virus that infects bacteria - to target variousE.coli-Target receptors expressed in the intestinal environment. This vector carried a base editor, the specificE.coli-genes targeted. The researchers also refined the system to prevent the edited genes from replicating and spreading.

The team introduced the base editor into mice and used it to create A in theE.coli-Change gene that produces β-lactamases – enzymes that promote bacterial resistance to various types of antibiotics. About eight hours after treatment, around 93% of the targeted bacteria were edited.

The researchers then adapted the base editor so that it was aE.coli-Gene that produces a protein that is thought to play a role in several neurodegenerative and autoimmune diseases. The proportion of edited bacteria was around 70% three weeks after treatment. In the laboratory, the scientists were also able to use the tool to identify strains ofE.coliandKlebsiella pneumoniaewhich can cause pneumonia. This suggests that the editing system can be adapted to different bacterial strains and species.

This base editing system represents a "critical advance" in developing tools that can modify bacteria directly in the gut, says Chase Beisel, a chemical engineer at the Helmholtz Institute for RNA-based Infection Research in Würzburg, Germany. The study "opens the possibility of editing microbes to fight disease while preventing the manipulated DNA from spreading," he adds.

Duportet and his colleagues' next step is to develop mouse models with diseases caused by the microbiome to measure whether specific gene edits have a positive impact on their health.