A laboratory mouse looks over the green gloved fingers of a technician in a laboratory.

Making genetic tweaks to gut bacteria inside mice has been challenging.Credit: Robert F. Bukaty/AP via Alamy

Scientists have designed a gene-editing tool that can modify bacterial populations in the gut microbiome of living mice1.

The tool — a type of ‘base editor’ — modified the target gene in more than 90% of an Escherichia coli colony inside the mouse gut without the tweaked gene making potentially harmful copies of itself. “We were dreaming of being able to do that,” says Xavier Duportet, a synthetic biologist who co-founded Eligo Bioscience, a biotechnology company in Paris. The findings were published today in Nature.

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

Innovative delivery system

To address these hurdles, Duportet and his colleagues engineered a delivery vehicle using components of a bacteriophage — a virus that infects bacteria — to home in on several E. coli receptors that are expressed in the gut environment. This vector carried a base editor that targeted specific E. coli genes. The researchers also refined the system to prevent edited genes from replicating and spreading.

The team delivered the base editor into mice and used it to change A to G in the E. coli gene that produces β-lactamases — enzymes that drive bacterial resistance to several types of antibiotic. Some eight hours after the animals received the treatment, around 93% of the targeted bacteria had been edited.

The researchers then adapted the base editor so it could modify an E. coli gene that produces a protein that is thought to play a part in several neurodegenerative and autoimmune diseases. The proportion of edited bacteria hovered around 70% three weeks after the mice had been treated. In the laboratory, the scientists could also use the tool to edit strains of E. coli and Klebsiella pneumoniae, which can cause pneumonia infections. This suggests that the editing system can be adapted to target different bacteria strains and species.

This base-editing system represents a “critical leap forward” in developing tools that can modify bacteria directly inside 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 combat disease, all while preventing the engineered DNA from spreading”, he adds.

The next step for Duportet and his colleagues is to develop mouse models with microbiome-driven diseases to measure whether specific gene edits have a beneficial impact on their health.

Source link