Gene-Editing Tool Modifies Gut Bacteria in Living Mice

Researchers have developed a new gene-editing tool capable of modifying bacterial populations within the gut microbiome of living mice. This tool, known as a "base editor," successfully altered a target gene in over 90% of an Escherichia coli colony inside the mouse gut without causing unintended side effects.

This approach was spearheaded by Andreas Broedel, SynBio Team Lead at Eligo Bioscience, a Paris-based biotechnology firm. Their findings were published in Nature.

Previous research has utilized CRISPR-Cas editing systems to eliminate harmful gut bacteria in mice. However, Duportet's team aimed to edit bacterial genes without killing the bacteria. They achieved this using a base editor, which swaps one nucleotide base for another—such as converting adenine (A) to guanine (G)—without breaking the DNA double strand. Traditional base editors were ineffective at modifying sufficient target bacterial populations due to their limited receptor targeting, which was more effective in lab-cultured bacteria than in the gut environment.

To overcome these limitations, the team engineered a delivery system using bacteriophage components. This virus-like vehicle was designed to target multiple E. coli receptors expressed in the gut. It carried a base editor targeting specific E. coli genes and was refined to prevent replication and spread of the genetic material once inside the bacteria.

The base editor was administered to mice and successfully converted adenine to guanine in the E. coli gene responsible for producing β-lactamases, enzymes that confer bacterial resistance to various antibiotics. Eight hours post-treatment, around 93% of the targeted bacteria were edited.

See also: A Race For Better Gene Editing Tech Is On

Further adaptations of the base editor enabled it to modify an E. coli gene associated with proteins implicated in neurodegenerative and autoimmune diseases. Three weeks after treatment, approximately 70% of the bacteria remained edited. Additionally, the system was effective in editing strains of E. coli and Klebsiella pneumoniae in the lab, indicating its potential versatility across different bacterial species.

Chase Beisel, a chemical engineer at the Helmholtz Institute for RNA-based Infection Research in Würzburg, Germany, highlighted the significance of this development. He noted that this study marks a crucial advancement in the ability to modify gut bacteria to combat disease while preventing the engineered DNA from spreading.

The next phase for Duportet's team involves developing mouse models with microbiome-driven diseases to assess whether specific gene edits yield health benefits.

doi: 10.1038/d41586-024-02238-3