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“We have always dreamed of achieving this.” — Xavier Duportet, co-founder of the French biotechnology company Eligo Bioscience and synthetic biologist

On July 10, 2024, a technical team from the Pasteur Institute in Paris successfully used a CRISPR-derived tool to modify target genes in over 90% of E. coli colonies in the guts of mice. This breakthrough demonstrates the feasibility of directly editing bacteria within the gut, offering new avenues for designing targeted microbiome therapies.

Explaining the inspiration behind using CRISPR-derived tools to edit the gut microbiome, Duportet mentioned that previous studies using CRISPR-Cas editing tools to kill harmful bacteria in the mouse gut sparked this idea. He believes that editing gut bacteria to change the microbiome without directly killing the bacteria may be more beneficial for research and potential applications.

The team used a base editor that can exchange one nucleotide base for another without disrupting the DNA double helix. However, previous base editors lacked the ability to modify a sufficient number of target bacterial populations, prompting Duportet’s team to design a new delivery vehicle.

The research team chose a bacteriophage, a virus that infects bacteria, as their delivery tool. They engineered the bacteriophage to carry a base editor targeting specific E. coli genes. This system could precisely locate several E. coli receptors in the gut, and the team implemented modifications to prevent the genetic material from replicating and spreading within the bacteria.

Following these successful steps, the team introduced the base editor into mice. They used it to convert an A to a G in the gene responsible for producing β-lactamase in E. coli, an enzyme that renders bacteria resistant to several antibiotics. About eight hours after treatment, approximately 93% of the target bacteria had been edited.

The researchers then adjusted the base editor to modify an E. coli gene that produces a protein believed to play a role in several neurodegenerative and autoimmune diseases. Three weeks after treatment, around 70% of the edited bacteria were still present in the mice. In the laboratory, the team also used this tool to edit E. coli and Klebsiella pneumoniae strains responsible for pneumonia infections, showing that the editing system can adapt to different bacterial strains and species.

Editing the microbiome to combat diseases represents a groundbreaking approach. This tool not only fights disease but also prevents the spread of genetically engineered DNA, making it a pioneering editing tool. However, given the microbiome’s ability to quickly change gut bacterial populations, questions remain about potential side effects and the effectiveness of this treatment for human health. These concerns are part of Duportet’s team’s next steps, and we look forward to hearing more promising news from them in the future.

Reference:

Brödel, A.K., Charpenay, L.H., Galtier, M. et al. In situ targeted base editing of bacteria in the mouse gut. Nature (2024). https://doi.org/10.1038/s41586-024-07681-w.