In situ targeted base editing of bacteria in the mouse gut

Andreas K. Brödel, Loïc H. Charpenay, Matthieu Galtier, Fabien J. Fuche, Rémi Terrasse, Chloé Poquet, Jan Havránek, Simone Pignotti, Antonina Krawczyk, Marion Arraou, Gautier Prevot, Dalila Spadoni, Matthew T. N. Yarnall, Edith M. Hessel, Jesus Fernandez-Rodriguez (), Xavier Duportet () and David Bikard ()
Additional contact information
Andreas K. Brödel: Eligo Bioscience
Loïc H. Charpenay: Eligo Bioscience
Matthieu Galtier: Eligo Bioscience
Fabien J. Fuche: Eligo Bioscience
Rémi Terrasse: Eligo Bioscience
Chloé Poquet: Eligo Bioscience
Jan Havránek: Eligo Bioscience
Simone Pignotti: Eligo Bioscience
Antonina Krawczyk: Eligo Bioscience
Marion Arraou: Eligo Bioscience
Gautier Prevot: Eligo Bioscience
Dalila Spadoni: Eligo Bioscience
Matthew T. N. Yarnall: Eligo Bioscience
Edith M. Hessel: Eligo Bioscience
Jesus Fernandez-Rodriguez: Eligo Bioscience
Xavier Duportet: Eligo Bioscience
David Bikard: Eligo Bioscience

Nature, 2024, vol. 632, issue 8026, 877-884

Abstract: Abstract Microbiome research is now demonstrating a growing number of bacterial strains and genes that affect our health1. Although CRISPR-derived tools have shown great success in editing disease-driving genes in human cells2, we currently lack the tools to achieve comparable success for bacterial targets in situ. Here we engineer a phage-derived particle to deliver a base editor and modify Escherichia coli colonizing the mouse gut. Editing of a β-lactamase gene in a model E. coli strain resulted in a median editing efficiency of 93% of the target bacterial population with a single dose. Edited bacteria were stably maintained in the mouse gut for at least 42 days following treatment. This was achieved using a non-replicative DNA vector, preventing maintenance and dissemination of the payload. We then leveraged this approach to edit several genes of therapeutic relevance in E. coli and Klebsiella pneumoniae strains in vitro and demonstrate in situ editing of a gene involved in the production of curli in a pathogenic E. coli strain. Our work demonstrates the feasibility of modifying bacteria directly in the gut, offering a new avenue to investigate the function of bacterial genes and opening the door to the design of new microbiome-targeted therapies.

Date: 2024
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DOI: 10.1038/s41586-024-07681-w

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