Insertion sequence-mediated phage resistance contributes to attenuated colonization of cytolytic <i>Enterococcus faecalis</i> variants in the gut
Phage therapy is a promising approach for precise editing of the gut microbiota. Notably, the specific elimination of cytolytic <i>E. faecalis</i> from the intestinal microbiota by phages attenuates ethanol-induced liver disease in pre-clinical studies. Despite the great promise of phage therapy, the occurrence of phage-resistant variants represents a concern for the successful development of phage-based therapies. In this context, we assessed phage resistance using a cytolytic <i>E. faecalis</i> clinical isolate. Isolated phage-resistant variants acquired mutations or deletions of Epa biosynthesis-related genes and exhibited attenuated colonization in the gut. These phage-resistant variants showed less resistance to bile salts and reduced adherence to intestinal cell monolayers. These results suggest that even if phage-resistant variants arise during phage therapy, certain mechanisms of phage resistance may contribute to the rapid elimination of phage-resistant variants promoting favorable clinical outcomes in the treatment of alcohol-associated hepatitis.
Authors
- Bernd Schnabl (ORCID: https://orcid.org/0000-0002-6281-825X)
- Jumpei Fujiki (ORCID: https://orcid.org/0000-0002-0476-752X)
- Derrick E. Fouts (ORCID: https://orcid.org/0000-0003-4323-7668)
- Cristina Llorente (ORCID: https://orcid.org/0000-0001-8135-9186)
- Henriette Kreimeyer
- Tomohiro Nakamura (ORCID: https://orcid.org/0000-0002-8349-2367)
Institutions
- J. Craig Venter Institute (US)
- University of California San Diego (US)
- National Institute of Infectious Diseases (JP)
- VA San Diego Healthcare System (US)
- Azabu University (JP)
- Rakuno Gakuen University (JP)
Publication Details
- Journal
- Microbiology Spectrum
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1128/spectrum.03303-24
- Citations
- 4
- Primary Topic
- Bacteriophages and microbial interactions
- Type
- article
- Field-Weighted Citation Impact
- 6.87
Funders
- American Association for the Study of Liver Diseases
- Biomedical Laboratory Research and Development, VA Office of Research and Development
- Rakuno Gakuen University
- Deutsche Forschungsgemeinschaft
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health
- Harrington Discovery Institute, University Hospitals
- National Institute on Alcohol Abuse and Alcoholism
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- San Diego Digestive Diseases Research Center, School of Medicine, University of California, San Diego