1. An enterococcal phage-derived enzyme suppresses graft-versus-host disease.
- Author
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Fujimoto K, Hayashi T, Yamamoto M, Sato N, Shimohigoshi M, Miyaoka D, Yokota C, Watanabe M, Hisaki Y, Kamei Y, Yokoyama Y, Yabuno T, Hirose A, Nakamae M, Nakamae H, Uematsu M, Sato S, Yamaguchi K, Furukawa Y, Akeda Y, Hino M, Imoto S, and Uematsu S
- Subjects
- Adult, Aged, Animals, Female, Humans, Male, Mice, Middle Aged, Young Adult, Biofilms drug effects, Biofilms growth & development, Dysbiosis complications, Dysbiosis microbiology, Feces microbiology, Germ-Free Life, Hematopoietic Stem Cell Transplantation adverse effects, In Vitro Techniques, Intestines drug effects, Intestines microbiology, Perforin metabolism, Risk Factors, Transplantation, Homologous adverse effects, Whole Genome Sequencing, Drug Resistance, Bacterial drug effects, Anti-Bacterial Agents pharmacology, Bacteriophages enzymology, Bacteriophages genetics, Enterococcus faecalis drug effects, Enterococcus faecalis genetics, Enterococcus faecalis growth & development, Enterococcus faecalis metabolism, Enterococcus faecalis virology, Gastrointestinal Microbiome, Graft vs Host Disease complications, Graft vs Host Disease microbiology, Graft vs Host Disease prevention & control, Graft vs Host Disease therapy
- Abstract
Changes in the gut microbiome have pivotal roles in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogenic haematopoietic cell transplantation (allo-HCT)
1-6 . However, effective methods for safely resolving gut dysbiosis have not yet been established. An expansion of the pathogen Enterococcus faecalis in the intestine, associated with dysbiosis, has been shown to be a risk factor for aGVHD7-10 . Here we analyse the intestinal microbiome of patients with allo-HCT, and find that E. faecalis escapes elimination and proliferates in the intestine by forming biofilms, rather than by acquiring drug-resistance genes. We isolated cytolysin-positive highly pathogenic E. faecalis from faecal samples and identified an anti-E. faecalis enzyme derived from E. faecalis-specific bacteriophages by analysing bacterial whole-genome sequencing data. The antibacterial enzyme had lytic activity against the biofilm of E. faecalis in vitro and in vivo. Furthermore, in aGVHD-induced gnotobiotic mice that were colonized with E. faecalis or with patient faecal samples characterized by the domination of Enterococcus, levels of intestinal cytolysin-positive E. faecalis were decreased and survival was significantly increased in the group that was treated with the E. faecalis-specific enzyme, compared with controls. Thus, administration of a phage-derived antibacterial enzyme that is specific to biofilm-forming pathogenic E. faecalis-which is difficult to eliminate with existing antibiotics-might provide an approach to protect against aGVHD., (© 2024. The Author(s).)- Published
- 2024
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