An enterococcal phage-derived enzyme suppresses graft-versus-host disease

Kosuke Fujimoto, Tetsuya Hayashi, Mako Yamamoto, Noriaki Sato, Masaki Shimohigoshi, Daichi Miyaoka, Chieko Yokota, Miki Watanabe, Yuki Hisaki, Yukari Kamei, Yuki Yokoyama, Takato Yabuno, Asao Hirose, Mika Nakamae, Hirohisa Nakamae, Miho Uematsu, Shintaro Sato, Kiyoshi Yamaguchi, Yoichi Furukawa, Yukihiro Akeda, Masayuki Hino, Seiya Imoto () and Satoshi Uematsu ()
Additional contact information
Kosuke Fujimoto: Osaka Metropolitan University
Tetsuya Hayashi: Osaka Metropolitan University
Mako Yamamoto: University of Tokyo
Noriaki Sato: University of Tokyo
Masaki Shimohigoshi: Osaka Metropolitan University
Daichi Miyaoka: Osaka Metropolitan University
Chieko Yokota: Osaka Metropolitan University
Miki Watanabe: Osaka Metropolitan University
Yuki Hisaki: Osaka Metropolitan University
Yukari Kamei: Osaka Metropolitan University
Yuki Yokoyama: Osaka Metropolitan University
Takato Yabuno: Osaka Metropolitan University
Asao Hirose: Osaka Metropolitan University
Mika Nakamae: Osaka Metropolitan University
Hirohisa Nakamae: Osaka Metropolitan University
Miho Uematsu: Osaka Metropolitan University
Shintaro Sato: Osaka Metropolitan University
Kiyoshi Yamaguchi: University of Tokyo
Yoichi Furukawa: University of Tokyo
Yukihiro Akeda: National Institute of Infectious Diseases
Masayuki Hino: Osaka Metropolitan University
Seiya Imoto: University of Tokyo
Satoshi Uematsu: Osaka Metropolitan University

Nature, 2024, vol. 632, issue 8023, 174-181

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07667-8

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