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

• 成果类型: Article
• 署名作者: Fujimoto, Kosuke; Hayashi, Tetsuya; Yamamoto, Mako; Sato, Noriaki; Shimohigoshi, Masaki; Miyaoka, Daichi; Yokota, Chieko; Watanabe, Miki; Hisaki, Yuki; Kamei, Yukari; Yokoyama, Yuki; Yabuno, Takato; Hirose, Asao; Nakamae, Mika; Nakamae, Hirohisa; Uematsu, Miho; Sato, Shintaro; Yamaguchi, Kiyoshi; Furukawa, Yoichi; Akeda, Yukihiro; Hino, Masayuki; Imoto, Seiya; Uematsu, Satoshi
• 署名单位: Osaka Metropolitan University; University of Tokyo; Osaka Metropolitan University; University of Tokyo; Osaka Metropolitan University; Wakayama Medical University; University of Tokyo; Japan Institute for Health Security (JIHS); National Institute of Infectious Diseases (NIID); University of Tokyo; Osaka Metropolitan University; Osaka Metropolitan University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6594
• DOI: 10.1038/s41586-024-07667-8
• 发表日期: 2024-08-01
• 页码: 174-+
• 关键词: fecal microbiota transplantation; multiple sequence alignment; acute gvhd; biofilm formation; faecalis; mouse; bacteremia; contributes; virulence; colonization

摘要

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 aGVHD(7-10). 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.