日本大阪都立大学Satoshi Uematsu和东京大学Seiya Imoto课题组合作的最新研究发现，粪肠球菌噬菌体衍生酶可抑制移植物抵抗宿主疾病（acute graft-versus-host disease，acGVHD）。相关论文于2024年7月10日发表在《自然》杂志上。

研究人员分析了异体肝移植患者的肠道微生物组，发现粪肠球菌通过形成生物膜而非获得耐药基因来逃避清除并在肠道中增殖。研究人员从粪便样本中分离到细胞溶解酶阳性的高致病性粪肠球菌，并通过分析细菌的全基因组测序数据，发现了一种来自粪肠球菌特异性噬菌体的抗粪肠球菌酶。这种抗菌酶在体外和体内都对粪肠杆菌的生物膜具溶解活性。

此外，与对照组相比，在用粪肠杆菌定植或以肠球菌为主患者粪便样本诱导的无菌小鼠中，接受粪肠杆菌特异性酶治疗的小组，其肠道细胞溶解酶阳性粪肠杆菌水平降低，存活率显著提高。因此，使用这种噬菌体衍生的抗菌酶可能为预防aGVHD提供一种新方法，因为这种酶对形成生物膜的致病性粪肠球菌具有特异性且现有的抗生素很难消除这种病菌。

研究人员表示，肠道微生物组的变化在异基因造血细胞移植（allo-HCT）后急性移植物抗宿主病的发病过程中起着关键作用。然而，解决肠道菌群失调的有效方法尚未确立。肠道中与菌群失调有关的病原体粪肠球菌（Enterococcus faecalis）的扩增，已被证明是诱发急性肠道恶性肿瘤的危险因素。

附：英文原文

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

Author: 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

Issue&Volume: 2024-07-10

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)1,2,3,4,5,6. 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 aGVHD7,8,9,10. 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.

DOI: 10.1038/s41586-024-07667-8

Source: https://www.nature.com/articles/s41586-024-07667-8