Kambara Yui, Fujiwara Hideaki, Yamamoto Akira, Gotoh Kazuyoshi, Tsuji Shuma, Kunihiro Mari, Oyama Tadashi, Terao Toshiki, Sato Ayame, Tanaka Takehiro, Peltier Daniel, Seike Keisuke, Nishimori Hisakazu, Asada Noboru, Ennishi Daisuke, Fujii Keiko, Fujii Nobuharu, Matsuoka Ken-Ichi, Soga Yoshihiko, Reddy Pavan, Maeda Yoshinobu
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Medical School, Okayama, Japan.
Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
Blood. 2025 Feb 20;145(8):881-896. doi: 10.1182/blood.2024024540.
The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.
口腔微生物群的数量仅次于肠道，与慢性全身性疾病有关，但其在移植物抗宿主病（GVHD）发病机制中的具体作用尚不清楚。我们的研究发现，造血细胞移植（HCT）后患者因黏膜炎引起的口腔生态失调与慢性GVHD（cGVHD）增加有关，即使是接受移植后环磷酰胺治疗的患者也是如此。在小鼠HCT模型中，双侧磨牙结扎导致的口腔生态失调加剧了cGVHD，并增加了口腔和肠道中的细菌负荷，肠球菌科在这两个器官中均显著增加。在该模型中，移植前后肠球菌科向颈部淋巴结的迁移激活了抗原呈递细胞，从而促进了供体来源的炎性T细胞的扩增。基于这些结果，我们推测口腔中病原菌的增加可能不仅会加剧局部炎症，还会在整个HCT过程中增强全身炎症。此外，这些细菌转移到肠道并形成异位菌落，进一步放大全身炎症。此外，针对口腔微生物群的干预减轻了小鼠的cGVHD。总的来说，我们的研究结果突出了口腔生态失调在cGVHD中的重要性，并表明在移植期间调节口腔微生物群可能是预防或治疗cGVHD的有效方法。
