Oral inflammation and microbiome dysbiosis exacerbate chronic graft-versus-host disease
Abstract
Abstract 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.
Article Details
Authors (21)
Yui Kambara
1Department of Hematology, Oncology and Respiratory Medicine, Okayama University Medical School, Okayama, Japan
Hideaki Fujiwara
Akira Yamamoto
Kazuyoshi Gotoh
Shuma Tsuji
4Department of Microbiology and Genetics, Okayama University Graduate School of Health Sciences, Okayama, Japan
Mari Kunihiro
5Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Tadashi Oyama
5Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Toshiki Terao
5Okayama University Hospital, Department of Hematology and Oncology, Okayama, Japan
Ayame Sato
6Division of Hospital Dentistry, Okayama University Hospital, Okayama, Japan
Takehiro Tanaka
Daniel Peltier
8Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
Keisuke Seike
2Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
Hisakazu Nishimori
2Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
Noboru Asada
5Okayama University Hospital, Department of Hematology and Oncology, Okayama, Japan
Daisuke Ennishi
4Okayama University Hospital, Center for Comprehensive Genomic Medicine, Okayama, Japan
Keiko Fujii
10Department of Clinical Laboratory, Okayama University Hospital, Okayama, Japan
Nobuharu Fujii
11Division of Blood Transfusion, Okayama University Hospital, Okayama, Japan
Ken-ichi Matsuoka
Yoshihiko Soga
Pavan Reddy
16Baylor Cancer Center, Houston, United States
Yoshinobu Maeda