Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease

Recent research has shed light on the relationship between gut microbiota and graft-versus-host disease (GVHD), yet the role of microbiota from other body sites, such as the oral cavity, remains less explored. The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in GVHD pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients post-hematopoietic cell transplantation associated with increased chronic GVHD (cGVHD) independent of donor type, immunosuppressive GVHD prophylaxis, or conditioning intensity, even in patients receiving post-transplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures resulted in expansion of Enterococcaceae and exacerbated cGVHD. The migration of Enterococcaceae from the oral cavity to the cervical lymph nodes (LNs) both pre- and post-transplantation activated antigen-presenting cells (APCs), thereby promoting the expansion of donor-derived inflammatory T cells. Interventions like ligature-removal or applying oral antibiotic ointment mitigated murine cGVHD severity. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be a novel, effective approach for prevention and treatment of cGVHD.