Fecal microbiota transplantation ameliorates refractory chronic graft-versus-host disease through short-chain fatty acids-treg axis in allogeneic hematopoietic cell transplant recipients

Abstract Disruption of the intestinal microbiota plays a crucial role on the initial and development of graft-versus-host disease (GVHD). Fecal microbiota transplantation (FMT) is effective for refractory acute GVHD, but unclear for refractory chronic GVHD (cGVHD). To investigate the effect of FMT on refractory cGVHD and its underlying mechanism, 12 patients with refractory cGVHD received FMT via colonoscopy, and response evaluated at 12 weeks after FMT in this study. Of the 12 patients underwent FMT, 6 patients obtained response including 1 complete response and 5 partial responses. The patients with refractory cGVHD exhibited lower α-diversity, higher levels of Escherichia-Shigellaand Enterobacteriaceae. FMT increased gut microbial diversity, especially expanded short-chain fatty acids (SCFAs) producing bacteria, decreased Escherichia-Shigella and Enterobacteriaceae in the responding patients. Meanwhile, it elevated SCFAs levels in the fecal sample of responder group and promoting the expansion of peripheral CD4+CD127- regulatory T (Treg) cells. Colon pathology revealed that CD4+ T and CD19+ B cells infiltration were decreased and CD4+ Treg cells increased after FMT. By cohousing experiment, we confirmed that healthy donor microbiota alleviated cGVHD recipients through SCFAs-Treg cells axis. The current study suggest that FMT effectively ameliorates refractory cGVHD through SCFAs-Treg cells axis.