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ABSTRACTDespite significant achievements in hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD), especially intestinal GVHD, remains a major obstacle to this procedure. GVHD has long been regarded as a pathogenic immune response, and the intestine has been simply considered as a target of immune attack. In effect, multiple factors contribute to intestinal damage after transplantation. Impaired intestinal homeostasis including altered intestinal microbiome and epithelial damage results in delayed wound healing, amplified immune response and sustained tissue destruction, and it may not fully recover following immunosuppression. In this review, we summarize factors leading to intestinal damage and discuss the relationship between intestinal damage and GVHD. We also describe the great potential of remodeling intestinal homeostasis in GVHD management.