6-gingerol ameliorates murine gastrointestinal graft-versus-host disease by inhibiting pyroptosis of intestinal epithelial cell

Abstract Aims Gastrointestinal graft-versus-host disease (GI-GvHD) is a major cause of post-allo hematopoietic stem cell transplantation (HSCT) morbidity and mortality. 6-gingerol (6-G), which is predominantly found in ginger, has been recognized for its anti-inflammatory effect and intestinal health benefits, although the potential mechanisms are not well understood. This study is to evaluate whether 6-G can alleviate GI-GvHD and find the preliminary mechanisms of 6-G to further provide new strategies for the prophylaxis or treatment of GI-GvHD. Methods The therapeutic effect of 6-G was evaluated using a murine GI-GvHD model with acute colitis. The protection effect of 6-G on gut epithelial injury was assessed using TNF-α-induced intestinal epithelial cell lines and colonic organoids. Additinally, RNA sequencing was applied to observe the regulatory mechanisms in intestinal epithelial cell lines.Results Intraperitoneal injection administration of 6-G significantly prolonged survival and restored colon length in mice. Notably, 6-G treatment led to decreased levels of pro-inflammatory cytokines. Importantly, 6-G restored intestinal despair by increasing the number of goblet cells in colons of GvHD mice and displaying recovered barrier function. In TNF-α-induced intestinal epithelial cell lines and colonic organoids, 6-G reduced epithelial cell inflammation and protected against TNF-α-induced damage. Mechanically, 6-G mitigated colonic damage and enhanced barrier function, potentially through the NLRP3/Caspase-1/Gasdermin D pyroptosis pathway.Conclusion 6-G holds potential as a natural prophylactic agent against GI-GvHD, with its protective action on the intestinal epithelium being crucial for its therapeutic efficacy.Key Words 6-gingerol, GI-GvHD, organoids, pyroptosis