Commensal <i>Bacteroides</i> T6SS alleviate GI-aGVHD via mediating gut microbiota composition and bile acids metabolism.

Abstract

Gastrointestinal acute graft-versus-host disease (GI-aGVHD) is one of the main complications of patients undergoing allogenic haematopoietic stem cell transplantation (allo-HSCT). A deeper understanding of the mechanisms of sustaining intestinal homeostasis is essential. Here, we investigated micro-organisms and microbial metabolites that were crucial for intestinal homeostasis in the context of GI-aGVHD management. We profiled the gut microbiota, immune indices and gut metabolism of 71 patients undergoing allo-HSCT. Initially, we set up a mouse aGVHD model to confirm the effect of <i>Bacteroides fragilis</i> type VI secretion system (T6SS) on aGVHD progression. Subsequently, we applied 16S amplicon sequencing and metabolic profiling to reveal the function of <i>B. fragilis</i> T6SS on microbial structure intestinal and metabolome. Finally, the mediation package was used to validate our findings in clinical samples. A higher abundance of <i>Bacteroides</i> spp contributes to reducing the incidence of GI-aGVHD, and the T6SS is required for <i>Bacteroides</i> spp protection on aGVHD. T6SS-mediated antagonism regulates the structure and composition of gut microbiota, affecting the entire gut metabolome, particularly the bile acids metabolism, subsequently reducing inflammation response in the intestine and protecting intestinal barrier integrity. Notably, accumulating primary bile acids such as chenodeoxycholic acid exacerbated aGVHD by enhancing the activation of T cells. Mediation analysis further validated that T6SS affects the incidence of GI-aGVHD through its effect on primary bile acid metabolism. T6SS in commensal bacteria could modulate bile acid metabolism, potentially impacting aGVHD outcomes and offering a novel target for therapeutic interventions.