GNPS - Microbial Bile Acid Metabolism Shapes T Cell Responses During Inflammation

Microbial transformation of bile acids (BAs) affects intestinal immune homeostasis but the impact of changes in BA metabolism on T cell-driven pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that GVHD decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of microbiota-dependent unconjugated and secondary BAs (SBAs). Several SBAs attenuated farnesoid X receptor (FXR) activity, posing that loss of SBAs may increase FXR activation and exacerbate inflammation. Mortality in GVHD mice increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and SBAs. Moreover, the FXR antagonist ursodeoxycholic acid reduced the activation of human T cells and was associated with a reduced risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of SBAs may be an important mechanism to amplify T cell-mediated diseases.