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Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease

ABSTRACT: Microbial transformation of bile acids affects intestinal immune homeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. Additionally, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253360 | GEO | 2024/02/09

REPOSITORIES: GEO

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Microbial Bile Acid Metabolism Shapes T Cell Responses During Inflammation

Project description: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.

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