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

Microbial transformation of bile acids affects intestinal immune homoeostasis 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. In addition, 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.

Infection leaves a genetic and functional mark on the gut population of a commensal bacterium.

Gastrointestinal infection changes microbiome composition and gene expression. In this study, we demonstrate that enteric infection also promotes rapid genetic adaptation in a gut commensal. Measurements of Bacteroides thetaiotaomicron population dynamics within gnotobiotic mice reveal that these populations are relatively stable in the absence of infection, and the introduction of the enteropathogen Citrobacter rodentium reproducibly promotes rapid selection for a single-nucleotide variant with increased fitness. This mutation promotes resistance to oxidative stress by altering the sequence of a protein, IctA, that is essential for fitness during infection. We identified commensals from multiple phyla that attenuate the selection of this variant during infection. These species increase the levels of vitamin B6 in the gut lumen. Direct administration of this vitamin is sufficient to significantly reduce variant expansion in infected mice. Our work demonstrates that a self-limited enteric infection can leave a stable mark on resident commensal populations that increase fitness during infection.