Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease Journal Article
| Authors: | Lindner, S.; Miltiadous, O.; Ramos, R. J. F.; Paredes, J.; Kousa, A. I.; Dai, A.; Fei, T.; Lauder, E.; Frame, J.; Waters, N. R.; Sadeghi, K.; Armijo, G. K.; Ghale, R.; Victor, K.; Gipson, B.; Monette, S.; Russo, M. V.; Nguyen, C. L.; Slingerland, J.; Taur, Y.; Markey, K. A.; Andrlova, H.; Giralt, S.; Perales, M. A.; Reddy, P.; Peled, J. U.; Smith, M.; Cross, J. R.; Burgos da Silva, M.; Campbell, C.; van den Brink, M. R. M. |
| Article Title: | Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease |
| Abstract: | 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. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | signal transduction; controlled study; human cell; major clinical study; case control study; disease course; mortality; nonhuman; cell proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; animal tissue; animal experiment; animal model; inflammation; cohort analysis; graft versus host reaction; hematopoietic cell; graft vs host disease; intestine; metabolite; intestines; cell transplantation; clinical outcome; ursodeoxycholic acid; hydrolase; microbiome; bile acid; pharmacological parameters; liver metabolism; humans; human; female; article; bile salt; bile acids and salts; dysbiosis; mortality risk; farnesoid x receptor; bile acid metabolism |
| Journal Title: | Nature Microbiology |
| Volume: | 9 |
| Issue: | 3 |
| ISSN: | 2058-5276 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-03-01 |
| Start Page: | 614 |
| End Page: | 630 |
| Language: | English |
| DOI: | 10.1038/s41564-024-01617-w |
| PUBMED: | 38429422 |
| PROVIDER: | scopus |
| PMCID: | PMC11196888 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK authors are Clarissa Campbell and Marcel R. M. van den Brink -- Source: Scopus |
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