Defined microbiota transplant restores Th17/RORγt+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

Graham J. Britton*, Eduardo J. Contijoch, Matthew P. Spindler, Varun Aggarwala, Belgin Dogan, Gerold Bongers, Lani San Mateo, Andrew Baltus, Anuk Das, Dirk Gevers, Thomas J. Borody, Nadeem O. Kaakoush, Michael A. Kamm, Hazel Mitchell, Sudarshan Paramsothy, Jose C. Clemente, Jean Frederic Colombel, Kenneth W. Simpson, Marla C. Dubinsky, Ari GrinspanJeremiah J. Faith

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
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Abstract

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn’s disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.

Original languageEnglish
Pages (from-to)21536-21545
Number of pages10
Journal Proceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number35
DOIs
Publication statusPublished - 1 Sep 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Fecal microbiota transplant
  • Microbiome
  • Mucosal immunology
  • Regulatory T cells
  • Th17 cells

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