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

By Graham J Britton, Eduardo J. Contijoch, Matthew P. Spindler, Varun Aggarwala, 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, Marla C Dubinsky, Ari Grinspan, Jeremiah J Faith

Posted 16 Nov 2019
bioRxiv DOI: 10.1101/844662 (published DOI: 10.1073/pnas.1922189117)

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, where clinical trials of fecal microbiota transplant 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 and a deficit in the tolerogenic RORγt+ Treg cell subset. Transplanting healthy donor-derived microbiota into mice colonized with human IBD microbiotas lead 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, correlated with a reduction in Th17 cells.

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