Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 35, Pages 21536-21545Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1922189117
Keywords
mucosal immunology; microbiome; fecal microbiota transplant; Th17 cells; regulatory T cells
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Funding
- Research Fellowship Award from the Crohn's and Colitis Foundation of America (CCFA)
- NIH National Institute of General Medical Sciences Grant [GM108505]
- National Institute of Diabetes and Digestive Diseases [DK112978, DK124133]
- Janssen Human Microbiome Institute
- CCFA Microbiome Innovation Award [362048]
- New York Crohn's Foundation
- NIH [DK112679, AI078892]
- CCFA Research Fellowship Award
- Cancer Center Support Grant [P30CA016087]
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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 ROR gamma t(+) 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 ROR gamma t(+) 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.
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