Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt+ Regulatory T Cells and Exacerbate Colitis in Mice

Graham J Britton; Eduardo J Contijoch; Ilaria Mogno; Olivia H Vennaro; Sean R Llewellyn; Ruby Ng; Zhihua Li; Arthur Mortha; Miriam Merad; Anuk Das; Dirk Gevers; Dermot P B McGovern; Namita Singh; Jonathan Braun; Jonathan P Jacobs; Jose C Clemente; Ari Grinspan; Bruce E Sands; Jean-Frederic Colombel; Marla C Dubinsky; Jeremiah J Faith

doi:10.1016/j.immuni.2018.12.015

Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt⁺ Regulatory T Cells and Exacerbate Colitis in Mice

Immunity. 2019 Jan 15;50(1):212-224.e4. doi: 10.1016/j.immuni.2018.12.015.

Authors

Graham J Britton¹, Eduardo J Contijoch¹, Ilaria Mogno¹, Olivia H Vennaro¹, Sean R Llewellyn¹, Ruby Ng¹, Zhihua Li¹, Arthur Mortha², Miriam Merad³, Anuk Das⁴, Dirk Gevers⁴, Dermot P B McGovern⁵, Namita Singh⁶, Jonathan Braun⁷, Jonathan P Jacobs⁸, Jose C Clemente¹, Ari Grinspan⁹, Bruce E Sands⁹, Jean-Frederic Colombel⁹, Marla C Dubinsky¹⁰, Jeremiah J Faith¹¹

Affiliations

¹ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology, University of Toronto, Toronto, ON, Canada.
³ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Janssen Human Microbiome Institute, Janssen Research and Development, LLC, Spring House, PA, USA.
⁵ Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Pediatric Gastroenterology and Inflammatory Bowel Disease, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
⁸ Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Pediatric Gastroenterology and Hepatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: [email protected].

Abstract

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt⁺ Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1^-/- mice. The proportions of Th17 and RORγt⁺ Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1^-/- colitis model. Thus, an impact on intestinal Th17 and RORγt⁺ Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Colitis / chemically induced
Colitis / immunology
Colitis / microbiology*
Disease Models, Animal
Disease Progression
Gastrointestinal Microbiome / genetics*
Homeostasis
Humans
Inflammatory Bowel Diseases / immunology*
Inflammatory Bowel Diseases / microbiology*
Mice
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
RNA, Ribosomal, 16S / genetics*
T-Lymphocytes, Regulatory / immunology*
Th17 Cells / metabolism*

Substances

Nuclear Receptor Subfamily 1, Group F, Member 3
RNA, Ribosomal, 16S

Abstract

Publication types

MeSH terms

Substances

Grants and funding