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Gut Microbes. 2017 Jan 2;8(1):1-16. doi: 10.1080/19490976.2016.1257469. Epub 2016 Nov 22.

Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency.

Author information

1
a Division of Digestive Diseases, Department of Medicine , University of California Los Angeles , Los Angeles , California , USA.
2
b Department of Pathology , University of California Los Angeles , Los Angeles , California , USA.
3
c Department of Biochemistry and Molecular & Cellular Biology , Georgetown University , Washington , D.C. , USA.
4
d Plant Pathology and Microbiology , University of California Riverside , Riverside , California , USA.
5
e F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center , Los Angeles , California , USA.
6
f Department of Biochemistry and Molecular Biology , University of Oklahoma Health Sciences Center , Oklahoma City , Oklahoma , USA.

Abstract

Intestinal dysbiosis is thought to confer susceptibility to inflammatory bowel disease (IBD), but it is unknown whether dynamic changes in the microbiome contribute to fluctuations in disease activity. We explored this question using mice with intestine-specific deletion of C1galt1 (also known as T-synthase) (Tsyn mice). These mice develop spontaneous microbiota-dependent colitis with a remitting/relapsing course due to loss of mucin core-1 derived O-glycans. 16S rRNA sequencing and untargeted metabolomics demonstrated age-specific perturbations in the intestinal microbiome and metabolome of Tsyn mice compare with littermate controls at weeks 3 (disease onset), 5 (during remission), and 9 (after relapse). Colitis remission corresponded to increased levels of FoxP3+RORγt+CD4+ T cells in the colonic lamina propria that were positively correlated with operational taxonomic units (OTUs) in the S24-7 family and negatively correlated with OTUs in the Clostridiales order. Relapse was characterized by marked expansion of FoxP3-RORγt+CD4+ T cells expressing IFNγ and IL17A, which were associated with Clostridiales OTUs distinct from those negatively correlated with FoxP3+RORγt+CD4+ T cells. Our findings suggest that colitis remission and relapse in the Tsyn model may reflect alterations in the microbiome due to reduced core-1 O-glycosylation that shift the balance of regulatory and pro-inflammatory T cell subsets. We investigated whether genetic variation in C1galt1 correlated with the microbiome in a cohort of 78 Crohn's disease patients and 101 healthy controls. Polymorphisms near C1galt1 (rs10486157) and its molecular chaperone, Cosmc (rs4825729), were associated with altered composition of the colonic mucosal microbiota, supporting the relevance of core-1 O-glycosylation to host regulation of the microbiome.

KEYWORDS:

C1galt1; T-synthase; colitis; core-1 O-glycans; microbiome

PMID:
27874308
PMCID:
PMC5341916
DOI:
10.1080/19490976.2016.1257469
[Indexed for MEDLINE]
Free PMC Article

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