title: Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency.
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.
authors.affiliation: a Division of Digestive Diseases, Department of Medicine , University of California Los Angeles , Los Angeles , California , USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Jacobs
authors.affiliation: b Department of Pathology , University of California Los Angeles , Los Angeles , California , USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: c Department of Biochemistry and Molecular & Cellular Biology , Georgetown University , Washington , D.C. , USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Goudarzi
authors.affiliation: d Plant Pathology and Microbiology , University of California Riverside , Riverside , California , USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ruegger
authors.affiliation: e F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center , Los Angeles , California , USA.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: c Department of Biochemistry and Molecular & Cellular Biology , Georgetown University , Washington , D.C. , USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.affiliation: d Plant Pathology and Microbiology , University of California Riverside , Riverside , California , USA.
authors.forename: James
authors.initials: J
authors.lastname: Borneman
authors.affiliation: f Department of Biochemistry and Molecular Biology , University of Oklahoma Health Sciences Center , Oklahoma City , Oklahoma , USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.affiliation: b Department of Pathology , University of California Los Angeles , Los Angeles , California , USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D015331:Cohort Studies; D003092:Colitis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D006801:Humans; D051379:Mice; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D009077:Mucins; C505293:C1GALT1 protein, human; C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases
keywords: C1galt1; T-synthase; colitis; core-1 O-glycans; microbiome