We propose to study the influence of specific gut bacteria in a novel model of Ulcerative Colitis. The model was created by the Lijun Xia laboratory and develops spontaneous colitis when the production of one of the 2 main core glycans (Core 1) of colonic mucus is disrupted by gene knockout technology (TM-IEC C1galt1-/-). Having observed specific changes in the microbiota of the conventional TM-IEC C1galt1-/- mice 2 weeks after the induction of the knockout we propose to examine the microbiota over time to identify changes that occur after mucus production is lost, both before and after the onset of colitis. We will examine gut microbes that are known to be able to degrade mucus (Bacteroides thetaiotaomicronsm, Akkermansia muciniphila, Ruminococcus gnavus, and R. torques), bacteria that have demonstrated to be involved in colitis in other mouse models, and microbes identified in our own model by 16s rRNA gene pyrosequencing based analysis of the microbial communities. We will compare the genomic composition of the various microbes tested to define the metabolic and other pathways associated with colitis development. We will examine the impact of IgA and the rest of the adaptive immune system on colitis by crossing the TM-IEC C1galt1-/- mice with Rag1-/- in the germ-free mouse facility. Using tools that we have previously established (such as a symbiont specific IgA) we will examine how this immune response can influence colitis development. The results of these studies will provide the basis of future studies that will examine the specific host microbial interactions that contribute to coliti development. The project has the potential to identify the microbial components and host adaptive immune components that modulate Ulcerative Colitis in the context of O-glycans loss in the colon.

Public Health Relevance

Ulcerative Colitis (UC) is an inflammatory disease of the colon that has significant morbidity and mortality. Its etiology likely involves a complex interaction between the patient's genetic predisposition and specific microbes that live in the gut. The proposed research examines potential causative bacteria using a novel mouse model that contains a defect in the mucus barrier. The goal is to identify both the microbial genetic components that trigger disease and host immune factors that help make decrease disease severity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI097419-02
Application #
8497618
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$190,186
Indirect Cost
$52,452
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Perez-Muñoz, Maria Elisa; Bergstrom, Kirk; Peng, Vincent et al. (2014) Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis. Gut Microbes 5:286-95