Inflammatory bowel disease (IBD) is characterized by the development of an abnormal inflammatory response in the gastrointestinal tract. The microbiota of the intestinal tract, in part via interactions with the host epithelium and immune system are thought to drive this proinflammatory state. The gut microbiota represents a complex community of bacteria that until recently has only been partly characterized. The use of culture-independent techniques to examine complex microbial communities has started to reveal details about the structure and composition of the gut microbiota. To date, minimal work has been done to define differences in the structure of the mucosa-associated microbiota of the intestinal tract secondary to alterations in the host immune system, the presence of pathogens, antibiotic treatment or the presence of beneficial (probiotic) organisms. In this proposal, an existing collaboration between scientists with interests in microbial ecology and infectious diseases/bacterial pathogenesis plan to investigate the role of the intestinal microbiota in IBD utilizing a well developed murine model of IBD in IL-10-/- mice triggered by the presence of the bacterium Helicobacter hepaticus. Specifically we propose to 1) determine the influence of the host immune system on shaping the community structure of the mucosa-associated intestinal microbiota 2) determine how H. hepaticus infection and the development of colitis changes the mucosa-associated intestinal microbiota and 3) determine if antibiotics can modify the development of IBD in H. hepaticus-infected IL-10-/- animals. The proposed experiments will provide insight into the mechanism by which infectious agents can trigger shifts in the indigenous microbiota that lead to aberrant host responses and disease states. This information will directly impact patients with inflammatory bowel disease, leading to a greater understanding of the underlying disease mechanisms and the development of novel treatment modalities. Relevance: Inflammatory bowel disease in humans is thought to arise from an abnormal interaction between the immune system and the microbes that normally inhabit the gut. This project intends to define abnormalities in the community of gut microbes that predispose to the development of inflammatory bowel disease, pointing the way towards new therapies for this chronic disease that affects 1 in 1000 people in developed countries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070875-05
Application #
7837667
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$278,357
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Irwin, Regina; Lee, Taehyung; Young, Vincent B et al. (2013) Colitis-induced bone loss is gender dependent and associated with increased inflammation. Inflamm Bowel Dis 19:1586-97
Denson, Lee A; Long, Millie D; McGovern, Dermot P B et al. (2013) Challenges in IBD research: update on progress and prioritization of the CCFA's research agenda. Inflamm Bowel Dis 19:677-82
Schloss, Patrick D; Schubert, Alyxandria M; Zackular, Joseph P et al. (2012) Stabilization of the murine gut microbiome following weaning. Gut Microbes 3:383-93
Mason, Katie L; Erb Downward, John R; Mason, Kelly D et al. (2012) Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect Immun 80:3371-80
Gillilland 3rd, Merritt G; Erb-Downward, John R; Bassis, Christine M et al. (2012) Ecological succession of bacterial communities during conventionalization of germ-free mice. Appl Environ Microbiol 78:2359-66
Young, Vincent B (2012) The intestinal microbiota in health and disease. Curr Opin Gastroenterol 28:63-9
Britton, Robert A; Young, Vincent B (2012) Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol 20:313-9
Reeves, Angela E; Koenigsknecht, Mark J; Bergin, Ingrid L et al. (2012) Suppression of Clostridium difficile in the gastrointestinal tracts of germfree mice inoculated with a murine isolate from the family Lachnospiraceae. Infect Immun 80:3786-94
Han, Meilan K; Huang, Yvonne J; Lipuma, John J et al. (2012) Significance of the microbiome in obstructive lung disease. Thorax 67:456-63
Mason, Katie L; Erb Downward, John R; Falkowski, Nicole R et al. (2012) Interplay between the gastric bacterial microbiota and Candida albicans during postantibiotic recolonization and gastritis. Infect Immun 80:150-8

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