Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality. Disease related to CDI ranges from asymptomatic colonization to mild diarrheal disease to severe pseudomembranous colitis. Despite the extensive characterization of the histologic lesions associated with C. difficile infection, virtually nothing is known mechanistically about the contribution of host factors in disease. It is likely that some of the clinical differences encountered in infected individuals are due to variation in host response to colonization with C. difficile. We hypothesize that variation in the host innate and adaptive responses for C. difficile are in part responsible for the different clinical phenotypes that are seen in the setting of CDI. Furthermore, we speculate that these variable responses reflect underlying genetic and possibly epigenetic differences in the host. To address these hypotheses we propose the following specific aims: In the first aim we will characterize the innate and adaptive immune response to C. difficile colonization and determine the role of this response in determining the disease manifestations. In the second aim we will identify serum fecal biomarkers and epigenetic changes that correlate distinct clinical outcomes.
This aim will examine samples obtained from the Project area #1 for this purpose.
The third aim will examine the interaction between host genetics/immune response and C. difficile genotype in the pathogenesis of disease. Mice with defined differences in host response will be challenged with C. difficile strains generated and characterized from the human studies in Project area #1. This will provide an examination ofthe relative contribution of host and pathogen factors in disease. These experiments will increase our understanding ofthe host and microbial mechanisms of C. difficile-induced colonic inflammation vs. asymptomatic colonization and identify biomarkers that can be used to improve clinical treatments and outcomes.

Public Health Relevance

Clostridium difficile infection is associated with the development of severe inflammation of the large intestine, resulting in significant morbidity and mortality. Our objective is to understand the mechanisms of this inflammation and identify biomarkers that can be used to improve clinical treatments and outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090871-04
Application #
8508842
Study Section
Special Emphasis Panel (ZAI1-BLG-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$411,088
Indirect Cost
$146,723
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Theriot, Casey M; Bowman, Alison A; Young, Vincent B (2016) Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. mSphere 1:
Seekatz, Anna Maria; Rao, Anna Maria; Santhosh, Kavitha et al. (2016) Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. Genome Med 8:47
Leslie, Jhansi L; Young, Vincent B (2016) A whole new ball game: Stem cell-derived epithelia in the study of host-microbe interactions. Anaerobe 37:25-8
Rao, Krishna; Santhosh, Kavitha; Mogle, Jill A et al. (2016) Elevated fecal calprotectin associates with adverse outcomes from Clostridium difficile infection in older adults. Infect Dis (Lond) 48:663-9
Young, V B (2016) Therapeutic manipulation of the microbiota: past, present, and considerations for the future. Clin Microbiol Infect 22:905-909
Stokely, Janelle N; Niendorf, Sandra; Taube, Stefan et al. (2016) Prevalence of human norovirus and Clostridium difficile coinfections in adult hospitalized patients. Clin Epidemiol 8:253-60
McDermott, Andrew J; Falkowski, Nicole R; McDonald, Roderick A et al. (2016) Interleukin-23 (IL-23), independent of IL-17 and IL-22, drives neutrophil recruitment and innate inflammation during Clostridium difficile colitis in mice. Immunology 147:114-24
Rogers, M A M; Aronoff, D M (2016) The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 22:178.e1-9
Young, Vincent B; Hayden, Mary K (2016) Environmental management in the gut: fecal transplantation to restore the intestinal ecosystem. Infect Dis (Lond) 48:593-5
Micic, Dejan; Rao, Krishna; Trindade, Bruno Caetano et al. (2015) Serum 25-Hydroxyvitamin D Levels are not Associated with Adverse Outcomes in Clostridium Difficile Infection. Infect Dis Rep 7:5979

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