The University of Michigan Enterics Research Investigational Network Cooperative Research Center (UM ERIN CRC) is composed of an integrated, multidisciplinary team of investigators who have expertise in bacterial pathogenesis, microbial ecology, immunology, human genetics, infectious diseases, bioinformatics, clinical medicine and geriatrics. To leverage the expertise of the assembled team, their current research interests and past research accomplishments, the UM ERIN CRC will focus its efforts on the study of antibiotic-associated colitis due to Clostridium difficile. C. difficile infection (CDI) is a re-emerging infectious disease that is responsible for significant morbidity and mortality. However, despite the significance of CDI, there are major gaps in our knowledge of the pathogenesis of this infection. To address these gaps, the UM ERIN CRC will carry out three projects. In the first project a clinical survey will be conducted to collect clinical specimens (feces, blood and human DNA) and C. difficile strains from asymptomatically infected individuals and patients with initial episodes or recurrent CDI of varying severity. The C. difficile strains will be genetically characterized to understand the role of bacterial diversity/evolution in the disease process. This information will be used to develop a rapid single-nucleotide polymorphism typing scheme to aid in rapid diagnosis and molecular epidemiology. The second project will utilize the clinical specimens and clinical strains to determine the role of the indigenous microbiota in CDI. Specific hypotheses regarding gut microbial ecology and CDI will be tested in a novel murine model that we have activated in our laboratory group. The last portion of this project involves examination of the relationship between the ability of C. difficile to sporulate/germ in ate and the pathogenesis of CDI. The spore biology of the clinical strains from the first project will be characterized and variants tested for the ability to persist and cause disease using the murine model. Targeted mutants of the sporulation pathway will also be constructed and characterized. The third project will leverage the clinical specimens and the murine model of CDI to characterize the role of the host response in CDI pathogenesis. The role of innate and adaptive immune responses in mediating clinical disease and susceptibility will be determined by examining responses and biomarkers in samples from human clinical cases and the murine model. These integrated projects will increase our understanding of C. difficile disease and lead to novel diagnostic and therapeutic modalities for this increasingly important pathogen.

Public Health Relevance

Treatment with antibiotics can lead to antibiotic-associated colitis due to infection with the bacterium Clostridium difficile. The proposed research will study the role of specific types of C. difficile, human genetics and immune responses and the existing gut bacteria in disease related to C. difficile infection. The overall goal is to increase our ability to come up with novel ways to prevent and treat this important human infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090871-03
Application #
8308974
Study Section
Special Emphasis Panel (ZAI1-BLG-M (M2))
Program Officer
Ranallo, Ryan
Project Start
2010-08-02
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$1,487,445
Indirect Cost
$530,542
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
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Rao, Krishna; Higgins, Peter D R; Young, Vincent B (2018) An Observational Cohort Study of Clostridium difficile Ribotype 027 and Recurrent Infection. mSphere 3:
Seekatz, Anna M; Theriot, Casey M; Rao, Krishna et al. (2018) Restoration of short chain fatty acid and bile acid metabolism following fecal microbiota transplantation in patients with recurrent Clostridium difficile infection. Anaerobe :
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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.e1-178.e9
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
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:

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