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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BLG-M (M2))
Program Officer
Ranallo, Ryan
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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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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