Clostridium difficile is a toxin-producing bacterium that is a frequent cause of hospital-acquired and antibiotic-associated diarrhea. The incidence and severity of C. difficile infection (CDI) are increasing, in parallel with increases in community-acquired infections, making CDI a major public health problem. Following inoculation, patients may clear C. difficile from their intestinal tract, become asymptomatically colonized, or develop CDI, ranging in severity from mild diarrhea to fulminant colitis and/or death. Older adults are disproportionately affected by CDI, experiencing greater morbidity and mortality. Antibiotics treat CDI, but refractory disease and relapses occur. Major gaps exist in our understanding ofthe host and microbial factors that determine the outcome of human contact with C. difficile. The broad objective of this ERIN CRC is to develop innovative approaches to the diagnosis, prevention, and treatment of CDI based on understanding the molecular mechanisms of disease. The goals of this Proiect are to use genomic information obtained from clinical C. difficile strains, to identify microbial determinants of infection and develop a rapid, high-throughput assay to predict the clinical behavior of individual C. difficile strains. We hypothesize that there is a genomic basis for the different clinical presentations of C. difficile (colonization, mild or severe infection, and relapse) in susceptible hosts.
The Specific Aims of this proposal seek to: (1) Establish a collection of isolates that spans the genetic diversity of C. difficile associated with both asymptomatically colonized adults and those with initial and recurrent infection;(2) Perform a comparative phylogenomic analysis of representative C. difficile isolates obtained from Aim 1;and (3) Develop a high-throughput single nucleotide polymorphism (SNP) typing system for the rapid discrimination and risk-assessment ofC. difficile infection. This project will collect clinicoepidemiological data, biological specimens and C. difficile strains, which will be used in all three major projects of this ERIN.

Public Health Relevance

Clostridium difficile is a common cause of antibiotic-associated and hospital-associated diarrhea. It is an emerging pathogen that is highly transmissible and opportunistic, imposing a significant burden on global health and healthcare resources. The best method to control the spread of CDI is to better understand its pathogenesis. These studies will provide an important foundation for developing more accurate diagnostic, preventive, and therapeutic regimens against this important problem.

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)
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University of Michigan Ann Arbor
Ann Arbor
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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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