Clostridium difficile infection is the most common nosocomial infection in the US and other developed countries, yet standard antibiotic therapy for this infection fails to cure nearly a quarter of patients. These individuals experience a recurrence of the infection, and a large subset of patients with a single recurrence go on to develop recurrent C. difficile infection syndrome (R-CDI), characterized by vicious cycles of repeated antibiotic use and recurrence of disease. Although fecal microbiota transplantation (FMT) is now widely recognized as an extremely effective therapy for R-CDI, its mechanisms were heretofore unknown. This substantial gap in our knowledge limited both our ability to design novel therapies for R-CDI and our understanding of the role our native intestinal microbes play in our health. The work herein summarizes our efforts to identify and test the mechanisms behind this important treatment. Our findings indicate that fecal bile acid composition, which is significantly altered following FMT, also dramatically impacts C. difficile physiology. Bile acids present after FMT, compared to those present prior to the procedure, prevent germination of C. difficile spores and limit the growth of vegetative cells. With this knowledge, we demonstrated that a bile acid already clinically available, ursodeoxycholic acid (UDCA), can also prevent C. difficile germination and growth. Although unfortunately UDCA is a poor treatment option for many patients due to its absorption in the small intestine, we showed both that a non-absorbed derivative of UDCA, C7-sulfated UDCA, may be a promising novel therapy for R-CDI, and that UDCA may still have clinical utility in patients with altered gastrointestinal anatomy. These findings have paved the way for novel treatments for this widespread infection.
University of Minnesota Ph.D. dissertation. August 2015. Major: Microbiology, Immunology and Cancer Biology. Advisors: Michael Sadowsky, Alexander Khoruts. 1 computer file (PDF); xiii, 240 pages.
Mechanisms of Fecal Microbiota Transplantation and Development of Novel Therapies for Clostridium difficile Infection.
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