Over the past two decades Clostridium difficile infection (CDI) has reached epidemic proportions due to emergence of more virulent strains of the pathogen. Fecal microbiota transplantation (FMT) has emerged as a potential solution for many patients refractory to antibiotic treatment alone. We and others have previously shown that FMT promptly restores normal fecal bacterial composition similar to that of the donors. We had also shown that recovery of normal microbial gut ecology is accompanied by major changes in the fecal metabolome, which importantly includes normalization of fecal bile acid composition. The focus on bile acids is mechanistically relevant because they are known to play important roles in the lifecycle of C. difficile. Specifically, taurocholate (a major primary bile acid) is a potent germinant of C. difficile spores, and a critical component of C. difficile growth media in the laboratory. In contrast, lithocholate and deoxycholate (dominant secondary bile acids) are inhibitors of C. difficile spore germination and vegetative growth, respectively. We found that fecal samples from RCDI patients before FMT contain no detectable secondary bile acids, but do have elevated concentrations of primary bile acids. Fecal samples taken from the same patients after FMT contain donor-like fecal bile acid composition. Therefore, our central hypothesis is that antibiotics used to treat CDI patients alter bile acid metabolism to favor C. difficile germination and growth, and FMT restores the normal bile acid composition that is inhospitable to C. difficile expansion. In this proposal we will extend our exploratory preliminary results and test this hypothesis by performing quantitative analysis of bile acid metabolism in patients with RCDI pre- and post-FMT and testing pre- and post-FMT fecal samples for germinant activity and growth inhibition on clinical isolates of C. difficile bacteria. In additionwe will test one non-FMT approach to alter bile acid composition unfavorable to C. difficile: a bile acid sequestrant resin, cholestyramine, in combination with lovastatin. The latter will be used to inhibit compensatory increase in de novo bile acid synthesis in the liver. Results of this work wil inform future clinical trials in treating patients with refractory CDI by targeting bile acid metabolism.

Public Health Relevance

Fecal transplantation (FMT) has emerged as an effective approach to treat C. difficile infection that does not respond to antibiotics. However, mechanisms of this procedure are poorly understood. Here we test a compelling hypothesis for how this procedure works involving changes in bile acid metabolism. This hypothesis, if true, can form a foundation for next generation therapeutics for this challenging problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI114722-01
Application #
8802719
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Ranallo, Ryan
Project Start
2015-04-22
Project End
2017-03-31
Budget Start
2015-04-22
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$226,254
Indirect Cost
$76,254
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Staley, Christopher; Kaiser, Thomas; Vaughn, Byron P et al. (2018) Predicting recurrence of Clostridium difficile infection following encapsulated fecal microbiota transplantation. Microbiome 6:166
Stoltz, Kristen L; Erickson, Raymond; Staley, Christopher et al. (2017) Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination. J Med Chem 60:3451-3471
Staley, Christopher; Hamilton, Matthew J; Vaughn, Byron P et al. (2017) Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study. Am J Gastroenterol 112:940-947
Staley, Christopher; Weingarden, Alexa R; Khoruts, Alexander et al. (2017) Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol 101:47-64
Staley, Christopher; Vaughn, Byron P; Graiziger, Carolyn T et al. (2017) Community dynamics drive punctuated engraftment of the fecal microbiome following transplantation using freeze-dried, encapsulated fecal microbiota. Gut Microbes 8:276-288
Staley, Christopher; Kaiser, Thomas; Beura, Lalit K et al. (2017) Stable engraftment of human microbiota into mice with a single oral gavage following antibiotic conditioning. Microbiome 5:87
Kelly, Colleen R; Khoruts, Alexander; Staley, Christopher et al. (2016) Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med 165:609-616
Khoruts, Alexander; Sadowsky, Michael J (2016) Understanding the mechanisms of faecal microbiota transplantation. Nat Rev Gastroenterol Hepatol 13:508-16
Staley, Christopher; Kelly, Colleen R; Brandt, Lawrence J et al. (2016) Complete Microbiota Engraftment Is Not Essential for Recovery from Recurrent Clostridium difficile Infection following Fecal Microbiota Transplantation. MBio 7:
Weingarden, Alexa R; Dosa, Peter I; DeWinter, Erin et al. (2016) Changes in Colonic Bile Acid Composition following Fecal Microbiota Transplantation Are Sufficient to Control Clostridium difficile Germination and Growth. PLoS One 11:e0147210

Showing the most recent 10 out of 11 publications