Alexa R Weingarden1, Chi Chen, Ningning Zhang, Carolyn T Graiziger, Peter I Dosa, Clifford J Steer, Megan K Shaughnessy, James R Johnson, Michael J Sadowsky, Alexander Khoruts. 1. Departments of *Microbiology and The BioTechnology Institute †Food Science and Nutrition ‡Medicine, Division of Gastroenterology, Center for Immunology, BioTechnology Institute §Medicinal Chemistry, Institute for Therapeutics Discovery and Development ∥Medicine and Genetics, Cell Biology, and Development ¶Medicine, Division of Infectious Diseases **Soil, Water & Climate, and The BioTechnology Institute, University of Minnesota #Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN.
Abstract
GOALS: To test whether ursodeoxycholic acid (UDCA) is inhibitory to Clostridium difficile and can be used in the treatment of C. difficile-associated ileal pouchitis. BACKGROUND: The restoration of secondary bile metabolism may be the key mechanism for fecal microbiota transplantation (FMT) in treating recurrent C. difficile infections (RCDI). Therefore, it is possible that exogenous administration of inhibitory bile acids may be used directly as nonantibiotic therapeutics for this indication. The need for such a treatment alternative is especially significant in patients with refractory C. difficile-associated pouchitis, where the efficacy of FMT may be limited. STUDY: We measured the ability of UDCA to suppress the germination and the vegetative growth of 11 clinical isolate strains of C. difficile from patients treated with FMT for RCDI. In addition, we used oral UDCA to treat a patient with RCDI pouchitis that proved refractory to multiple antibiotic treatments and FMT. RESULTS: UDCA was found to be inhibitory to the germination and the vegetative growth of all C. difficile strains tested. Fecal concentrations of UDCA from the patient with RCDI pouchitis exceeded levels necessary to inhibit the germination and the growth of C. difficile in vitro. The patient has remained infection free for over 10 months after the initiation of UDCA. CONCLUSIONS: UDCA can be considered as a therapeutic option in patients with C. difficile-associated pouchitis. Further studies need to be conducted to define the optimal dose and duration of such a treatment. In addition, bile acid derivatives inhibitory to C. difficile that are able to achieve high intracolonic concentrations may be developed as therapeutics for RCDI colitis.
GOALS: To test whether ursodeoxycholic acid (UDCA) is inhibitory to Clostridium difficile and can be used in the treatment of C. difficile-associated ileal pouchitis. BACKGROUND: The restoration of secondary bile metabolism may be the key mechanism for fecal microbiota transplantation (FMT) in treating recurrent C. difficile infections (RCDI). Therefore, it is possible that exogenous administration of inhibitory bile acids may be used directly as nonantibiotic therapeutics for this indication. The need for such a treatment alternative is especially significant in patients with refractory C. difficile-associated pouchitis, where the efficacy of FMT may be limited. STUDY: We measured the ability of UDCA to suppress the germination and the vegetative growth of 11 clinical isolate strains of C. difficile from patients treated with FMT for RCDI. In addition, we used oral UDCA to treat a patient with RCDI pouchitis that proved refractory to multiple antibiotic treatments and FMT. RESULTS:UDCA was found to be inhibitory to the germination and the vegetative growth of all C. difficile strains tested. Fecal concentrations of UDCA from the patient with RCDI pouchitis exceeded levels necessary to inhibit the germination and the growth of C. difficile in vitro. The patient has remained infection free for over 10 months after the initiation of UDCA. CONCLUSIONS:UDCA can be considered as a therapeutic option in patients with C. difficile-associated pouchitis. Further studies need to be conducted to define the optimal dose and duration of such a treatment. In addition, bile acid derivatives inhibitory to C. difficile that are able to achieve high intracolonic concentrations may be developed as therapeutics for RCDI colitis.
Authors: Alexa R Weingarden; Chi Chen; Aleh Bobr; Dan Yao; Yuwei Lu; Valerie M Nelson; Michael J Sadowsky; Alexander Khoruts Journal: Am J Physiol Gastrointest Liver Physiol Date: 2013-11-27 Impact factor: 4.052
Authors: Susana Fuentes; Els van Nood; Sebastian Tims; Ineke Heikamp-de Jong; Cajo J F ter Braak; Josbert J Keller; Erwin G Zoetendal; Willem M de Vos Journal: ISME J Date: 2014-02-27 Impact factor: 10.302
Authors: Shelley S Magill; Jonathan R Edwards; Wendy Bamberg; Zintars G Beldavs; Ghinwa Dumyati; Marion A Kainer; Ruth Lynfield; Meghan Maloney; Laura McAllister-Hollod; Joelle Nadle; Susan M Ray; Deborah L Thompson; Lucy E Wilson; Scott K Fridkin Journal: N Engl J Med Date: 2014-03-27 Impact factor: 91.245
Authors: Charlie G Buffie; Vanni Bucci; Richard R Stein; Peter T McKenney; Lilan Ling; Asia Gobourne; Daniel No; Hui Liu; Melissa Kinnebrew; Agnes Viale; Eric Littmann; Marcel R M van den Brink; Robert R Jenq; Ying Taur; Chris Sander; Justin R Cross; Nora C Toussaint; Joao B Xavier; Eric G Pamer Journal: Nature Date: 2014-10-22 Impact factor: 49.962
Authors: Kristen L Stoltz; Raymond Erickson; Christopher Staley; Alexa R Weingarden; Erin Romens; Clifford J Steer; Alexander Khoruts; Michael J Sadowsky; Peter I Dosa Journal: J Med Chem Date: 2017-04-12 Impact factor: 7.446