Changes in colonic bile acid composition following fecal microbiota transplantation are sufficient to control Clostridium difficile germination and growth

Alexa R. Weingarden, Peter I. Dosa, Erin DeWinter, Clifford J. Steer, Megan K. Shaughnessy, James R. Johnson, Alexander Khoruts, Michael J. Sadowsky

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67 Scopus citations

Abstract

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridium difficile infection (R-CDI), but its mechanisms remain poorly understood. Emerging evidence suggests that gut bile acids have significant influence on the physiology of C. difficile, and therefore on patient susceptibility to recurrent infection. We analyzed spore germination of 10 clinical C. difficile isolates exposed to combinations of bile acids present in patient feces before and after FMT. Bile acids at concentrations found in patients' feces prior to FMT induced germination of C. difficile, although with variable potency across different strains. However, bile acids at concentrations found in patients after FMT did not induce germination and inhibited vegetative growth of all C. difficile strains. Sequencing of the newly identified germinant receptor in C. difficile, CspC, revealed a possible correspondence of variation in germination responses across isolates with mutations in this receptor. This may be related to interstrain variability in spore germination and vegetative growth in response to bile acids seen in this and other studies. These results support the idea that intra-colonic bile acids play a key mechanistic role in the success of FMT, and suggests that novel therapeutic alternatives for treatment of R-CDI may be developed by targeted manipulation of bile acid composition in the colon.

Original languageEnglish (US)
Article numbere0147210
JournalPloS one
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2016

Bibliographical note

Funding Information:
This work was supported in part by NIH grant 1R21-AI114722-01 (AK, MJS, CC) and NIH Training Grant UL1TR00114 to University ofMinnesota CTSI (ARW). Research reported in this publication was also supported, in part, by NIAID Grant R21AI-091907 (AK and MJS). MKS was supported by training grant award 2T32AI055433-06A1 from the National Center for Allergy and Infectious Diseases and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AK and MJS received funding from CIPAC LLC to carry out research on FMT using frozen and freeze-dried fecal microbiota. AK and MJS have provided consulting services for CIPAC; conflicts of interest are being managed by the University of Minnesota Conflicts of Interest Program. All other authors have no potential conflicts of interest to declare. This does not alter the authors'' adherence to PLOS ONE policies on sharing data and materials. This work was supported in part by NIH grant 1R21-AI114722-01 (AK, MJS, CC) and NIH Training Grant UL1TR00114 to University of Minnesota CTSI (ARW). Research reported in this publication was also supported, in part, by NIAID Grant R21AI-091907 (AK and MJS). MKS was supported by training grant award 2T32AI055433-06A1 from the National Center for Allergy and Infectious Diseases and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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