Bile salt metabolism is not the only factor contributing to Clostridioides (Clostridium) difficile disease severity in the murine model of disease

Jukes, C., Ijaz, U. Z. , Buckley, A., Spencer, J., Irvine, J., Li, J. V., Marchesi, J. R., Candlish, D. and Douce, G. (2020) Bile salt metabolism is not the only factor contributing to Clostridioides (Clostridium) difficile disease severity in the murine model of disease. Gut Microbes, 11(3), pp. 481-496. (doi: 10.1080/19490976.2019.1678996) (PMID:31793403) (PMCID:PMC7524298)

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Abstract

Susceptibility of patients to antibiotic-associated C. difficile disease is intimately associated with specific changes to gut microbiome composition. In particular, loss of microbes that modify bile salt acids (BSA) play a central role; primary bile acids stimulate spore germination whilst secondary bile acids limit C. difficile vegetative growth. To determine the relative contribution of bile salt (BS) metabolism on C. difficile disease severity, we treated mice with three combinations of antibiotics prior to infection. Mice given clindamycin alone became colonized but displayed no tissue pathology while severe disease, exemplified by weight loss and inflammatory tissue damage occurred in animals given a combination of five antibiotics and clindamycin. Animals given only the five antibiotic cocktails showed only transient colonization and no disease. C. difficile colonization was associated with a reduction in bacterial diversity, an inability to amplify bile salt hydrolase (BSH) sequences from fecal DNA and a relative increase in primary bile acids (pBA) in cecal lavages from infected mice. Further, the link between BSA modification and the microbiome was confirmed by the isolation of strains of Lactobacillus murinus that modified primary bile acids in vitro, thus preventing C. difficile germination. Interestingly, BSH activity did not correlate with disease severity which appeared linked to alternations in mucin, which may indirectly lead to increased exposure of the epithelial surface to inflammatory signals. These data confirm the role of microbial metabolic activity in protection of the gut and highlights the need for greater understanding the function of bacterial communities in disease prevention.

Item Type:Articles
Additional Information:This work was supported by the Biotechnology and Biological Sciences Research Council [DTP programme BB/J013854/1]; National Institute for Health Research [Imperial Biomedical Research Centre]; Natural Environment Research Council [NE/LO11956/1]; Wellcome Trust [086418].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Douce, Dr Gillian and Jukes, Caitlin and Candlish, Mrs Denise and Ijaz, Dr Umer and Spencer, Dr Janice and Buckley, Dr Anthony and Irvine, Ms June
Authors: Jukes, C., Ijaz, U. Z., Buckley, A., Spencer, J., Irvine, J., Li, J. V., Marchesi, J. R., Candlish, D., and Douce, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Gut Microbes
Publisher:Taylor and Francis
ISSN:1949-0976
ISSN (Online):1949-0984
Published Online:02 December 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Gut Microbes 11(3):481-496
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
161382Genetic and phenotypic characterisation of emerging virulent Clostridium difficileGillian DouceWellcome Trust (WELLCOTR)086418/B/08/ZIII - Bacteriology
170256Understanding microbial community through in situ environmental 'omic data synthesisUmer Zeeshan IjazNatural Environment Research Council (NERC)NE/L011956/1ENG - Infrastructure & Environment