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Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria

Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Fu...

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Autores principales: Passmore, Ian J., Letertre, Marine P. M., Preston, Mark D., Bianconi, Irene, Harrison, Mark A., Nasher, Fauzy, Kaur, Harparkash, Hong, Huynh A., Baines, Simon D., Cutting, Simon M., Swann, Jonathan R., Wren, Brendan W., Dawson, Lisa F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135563/
https://www.ncbi.nlm.nih.gov/pubmed/30208103
http://dx.doi.org/10.1371/journal.ppat.1007191
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author Passmore, Ian J.
Letertre, Marine P. M.
Preston, Mark D.
Bianconi, Irene
Harrison, Mark A.
Nasher, Fauzy
Kaur, Harparkash
Hong, Huynh A.
Baines, Simon D.
Cutting, Simon M.
Swann, Jonathan R.
Wren, Brendan W.
Dawson, Lisa F.
author_facet Passmore, Ian J.
Letertre, Marine P. M.
Preston, Mark D.
Bianconi, Irene
Harrison, Mark A.
Nasher, Fauzy
Kaur, Harparkash
Hong, Huynh A.
Baines, Simon D.
Cutting, Simon M.
Swann, Jonathan R.
Wren, Brendan W.
Dawson, Lisa F.
author_sort Passmore, Ian J.
collection PubMed
description Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Furthermore, failure of the gut microbiota to recover colonisation resistance can result in recurrence of infection. An unusual characteristic of C. difficile among gut bacteria is its ability to produce the bacteriostatic compound para-cresol (p-cresol) through fermentation of tyrosine. Here, we demonstrate that the ability of C. difficile to produce p-cresol in vitro provides a competitive advantage over gut bacteria including Escherichia coli, Klebsiella oxytoca and Bacteroides thetaiotaomicron. Metabolic profiling of competitive co-cultures revealed that acetate, alanine, butyrate, isobutyrate, p-cresol and p-hydroxyphenylacetate were the main metabolites responsible for differentiating the parent strain C. difficile (630Δerm) from a defined mutant deficient in p-cresol production. Moreover, we show that the p-cresol mutant displays a fitness defect in a mouse relapse model of C. difficile infection (CDI). Analysis of the microbiome from this mouse model of CDI demonstrates that colonisation by the p-cresol mutant results in a distinctly altered intestinal microbiota, and metabolic profile, with a greater representation of Gammaproteobacteria, including the Pseudomonales and Enterobacteriales. We demonstrate that Gammaproteobacteria are susceptible to exogenous p-cresol in vitro and that there is a clear divide between bacterial Phyla and their susceptibility to p-cresol. In general, Gram-negative species were relatively sensitive to p-cresol, whereas Gram-positive species were more tolerant. This study demonstrates that production of p-cresol by C. difficile has an effect on the viability of intestinal bacteria as well as the major metabolites produced in vitro. These observations are upheld in a mouse model of CDI, in which p-cresol production affects the biodiversity of gut microbiota and faecal metabolite profiles, suggesting that p-cresol production contributes to C. difficile survival and pathogenesis.
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spelling pubmed-61355632018-09-27 Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria Passmore, Ian J. Letertre, Marine P. M. Preston, Mark D. Bianconi, Irene Harrison, Mark A. Nasher, Fauzy Kaur, Harparkash Hong, Huynh A. Baines, Simon D. Cutting, Simon M. Swann, Jonathan R. Wren, Brendan W. Dawson, Lisa F. PLoS Pathog Research Article Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Furthermore, failure of the gut microbiota to recover colonisation resistance can result in recurrence of infection. An unusual characteristic of C. difficile among gut bacteria is its ability to produce the bacteriostatic compound para-cresol (p-cresol) through fermentation of tyrosine. Here, we demonstrate that the ability of C. difficile to produce p-cresol in vitro provides a competitive advantage over gut bacteria including Escherichia coli, Klebsiella oxytoca and Bacteroides thetaiotaomicron. Metabolic profiling of competitive co-cultures revealed that acetate, alanine, butyrate, isobutyrate, p-cresol and p-hydroxyphenylacetate were the main metabolites responsible for differentiating the parent strain C. difficile (630Δerm) from a defined mutant deficient in p-cresol production. Moreover, we show that the p-cresol mutant displays a fitness defect in a mouse relapse model of C. difficile infection (CDI). Analysis of the microbiome from this mouse model of CDI demonstrates that colonisation by the p-cresol mutant results in a distinctly altered intestinal microbiota, and metabolic profile, with a greater representation of Gammaproteobacteria, including the Pseudomonales and Enterobacteriales. We demonstrate that Gammaproteobacteria are susceptible to exogenous p-cresol in vitro and that there is a clear divide between bacterial Phyla and their susceptibility to p-cresol. In general, Gram-negative species were relatively sensitive to p-cresol, whereas Gram-positive species were more tolerant. This study demonstrates that production of p-cresol by C. difficile has an effect on the viability of intestinal bacteria as well as the major metabolites produced in vitro. These observations are upheld in a mouse model of CDI, in which p-cresol production affects the biodiversity of gut microbiota and faecal metabolite profiles, suggesting that p-cresol production contributes to C. difficile survival and pathogenesis. Public Library of Science 2018-09-12 /pmc/articles/PMC6135563/ /pubmed/30208103 http://dx.doi.org/10.1371/journal.ppat.1007191 Text en © 2018 Passmore et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Passmore, Ian J.
Letertre, Marine P. M.
Preston, Mark D.
Bianconi, Irene
Harrison, Mark A.
Nasher, Fauzy
Kaur, Harparkash
Hong, Huynh A.
Baines, Simon D.
Cutting, Simon M.
Swann, Jonathan R.
Wren, Brendan W.
Dawson, Lisa F.
Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria
title Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria
title_full Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria
title_fullStr Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria
title_full_unstemmed Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria
title_short Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria
title_sort para-cresol production by clostridium difficile affects microbial diversity and membrane integrity of gram-negative bacteria
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135563/
https://www.ncbi.nlm.nih.gov/pubmed/30208103
http://dx.doi.org/10.1371/journal.ppat.1007191
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