Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model

ABSTRACT Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in...

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Autores principales:	Joshua R. Fletcher, Samantha Erwin, Cristina Lanzas, Casey M. Theriot
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Clostridium difficile amino acids intestinal colonization metabolomics peptides transcriptomics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9fc0a6df613c40b7a6f7b7cca3b2b7d7
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spelling	oai:doaj.org-article:9fc0a6df613c40b7a6f7b7cca3b2b7d72021-11-15T15:22:14ZShifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model10.1128/mSphere.00089-182379-5042https://doaj.org/article/9fc0a6df613c40b7a6f7b7cca3b2b7d72018-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00089-18https://doaj.org/toc/2379-5042ABSTRACT Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in the gut metabolome, specifically, with increases in levels of nutrients that C. difficile can utilize for growth in vitro. To define the nutrients that C. difficile requires for colonization and pathogenesis in vivo, we used a combination of mass spectrometry and RNA sequencing (RNA Seq) to model the gut metabolome and C. difficile transcriptome throughout an acute infection in a mouse model at the following time points: 0, 12, 24, and 30 h. We also performed multivariate-based integration of the omics data to define the signatures that were most important throughout colonization and infection. Here we show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time in the mouse cecum and that C. difficile gene expression is consistent with their utilization in vivo. This was also reinforced by the multivariate-based integration of the omics data where we were able to discriminate the metabolites and transcripts that support C. difficile physiology between the different time points throughout colonization and infection. This report illustrates how important the availability of amino acids and other nutrients is for the initial stages of C. difficile colonization and progression of disease. Future studies identifying the source of the nutrients and engineering bacteria capable of outcompeting C. difficile in the gut will be important for developing new targeted bacterial therapeutics. IMPORTANCE Clostridium difficile is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring C. difficile growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of C. difficile colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that C. difficile gene expression is consistent with their utilization by the bacterium in vivo. We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for C. difficile colonization and disease.Joshua R. FletcherSamantha ErwinCristina LanzasCasey M. TheriotAmerican Society for MicrobiologyarticleClostridium difficileamino acidsintestinal colonizationmetabolomicspeptidestranscriptomicsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile amino acids intestinal colonization metabolomics peptides transcriptomics Microbiology QR1-502
spellingShingle	Clostridium difficile amino acids intestinal colonization metabolomics peptides transcriptomics Microbiology QR1-502 Joshua R. Fletcher Samantha Erwin Cristina Lanzas Casey M. Theriot Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model
description	ABSTRACT Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in the gut metabolome, specifically, with increases in levels of nutrients that C. difficile can utilize for growth in vitro. To define the nutrients that C. difficile requires for colonization and pathogenesis in vivo, we used a combination of mass spectrometry and RNA sequencing (RNA Seq) to model the gut metabolome and C. difficile transcriptome throughout an acute infection in a mouse model at the following time points: 0, 12, 24, and 30 h. We also performed multivariate-based integration of the omics data to define the signatures that were most important throughout colonization and infection. Here we show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time in the mouse cecum and that C. difficile gene expression is consistent with their utilization in vivo. This was also reinforced by the multivariate-based integration of the omics data where we were able to discriminate the metabolites and transcripts that support C. difficile physiology between the different time points throughout colonization and infection. This report illustrates how important the availability of amino acids and other nutrients is for the initial stages of C. difficile colonization and progression of disease. Future studies identifying the source of the nutrients and engineering bacteria capable of outcompeting C. difficile in the gut will be important for developing new targeted bacterial therapeutics. IMPORTANCE Clostridium difficile is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring C. difficile growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of C. difficile colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that C. difficile gene expression is consistent with their utilization by the bacterium in vivo. We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for C. difficile colonization and disease.
format	article
author	Joshua R. Fletcher Samantha Erwin Cristina Lanzas Casey M. Theriot
author_facet	Joshua R. Fletcher Samantha Erwin Cristina Lanzas Casey M. Theriot
author_sort	Joshua R. Fletcher
title	Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model
title_short	Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model
title_full	Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model
title_fullStr	Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model
title_full_unstemmed	Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model
title_sort	shifts in the gut metabolome and <named-content content-type="genus-species">clostridium difficile</named-content> transcriptome throughout colonization and infection in a mouse model
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/9fc0a6df613c40b7a6f7b7cca3b2b7d7
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Shifts in the Gut Metabolome and <named-content content-type="genus-species">Clostridium difficile</named-content> Transcriptome throughout Colonization and Infection in a Mouse Model

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