<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes

ABSTRACT Clostridium difficile is the largest single cause of hospital-acquired infection in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they disrupt the gut bacterial community which protects from C. difficile colonization. M...

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Autores principales:	Matthew L. Jenior, Jhansi L. Leslie, Vincent B. Young, Patrick D. Schloss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Clostridium difficile infection microbiome metabolomics network modeling systems biology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9344bc90bbc547699cbf618cb4bcd6ab
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spelling	oai:doaj.org-article:9344bc90bbc547699cbf618cb4bcd6ab2021-12-02T18:39:33Z<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes10.1128/mSystems.00063-172379-5077https://doaj.org/article/9344bc90bbc547699cbf618cb4bcd6ab2017-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00063-17https://doaj.org/toc/2379-5077ABSTRACT Clostridium difficile is the largest single cause of hospital-acquired infection in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they disrupt the gut bacterial community which protects from C. difficile colonization. Multiple antibiotic classes have been associated with CDI susceptibility, many leading to distinct community structures stemming from variation in bacterial targets of action. These community structures present separate metabolic challenges to C. difficile. Therefore, we hypothesized that the pathogen adapts its physiology to the nutrients within different gut environments. Utilizing an in vivo CDI model, we demonstrated that C. difficile highly colonized ceca of mice pretreated with any of three antibiotics from distinct classes. Levels of C. difficile spore formation and toxin activity varied between animals based on the antibiotic pretreatment. These physiologic processes in C. difficile are partially regulated by environmental nutrient concentrations. To investigate metabolic responses of the bacterium in vivo, we performed transcriptomic analysis of C. difficile from ceca of infected mice across pretreatments. This revealed heterogeneous expression in numerous catabolic pathways for diverse growth substrates. To assess which resources C. difficile exploited, we developed a genome-scale metabolic model with a transcriptome-enabled metabolite scoring algorithm integrating network architecture. This platform identified nutrients that C. difficile used preferentially between pretreatments, which were validated through untargeted mass spectrometry of each microbiome. Our results supported the hypothesis that C. difficile inhabits alternative nutrient niches across cecal microbiomes with increased preference for nitrogen-containing carbon sources, particularly Stickland fermentation substrates and host-derived glycans. IMPORTANCE Infection by the bacterium Clostridium difficile causes an inflammatory diarrheal disease which can become life threatening and has grown to be the most prevalent nosocomial infection. Susceptibility to C. difficile infection is strongly associated with previous antibiotic treatment, which disrupts the gut microbiota and reduces its ability to prevent colonization. In this study, we demonstrated that C. difficile altered pathogenesis between hosts pretreated with antibiotics from separate classes and exploited different nutrient sources across these environments. Our metabolite score calculation also provides a platform to study nutrient requirements of pathogens during an infection. Our results suggest that C. difficile colonization resistance is mediated by multiple groups of bacteria competing for several subsets of nutrients and could explain why total reintroduction of competitors through fecal microbial transplant currently is the most effective treatment for recurrent CDI. This work could ultimately contribute to the identification of targeted, context-dependent measures that prevent or reduce C. difficile colonization, including pre- and probiotic therapies.Matthew L. JeniorJhansi L. LeslieVincent B. YoungPatrick D. SchlossAmerican Society for MicrobiologyarticleClostridium difficileinfectionmicrobiomemetabolomicsnetwork modelingsystems biologyMicrobiologyQR1-502ENmSystems, Vol 2, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile infection microbiome metabolomics network modeling systems biology Microbiology QR1-502
spellingShingle	Clostridium difficile infection microbiome metabolomics network modeling systems biology Microbiology QR1-502 Matthew L. Jenior Jhansi L. Leslie Vincent B. Young Patrick D. Schloss <italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes
description	ABSTRACT Clostridium difficile is the largest single cause of hospital-acquired infection in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they disrupt the gut bacterial community which protects from C. difficile colonization. Multiple antibiotic classes have been associated with CDI susceptibility, many leading to distinct community structures stemming from variation in bacterial targets of action. These community structures present separate metabolic challenges to C. difficile. Therefore, we hypothesized that the pathogen adapts its physiology to the nutrients within different gut environments. Utilizing an in vivo CDI model, we demonstrated that C. difficile highly colonized ceca of mice pretreated with any of three antibiotics from distinct classes. Levels of C. difficile spore formation and toxin activity varied between animals based on the antibiotic pretreatment. These physiologic processes in C. difficile are partially regulated by environmental nutrient concentrations. To investigate metabolic responses of the bacterium in vivo, we performed transcriptomic analysis of C. difficile from ceca of infected mice across pretreatments. This revealed heterogeneous expression in numerous catabolic pathways for diverse growth substrates. To assess which resources C. difficile exploited, we developed a genome-scale metabolic model with a transcriptome-enabled metabolite scoring algorithm integrating network architecture. This platform identified nutrients that C. difficile used preferentially between pretreatments, which were validated through untargeted mass spectrometry of each microbiome. Our results supported the hypothesis that C. difficile inhabits alternative nutrient niches across cecal microbiomes with increased preference for nitrogen-containing carbon sources, particularly Stickland fermentation substrates and host-derived glycans. IMPORTANCE Infection by the bacterium Clostridium difficile causes an inflammatory diarrheal disease which can become life threatening and has grown to be the most prevalent nosocomial infection. Susceptibility to C. difficile infection is strongly associated with previous antibiotic treatment, which disrupts the gut microbiota and reduces its ability to prevent colonization. In this study, we demonstrated that C. difficile altered pathogenesis between hosts pretreated with antibiotics from separate classes and exploited different nutrient sources across these environments. Our metabolite score calculation also provides a platform to study nutrient requirements of pathogens during an infection. Our results suggest that C. difficile colonization resistance is mediated by multiple groups of bacteria competing for several subsets of nutrients and could explain why total reintroduction of competitors through fecal microbial transplant currently is the most effective treatment for recurrent CDI. This work could ultimately contribute to the identification of targeted, context-dependent measures that prevent or reduce C. difficile colonization, including pre- and probiotic therapies.
format	article
author	Matthew L. Jenior Jhansi L. Leslie Vincent B. Young Patrick D. Schloss
author_facet	Matthew L. Jenior Jhansi L. Leslie Vincent B. Young Patrick D. Schloss
author_sort	Matthew L. Jenior
title	<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes
title_short	<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes
title_full	<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes
title_fullStr	<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes
title_full_unstemmed	<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes
title_sort	<italic toggle="yes">clostridium difficile</italic> colonizes alternative nutrient niches during infection across distinct murine gut microbiomes
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/9344bc90bbc547699cbf618cb4bcd6ab
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<italic toggle="yes">Clostridium difficile</italic> Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes

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