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A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae
BACKGROUND: The human intestinal microbiome is a complex community that contributes to host health and disease. In addition to normal microbiota, pathogens like carbapenem-resistant Enterobacteriaceae may be asymptomatically present. When these bacteria are present at very low levels, they are often...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908617/ https://www.ncbi.nlm.nih.gov/pubmed/35272717 http://dx.doi.org/10.1186/s40168-021-01207-6 |
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author | Sim, Choon K. Kashaf, Sara Saheb Stacy, Apollo Proctor, Diana M. Almeida, Alexandre Bouladoux, Nicolas Chen, Mark Finn, Robert D. Belkaid, Yasmine Conlan, Sean Segre, Julia A. |
author_facet | Sim, Choon K. Kashaf, Sara Saheb Stacy, Apollo Proctor, Diana M. Almeida, Alexandre Bouladoux, Nicolas Chen, Mark Finn, Robert D. Belkaid, Yasmine Conlan, Sean Segre, Julia A. |
author_sort | Sim, Choon K. |
collection | PubMed |
description | BACKGROUND: The human intestinal microbiome is a complex community that contributes to host health and disease. In addition to normal microbiota, pathogens like carbapenem-resistant Enterobacteriaceae may be asymptomatically present. When these bacteria are present at very low levels, they are often undetectable in hospital surveillance cultures, known as occult or subclinical colonization. Through the receipt of antibiotics, these subclinical pathogens can increase to sufficiently high levels to become detectable, in a process called outgrowth. However, little is known about the interaction between gut microbiota and Enterobacteriaceae during occult colonization and outgrowth. RESULTS: We developed a clinically relevant mouse model for studying occult colonization. Conventional wild-type mice without antibiotic pre-treatment were exposed to Klebsiella pneumoniae but rapidly tested negative for colonization. This occult colonization was found to perturb the microbiome as detected by both 16S rRNA amplicon and shotgun metagenomic sequencing. Outgrowth of occult K. pneumoniae was induced either by a four-antibiotic cocktail or by individual receipt of ampicillin, vancomycin, or azithromycin, which all reduced overall microbial diversity. Notably, vancomycin was shown to trigger K. pneumoniae outgrowth in only a subset of exposed animals (outgrowth-susceptible). To identify factors that underlie outgrowth susceptibility, we analyzed microbiome-encoded gene functions and were able to classify outgrowth-susceptible microbiomes using pathways associated with mRNA stability. Lastly, an evolutionary approach illuminated the importance of xylose metabolism in K. pneumoniae colonization, supporting xylose abundance as a second susceptibility indicator. We showed that our model is generalizable to other pathogens, including carbapenem-resistant Escherichia coli and Enterobacter cloacae. CONCLUSIONS: Our modeling of occult colonization and outgrowth could help the development of strategies to mitigate the risk of subsequent infection and transmission in medical facilities and the wider community. This study suggests that microbiota mRNA and small-molecule metabolites may be used to predict outgrowth-susceptibility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01207-6. |
format | Online Article Text |
id | pubmed-8908617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-89086172022-03-18 A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae Sim, Choon K. Kashaf, Sara Saheb Stacy, Apollo Proctor, Diana M. Almeida, Alexandre Bouladoux, Nicolas Chen, Mark Finn, Robert D. Belkaid, Yasmine Conlan, Sean Segre, Julia A. Microbiome Research BACKGROUND: The human intestinal microbiome is a complex community that contributes to host health and disease. In addition to normal microbiota, pathogens like carbapenem-resistant Enterobacteriaceae may be asymptomatically present. When these bacteria are present at very low levels, they are often undetectable in hospital surveillance cultures, known as occult or subclinical colonization. Through the receipt of antibiotics, these subclinical pathogens can increase to sufficiently high levels to become detectable, in a process called outgrowth. However, little is known about the interaction between gut microbiota and Enterobacteriaceae during occult colonization and outgrowth. RESULTS: We developed a clinically relevant mouse model for studying occult colonization. Conventional wild-type mice without antibiotic pre-treatment were exposed to Klebsiella pneumoniae but rapidly tested negative for colonization. This occult colonization was found to perturb the microbiome as detected by both 16S rRNA amplicon and shotgun metagenomic sequencing. Outgrowth of occult K. pneumoniae was induced either by a four-antibiotic cocktail or by individual receipt of ampicillin, vancomycin, or azithromycin, which all reduced overall microbial diversity. Notably, vancomycin was shown to trigger K. pneumoniae outgrowth in only a subset of exposed animals (outgrowth-susceptible). To identify factors that underlie outgrowth susceptibility, we analyzed microbiome-encoded gene functions and were able to classify outgrowth-susceptible microbiomes using pathways associated with mRNA stability. Lastly, an evolutionary approach illuminated the importance of xylose metabolism in K. pneumoniae colonization, supporting xylose abundance as a second susceptibility indicator. We showed that our model is generalizable to other pathogens, including carbapenem-resistant Escherichia coli and Enterobacter cloacae. CONCLUSIONS: Our modeling of occult colonization and outgrowth could help the development of strategies to mitigate the risk of subsequent infection and transmission in medical facilities and the wider community. This study suggests that microbiota mRNA and small-molecule metabolites may be used to predict outgrowth-susceptibility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01207-6. BioMed Central 2022-03-10 /pmc/articles/PMC8908617/ /pubmed/35272717 http://dx.doi.org/10.1186/s40168-021-01207-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Sim, Choon K. Kashaf, Sara Saheb Stacy, Apollo Proctor, Diana M. Almeida, Alexandre Bouladoux, Nicolas Chen, Mark Finn, Robert D. Belkaid, Yasmine Conlan, Sean Segre, Julia A. A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae |
title | A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae |
title_full | A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae |
title_fullStr | A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae |
title_full_unstemmed | A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae |
title_short | A mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant Enterobacteriaceae |
title_sort | mouse model of occult intestinal colonization demonstrating antibiotic-induced outgrowth of carbapenem-resistant enterobacteriaceae |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908617/ https://www.ncbi.nlm.nih.gov/pubmed/35272717 http://dx.doi.org/10.1186/s40168-021-01207-6 |
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