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Research Article | Clinical Science and Epidemiology

Integrated Meta-omics Reveals a Fungus-Associated Bacteriome and Distinct Functional Pathways in Clostridioides difficile Infection

David B. Stewart Sr., Justin R. Wright, Maria Fowler, Christopher J. McLimans, Vasily Tokarev, Isabella Amaniera, Owen Baker, Hoi-Tong Wong, Jeff Brabec, Rebecca Drucker, Regina Lamendella
Rosa Krajmalnik-Brown, Editor
David B. Stewart Sr.
aDepartment of Surgery, University of Arizona, Tucson, Arizona, USA
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Justin R. Wright
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
cContamination Source Identification, LLC, Huntingdon, Pennsylvania, USA
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Maria Fowler
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
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Christopher J. McLimans
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
cContamination Source Identification, LLC, Huntingdon, Pennsylvania, USA
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Vasily Tokarev
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
cContamination Source Identification, LLC, Huntingdon, Pennsylvania, USA
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Isabella Amaniera
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
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Owen Baker
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
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Hoi-Tong Wong
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
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Jeff Brabec
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
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Rebecca Drucker
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
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Regina Lamendella
bDepartment of Biology, Juniata College, Huntingdon, Pennsylvania, USA
cContamination Source Identification, LLC, Huntingdon, Pennsylvania, USA
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Rosa Krajmalnik-Brown
Arizona State University
Roles: Editor
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DOI: 10.1128/mSphere.00454-19
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ABSTRACT

There has been no prior application of matched metagenomics and metatranscriptomics in Clostridioides difficile infection (CDI) evaluating the role of fungi in CDI or identifying community functions that contribute to the development of this disease. We collected diarrheal stools from 49 inpatients (18 of whom tested positive for CDI) under stringent inclusion criteria. We utilized a tiered sequencing approach to identify enriched bacterial and fungal taxa, using 16S and internal transcribed spacer (ITS) rRNA gene amplicon sequencing, with matched metagenomics and metatranscriptomics performed on a subset of the population. Distinct bacterial and fungal compositions distinguished CDI-positive and -negative patients, with the greatest differentiation between the cohorts observed based on bacterial metatranscriptomics. Bipartite network analyses demonstrated that Aspergillus and Penicillium taxa shared a strong positive relationship in CDI patients and together formed negative cooccurring relationships with several bacterial taxa, including the Oscillospira, Comamonadaceae, Microbacteriaceae, and Cytophagaceae. Metatranscriptomics revealed enriched pathways in CDI patients associated with biofilm production primarily driven by Escherichia coli and Pseudomonas, quorum-sensing proteins, and two-component systems related to functions such as osmotic regulation, linoleic acid metabolism, and flagellar assembly. Differential expression of functional pathways unveiled a mechanism by which the causal dysbiosis of CDI may self-perpetuate, potentially contributing to treatment failures. We propose that CDI has a distinct fungus-associated bacteriome, and this first description of metatranscriptomics in human subjects with CDI demonstrates that inflammation, osmotic changes, and biofilm production are key elements of CDI pathophysiology.

IMPORTANCE Our data suggest a potential role for fungi in the most common nosocomial bacterial infection in the United States, introducing the concept of a transkingdom interaction between bacteria and fungi in this disease. We also provide the first direct measure of microbial community function in Clostridioides difficile infection using patient-derived tissue samples, revealing antibiotic-independent mechanisms by which C. difficile infection may resist a return to a healthy gut microbiome.

  • Copyright © 2019 Stewart et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Integrated Meta-omics Reveals a Fungus-Associated Bacteriome and Distinct Functional Pathways in Clostridioides difficile Infection
David B. Stewart Sr., Justin R. Wright, Maria Fowler, Christopher J. McLimans, Vasily Tokarev, Isabella Amaniera, Owen Baker, Hoi-Tong Wong, Jeff Brabec, Rebecca Drucker, Regina Lamendella
mSphere Aug 2019, 4 (4) e00454-19; DOI: 10.1128/mSphere.00454-19

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Integrated Meta-omics Reveals a Fungus-Associated Bacteriome and Distinct Functional Pathways in Clostridioides difficile Infection
David B. Stewart Sr., Justin R. Wright, Maria Fowler, Christopher J. McLimans, Vasily Tokarev, Isabella Amaniera, Owen Baker, Hoi-Tong Wong, Jeff Brabec, Rebecca Drucker, Regina Lamendella
mSphere Aug 2019, 4 (4) e00454-19; DOI: 10.1128/mSphere.00454-19
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KEYWORDS

Clostridioides difficile
metagenomics
metatranscriptomics
microbiome
mycobiome

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