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Title
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Mining the human intestinal microbiota and the Clostridioides difficile genome to develop predictive biomarkers of C. difficile infection
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Author
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Abstract
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| Clostridioides difficile infection (CDI) is the most common form of infectious antibiotic-associated diarrhea (AAD) causing considerable morbidity and mortality in acute-care facilities. Hospitalized patients receiving broad-spectrum antibiotic treatment are particularly susceptible to CDI as a result of antibiotic-induced perturbations in the intestinal microbiota. Thanks to the evolution and increasing accessibility to next-generation sequencing (NGS) technologies, substantial advances have been made toward understanding C. difficile transmission, virulence, and phylogeny. However, much still remains unknown about this opportunistic pathogen. In this thesis, we aimed to identify early microbial biomarkers predictive of AAD in patients undergoing broad-spectrum antibiotic treatment, with a particular emphasis on CDI. We further aimed at understanding the phylogeny of toxigenic C. difficile strains by assigning a genomic context to their infection potential. Here, we present a high-resolution, genome-wide characterization of the Leeds-Leiden/ECDC strain collection of primarily toxigenic C. difficile strains (n = 73). This effort constitutes, to our knowledge, the largest chromosome-wide comparative genomics study to date that investigates C. difficile phylogeny. The human intestinal microbiota was mined for predictive microbiota-based biomarkers of CDI in a large, elderly, hospitalized population. This resulted in the development of a predictive algorithm enabling enrichment of patients at high-risk of CDI, which ultimately resulted in the filing of a patent. Longitudinally collected fecal samples from the same study population were further assessed for structural microbial alterations following broad-spectrum antibiotic treatment, which showed antibiotic-specific alterations in microbial composition with a resulting alteration in metabolism. In conclusion, this thesis provides a comprehensive investigation into genomic and microbiota-based facilitators of CDI by investigating C. difficile phylogeny and genomic features of C. difficile expressed as virulence and transmission traits as well as a thorough investigation into structural changes in the human intestinal microbiota pre and post antibiotic treatment. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Medicine and Health Sciences
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2020
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Volume/pages
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220 p.
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Note
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Malhotra-Kumar, Surbhi [Supervisor]
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Goossens, Herman [Supervisor]
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Full text (open access)
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The publisher created published version Available from 01.07.2025
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