Macronutrient Availability Influences Antibiotic Susceptibility Through Changes in Microbiome Metabolic Function

Wurster, Jenna Irene

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Overview

Year:: 2021
Contributor:: Wurster, Jenna Irene (creator); Vaishnava, Shipra (Reader); Jamieson, Amanda (Reader); Fuchs, Beth (Reader); Devkota, Suzanne (Reader); Belenky, Peter (Advisor); Brown University. Department of Molecular Microbiology and Immunology (sponsor)
Genre:: theses
Subject:: Metabolism; Diet; Microbiology; microbiome; Antibiotics; Metagenomics; Metatranscriptomics; 16S rRNA Amplicon Sequencing; Hyperglycemia; Metabolomics; Intestines--Infections
Extent:: xvii, 261 p.

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Abstract:: The gut microbiome is the assemblage of symbiotic microbes inhabiting distinct ecological niches within the host that participate in key physiological functions such as energy harvest, pathogen colonization resistance, and immune regulation. Disruption of these communities through antibiotics is associated with many acute and chronic negative consequences to the host. As such, understanding the determinants of antibiotic susceptibility within the gut will be key to the development of therapeutic strategies that mitigate antibiotic-mediated microbiome damage. Previously, our research group has demonstrated that both carbon source availability and microbial metabolism dictate the severity of bactericidal antibiotic susceptibility. Specifically, polysaccharide fermentation promotes antibiotic tolerance in select members of the gut microbiome. This work builds upon that knowledge by using an integrative multi-omic approach to characterize how host-related changes in nutrient availability impact antibiotic-induced dysbiosis within the murine cecal microbiome. First, we demonstrate that consumption of a high-sugar and high-fat (Western) diet promotes a functional shift towards mucolytic behavior and monosaccharide sequestration in the microbiome that increases respiration at the community level. The functional shifts caused by Western diet consumption result in distinct changes in taxonomy and transcription after exposure to the ciprofloxacin that suggest increased susceptibility. Next, we then demonstrate that chemically induced hyperglycemia is sufficient to dramatically restructure the transcriptional function and metabolome of the cecum. Specifically, hyperglycemia is associated with reduced fiber utilization in the gut and increased amino acid catabolism and respiration. These changes exacerbate amoxicillin susceptibility and trigger unique transcriptional behavior in surviving members of the microbiome. Finally, antibiotic-induced dysbiosis significantly reduces colonization resistance to the enteric pathogen Salmonella enterica specifically in hyperglycemic animals. Together these data highlight that changes to the gut nutrient pool, whether through modifications in diet or host metabolism, can potentiate antibiotic-induced microbiome damage. We demonstrate that host-related changes that reduce fiber utilization and increase microbial respiration result in dramatically worsened antibiotic-induced dysbiosis.
Notes:: Thesis (Ph. D.)--Brown University, 2021

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Citation

Wurster, Jenna Irene, "Macronutrient Availability Influences Antibiotic Susceptibility Through Changes in Microbiome Metabolic Function" (2021). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:cf6ccrz2/

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Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
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