Joohee Choi

ORCID

http://orcid.org/0000-0002-6368-2470

Date of Award

Spring 5-15-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Human & Statistical Genetics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Microbes not just surround us; they are inside of us. The gut microbiome has emerged in recent years as an important modulator of health and is thought to have co-evolved with us throughout evolutionary history. On the other hand, our immune systems are constantly surveilling and battling infection by external pathogens— some of which still manage to evade our immune response and colonize our bodies long-term. In this Thesis, I investigated microbes inhabiting our bodies in various contexts to understand their impact on human health.In Chapter 2, I discuss the effects of fecal microbiome transplant (FMT) study drug RBX2660 on the gut microbiome of recipients with Clostridium difficile. I parsed apart post-antibiotic microbiome recovery from true RBX2660 effects and assessed what characteristics deemed some recipients more permissive for microbiome transplantation over others. I found that RBX2660 administration transplanted healthy microbiota in the recipients in a dose-dependent manner. Veillonella atypica and intrinsic vancomycin resistant species were discriminative features of patients showing long-lasting microbiota transplantation and resisting microbiota transplantation, respectively. RBX2660 more efficiently decolonized antimicrobial resistant organisms (AROs) than placebo but simultaneously introduced new AROs. This study demonstrated the potential benefits of FMT and highlighted the importance of the design and quality control of microbiota-based drugs. In Chapter 3, I report evidence for in-host adaptation in a cohort of longitudinally collected Mycobacterium abscessus isolates. Through comparative genomics, I demonstrated the presence of clusters of highly related isolates from multiple hospital centers despite lack of evidence for transmission. I also identified within-lineage polymorphisms occurring in parallel across multiple patients, suggestive of shared adaptative behavior to survive in the lung milieu. Through drug susceptibility assays I show that the genomic changes have phenotypic consequences, potentially providing opportunistic windows for effective treatment. In Chapters 4 and 5, I share the findings from a multi-center cohort of participants with urinary tract infection (UTI). Some of these patients experienced recurrent UTI (rUTI) throughout the study period. Through regular stool and urine sampling, I obtained longitudinal gut microbiome and isolate WGS data. By tracing lineages of UPEC, I demonstrated four patterns of asymptomatic colonization: in the urinary tract, in the gastrointestinal tract, in both habitats, and no colonization. I then utilized comparative genomics to show niche-specific adaptive patterns that were putatively facilitated by mobile genetic elements. Finally, in the last chapter I discuss the results of a clinical model predicting risk factors for rUTI. Recent antimicrobials and steroids elevated rUTI risk, while change of antimicrobials and TMP-SMX were associated with decreased risk. I also found significant differences in gut microbiome composition between urinary tract colonized and non-colonized patients at post-antimicrobial days 7-14, marked by elevated E. coli abundance in urinary tract colonized patients. Together these studies explored in-host behavior of UPEC across two distinct habitats and point towards the gut as an important reservoir facilitating rUTI.

Language

English (en)

Chair and Committee

Gautam Dantas

Committee Members

Christina Stallings, Megan T. Baldridge, Andrew Kau, Jennie H. Kwon,

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