Doctor of Philosophy in Population and Public Health (PhD)
Examining the sinonasal microbiome and using a microbiome transplant as as potential treatment
Human microbiome research and molecular epidemiology
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Antibiotic resistance is the third largest contributor to mortality worldwide, and 30% of these deaths occur in newborns. The burden of resistant infections in children is disproportionately higher in low- and middle-income countries (LMICs) due to the overuse of antibiotics in food, food animals and health care settings. The prevalence of childhood co-morbidities like severe acute malnutrition (SAM) and human immunodeficiency virus (HIV) in LMICs increases the need for treatment and prophylactic antibiotic use. These conditions also increase the likelihood of secondary disease, thereby further increasing the need for antibiotics. Antibiotic resistance genes (ARGs) are the primary source of resistance in pathogens and are amplified with antibiotic exposure. There is an urgent need to understand the role of ARGs in diseases amongst infants and children, especially in LMICs, where their impact on mortality and morbidity is large. In this dissertation, chapter one reviews previous knowledge about the presence or carriage of ARGs and the impact ARGs have on morbidity and mortality in LMICs, especially morbidity and mortality due to SAM and HIV. Chapter 2 examines the natural acquisition of ARGs in healthy children living in rural areas of a LMIC using longitudinal data from the Sanitation Hygiene and Infant Nutrition Efficacy (SHINE) trial. Chapter 3 examines the changes in ARG carriage during hospitalization with SAM and HIV, and during SAM recovery using longitudinal data from the Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) observational study. Chapter 4 investigates the impact of stopping or continuing prophylactic antibiotic use in HIV-positive children using data from the Antiretroviral Research for Watoto (ARROW) trial. I find that healthy children acquire a diverse array of ARGs upon birth, ARG carriage decreases significantly with age in healthy children, and most ARGs are closely associated with the abundance of Enterobacteriaceae that colonize the infant gut. Hospitalization for SAM leads to a less mature microbiota, associated with increases in Enterobacteriaceae-related ARG abundance. This effect was transient and decayed over time following hospital discharge. Continued prophylactic antibiotic treatment in HIV-positive children does not significantly alter ARG carriage but does selectively increase resistance specific to antibiotics used.
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Childhood stunting or linear growth failure is a major global health issue, affecting 22% of children under 5 years of age worldwide. Stunting impacts people across the life course. Stunting is associated with a greater number of infections, reduced childhood survival, impaired cognitive development, and reduced adulthood productivity, and contributes to an intergenerational cycle of poor growth and development. Decreased linear growth has been associated with community-level changes in the gut microbiome as well as specific changes in individual bacterial and decreased overall microbial diversity. However, the literature addressing the role of the gut microbiome on poor child linear growth is limited. We conducted an analysis of the infant fecal microbiota composition from 1-18 months of life from infants participating in the Sanitation, Hygiene, Infant Nutrition Efficacy (SHINE) Trial, a large cluster-randomized trial, designed to evaluate the impact of improved household water quality, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on linear growth and anaemia during the first 18 months of infant life in rural Zimbabwe. Using whole metagenomic sequencing, we were able to describe the infant fecal microbiota composition of SHINE Trial infants and examine relationships between the microbiota composition and HIV exposure status, SHINE trial interventions, and stunting status. As expected, age was the major driver of microbiota composition and diversity. No major differences in the infant fecal microbiota by HIV exposure status, SHINE trial interventions, or stunting status were observed. These results highlight the complex nature of linear growth and demonstrate that infant fecal microbiota composition plays a smaller direct role on growth in SHINE infants. Our study also confirms that the SHINE WASH intervention did not influence infant growth through alterations to the fecal microbiota composition, confirming the primary SHINE results. However, the functional potential of the infant fecal microbiota of SHINE infants will be examined in future analyses; this may uncover relationships separate from microbiota composition and diversity alone.
Urinary tract infections (UTIs) are one of the most common bacterial infections worldwide. Extra-intestinal pathogenic Escherichia coli (ExPEC) are responsible for more than 80% of UTIs. ExPEC have been isolated from the environment, food sources and companion animals. Once acquired from an external source, ExPEC asymptomatically colonize the intestinal tract, and act as an immediate reservoir for subsequent extra-intestinal infection. Despite considerable ExPEC diversity, only a few multi-locus sequence types (STs) cause the majority of infections. Our study examines the population structure and exposures associated with UTI caused by major ExPEC lineages. A total of 385 women with community-acquired UTI caused by E. coli across Canada were questioned about their diet, travel and other exposure history. Genome sequencing was used to determine both ST and genomic similarity. ST69, ST73, ST95, ST127 and ST131 were responsible for 54% of all UTIs. Seven UTI clusters were identified, but genomes from the ST95 and ST420 clusters exhibited fewer than 4 single nucleotide variations, suggesting recent transmission from a common source. The predominant STs were all associated with consumption of high-risk foods such as seafood and raw meat, and all STs, except for ST73, were associated with travel. These results suggest specific exposures exist for pandemic ExPEC lineages. Identifying the reservoirs of common, community-acquired ExPEC lineages will aid our understanding of the evolution, emergence, and dissemination of high-risk clones within the community setting.
Background.Environmental enteric dysfunction (EED) is commonly defined as an acquired subclinicaldisorder of the small intestine, characterized by villous atrophy and crypt hyperplasia. EED hasbeen proposed to underlie stunted growth among children in developing countries. A collectionof biomarkers, organized into distinct domains, has been used to measure different aspects ofEED. Here, we examine whether these hypothesized relationships, among EED domains andbetween each domain and stunting, are supported by data from recent studies.Methodology.A systematic literature search was conducted using PubMed, MEDLINE, EMBASE, Web ofScience, and CINAHL between January 1, 2010 and April 20, 2017. Information on studyobjective, design, population, location, biomarkers, and results were recorded, as well asqualitative and quantitative definitions of EED. Biomarkers were organized into five EEDdomains, and the number of studies that support or do not support relationships among domainsand between each domain with stunting were summarized.Results.There was little evidence to support the pathway from intestinal permeability to microbialtranslocation and from microbial translocation to stunting, but stronger support existed for thelink between intestinal inflammation and systemic inflammation and for intestinal inflammationand stunting. There was conflicting evidence for the pathways from intestinal damage tointestinal permeability and intestinal damage to stunting.Conclusions.These results suggest that certain EED biomarkers may require reconsideration, particularlythose most difficult to measure, such as microbial translocation and intestinal permeability. Wediscuss several issues with currently used biomarkers and recommend further analysis ofpathogen-induced changes to the intestinal microbiota as a pathway leading to stunting.