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    • University of Missouri-Columbia
    • Graduate School - MU Theses and Dissertations (MU)
    • Theses and Dissertations (MU)
    • Dissertations (MU)
    • 2019 Dissertations (MU)
    • 2019 MU dissertations - Freely available online
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    Genetic and microbiota-mediated phenotype variability in the min mouse model of human colorectal cancer

    Moskowitz, Jacob E.
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    [PDF] MoskowitzJacob.pdf (4.708Mb)
    Date
    2019
    Format
    Thesis
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    Abstract
    Complex diseases develop as a result of genetic predisposition and environmental factors that determine individual risk. Environmental factors such as geographical location, diet, and lifestyle choices shape the gut microbiota (GM), a dynamic community of bacteria, viruses, fungi, and archaea that normally coexist symbiotically with mammalian hosts. Both genetic heterogeneity and the GM modulate various systems and influence the development of a wide range of diseases including intestinal pathologies, emphasizing the importance of the effects of genetic variants and perturbations of GM communities. Colorectal cancer (CRC) is the 2nd leading cause of cancer-related mortality for men and women combined in the United States, and exemplifies the multifactorial etiologies that define complex diseases. In this body of work, we leveraged quantitative phenotypic variation in the Apc-mutant Min mouse model of CRC to interrogate genetic and microbial factors that influence adenoma susceptibility. We used embryo rederivation to determine how genetic variation acquired through colony divergence, and distinct complex GMs representing two common mouse producers (GMJAX and GMHSD), each contribute to Min adenoma multiplicity. We found that genetic lineage and complex GM additively conferred overall adenoma multiplicity, and followed up with whole-genome sequencing (WGS) and 16S rRNA sequencing to characterize genetic divergence and GM differences, respectively. We integrated liquid chromatography coupled to mass spectrometry (LCMS) with WGS data to identify a candidate modifier variant associated with the Fabp6 gene, a regulator of bile acid reabsorption. In parallel, we identified bacteria of interest Bilophila wadsworthia and Akkermansia muciniphila associated with the adenoma-enhancing GMHSD, and tested the individual effects of these species on the Min phenotype. While A. muciniphila had no effect on adenoma burden, B. wadsworthia treatment resulted in modulation of the broader GM and host metabolism, and reduced adenoma multiplicity and overall burden. Finally, we asked whether the background genetics of related inbred mouse substrains C57BL/6J (B6/J) and C57BL/6NHsd (B6/N) have differential modifier effects with respect to the Min phenotype. Using F1 mice generated from B6/J or B6/N crosses to Min/D mice in combination with an embryo rederivation approach, we found that B6/N elicits stronger Min adenoma suppression than B6/J, and that the complex GM further modulates phenotype suppression. Together, this work begins to unravel the complex interactions between host and environment that drive cancer susceptibility. As such, we provide a framework for further mechanistic studies, identification of novel biomarkers, and targeted preventative and therapeutic strategies in CRC.
    URI
    https://hdl.handle.net/10355/76253
    Degree
    Ph. D.
    Thesis Department
    Pathobiology area program (MU)
    Rights
    OpenAccess.
    This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
    Collections
    • 2019 MU dissertations - Freely available online
    • Pathology and Anatomical Sciences electronic theses and dissertations (MU)

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