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Exploring the Application of Ecological Theory to the Human Gut Microbiota Using Complex Defined Microbial Communities As Models

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Exploring the Application of Ecological Theory to the Human Gut Microbiota Using Complex Defined Microbial Communities As Models Exploring the application of ecological theory to the human gut microbiota using complex defined microbial communities as models by Kaitlyn Oliphant A Thesis presented to the The University of Guelph In partial fulfillment of requirements for the degree of Doctor of Philosophy in Molecular and Cellular Biology Guelph, Ontario, Canada © Kaitlyn Oliphant, December, 2018 ABSTRACT EXPLORING THE APPLICATION OF ECOLOGICAL THEORY TO THE HUMAN GUT MICROBIOTA USING COMPLEX DEFINED MICROBIAL COMMUNITIES AS MODELS Kaitlyn Oliphant Advisor: University of Guelph, 2018 Dr. Emma Allen-Vercoe The ecosystem of microorganisms that inhabit the human gastrointestinal tract, termed the gut microbiota, critically maintains host homeostasis. Alterations in species structure and metabolic behaviour of the gut microbiota are thus unsurprisingly exhibited in patients of gastrointestinal disorders when compared to the healthy population. Therefore, strategies that aim to remediate such gut microbiota through microbial supplementation have been attempted, with variable clinical success. Clearly, more knowledge of how to assemble a health promoting gut microbiota is required, which could be drawn upon from the framework of ecological theory. Current theories suggest that the forces driving microbial community assembly include historical contingency, dispersal limitation, stochasticity and environmental selection. Environmental selection additionally encompasses habitat filtering, i.e., host-microbe interactions, and species assortment, i.e., microbe-microbe interactions. I propose to explore the application of this theory to the human gut microbiota, and I hypothesize that microbial ecological theory can be replicated utilizing complex defined microbial communities. To address my hypothesis, I first built upon existing methods to assess microbial community composition and behaviour, then applied such tools to human fecal-derived defined microbial communities cultured in bioreactors, for example, by using marker gene sequencing and metabonomics. I determined that stochasticity is an important influencer of species structure within the gut microbiota, whereas dietary interventions greatly impacted the metabolic behaviour. Additionally, habitat filtering predominated over species assortment. This assertion was based on the lack of competitive exclusion observed when beneficial microbes were added to an ulcerative colitis-associated microbial community with and without prior antibiotic treatment. The few unique functionalities that were provided by these microbes upon integration are related to starch and mucin degradation. Also, there was not a discernible overall difference between a microbial community and its non-coevolved species matched counterpart, in which each species was derived from a separate donor. However, the existence of species assortment was not precluded, since certain species that relied upon cross-feeding for polysaccharide utilization failed to integrate into the non-coevolved microbial community. Together, this work would suggest that successful modulation of the gut microbiota would involve providing microbes as coevolved guilds that can colonize niches ubiquitous amongst the human population. Acknowledgements The completion of the work presented in this thesis would not be possible without the mentorship, collaboration, consultation, instruction, funding and support I had received from many individuals and institutions throughout my doctorate studies. Particularly, I would like to acknowledge the following: Ph.D. Supervisor: Dr. Emma Allen-Vercoe Advisory Committee: Dr. Lucy Mutharia, Dr. Kari Dunfield, Dr. France-Isabelle Auzanneau Dr. Emma Allen-Vercoe Laboratory Personnel: Dr. Julie McDonald, Mr. Ian Brown, Dr. Kathleen Schroeter, Ms. Erin Bolte, Dr. Mike Toh, Dr. Kyla Cochrane, Dr. Christian Carlucci, Dr. Rafael Peixoto, Dr. Valeria Parreira, Mr. Chris Ambrose, Ms. Michelle Daigneault, Ms. Sandi Yen, Ms. Avery Robinson, Ms. Caroline Ganobis, Ms. Simone Renwick, Mr. Jacob Wilde, Ms. Mbita Nakazwe, Mr. AJ Stirling, Mr. Joseph Ciufo, Mr. Keith Sherriff, Ms. Emily Mercer, Ms. Isra Hussein Collaborators: Dr. Martin von Bergen, Dr. Elena Verdu, Dr. Oliver Kohlbacher Dr. Martin von Bergen Laboratory Personnel: Dr. Dirk Wissenbach, Dr. Robert Starke, Dr. Nico Jehmlich, Dr. Ulrike Rolle-Kampczyk, Mr. Sven Haange, Ms. Stephanie Schäpe, Dr. Henrike Höke, Dr. Sven Baumann, Ms. Dominique Türkowsky, Mr. Hannes Petruschke, Mr. Geoffroy Saint-Genis, Mr. Patrick Lohmann, Dr. Matthias Bernt, Ms. Kathleen Eismann, Dr. Jean Froment, Ms. Oliva Pleβow Consultants: Dr. Greg Gloor and Dr. Jean Macklaim, Dr. Marc Aucoin, Dr. Cezar Khursigara Dr. Cezar Khursigara Laboratory Personnel: Ms. Sherise Charles, Ms. Mara Goodyear, Dr. Alison Berezuk, Mr. Mitch Demelo, Ms. Nicole Garnier, Ms. Erin Anderson, Ms. Madison Wright Teaching Faculty: Dr. Wendy Keenleyside, Dr. Roselynn Stevenson, Dr. Lucy Mutharia (again), Ms. Debra Flett Advanced Analysis Center Staff: Dr. Sameer Al-Abdul-Wahid, Mr. Jeff Gross Funding Agencies: Canadian Institutes of Health Research, Ontario Ministry of Training, College and Universities, National Science and Research Council of Canada, University of Guelph Thank you. iii Table of Contents ABSTRACT .................................................................................................................................................. ii Acknowledgements ...................................................................................................................................... iii List of Tables .............................................................................................................................................. vii List of Figures ............................................................................................................................................ viii List of Abbreviations ................................................................................................................................... ix Chapter 1 - Introduction ................................................................................................................................ 1 1.1 The Human Gut Microbiota .......................................................................................................... 1 1.1.1 Strategies for modification of the human gut microbiota to enhance health......................... 1 1.1.2 Composition of the human gut microbiota ............................................................................ 3 1.1.3 Functions of the human gut microbiota .............................................................................. 14 1.1.4 Modulators of the human gut microbiota ............................................................................ 22 1.2 Ecological Theory and the Human Gut Microbiota .................................................................... 24 1.2.1 Assembly ............................................................................................................................. 25 1.2.2 Diversity and evolution of the human gut microbiota......................................................... 30 1.3 Study of the Human Gut Microbiota ........................................................................................... 34 1.3.1 Model systems .................................................................................................................... 34 1.3.2 Gut microbial ecosystem analysis methods ........................................................................ 37 1.4 Overview of thesis work and overall hypothesis ........................................................................ 41 Chapter 2 – 1H-NMR spectroscopy vs. LC-MS/MS ................................................................................... 43 2.1 Article Information ..................................................................................................................... 44 2.2 Abstract ....................................................................................................................................... 45 2.3 Introduction ................................................................................................................................. 45 2.4 Relevance for human health, potential for mechanistic insights, and feasibility define the strengths of model systems ..................................................................................................................... 47 2.5 Metabolic interaction as a key feature of microbiome:host interaction ...................................... 49 2.6 NMR and MS .............................................................................................................................. 50 2.7 Metabolomics detects many spectral features and 50 metabolites detected by NMR result in the same quality of group separation ............................................................................................................ 51 2.8 Targeted validation ..................................................................................................................... 58 2.9 Perspectives for metabolic flux and for linking community activity to the composition of the consortium............................................................................................................................................... 61 2.10 Conclusion .................................................................................................................................
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