Microbiome driven rewiring of host immunity and metabolism Restricted; Files Only

Owens, Joshua (Summer 2021)

Permanent URL: https://etd.library.emory.edu/concern/etds/p2676w62t?locale=en


The human microbiome contains trillions of prokaryotic cells existing in symbiosis with the human host. This relationship has long thought to be neutral or commensal, but recent studies suggest that this relationship is dynamic with far-reaching effects within the human host. Here, we show new evidence that the microbiome and specifically Lactobacillus rhamnosus GG is capable of inducing CD8 T-cells. This induction of CD8 T-cells is through a novel toll-like receptor 2 and dendritic cell axis. Utilizing this induction, we can reduce colonic tumor burden in a CD8 T-cell dependent manner. Additionally, we analyzed the small metabolites coming from the gut and the gut microbiome and discovered a novel microbial metabolite known as delta-valerobetaine. We determined that delta-valerobetaine is capable of inhibiting fatty-acid oxidation through depletion of the free fatty acid shuttle molecule, carnitine. Germ-free mice normally lack this molecule and are resistant to obesity from a high fat diet. When we gave physiologically relevant levels of delta-valerobetaine to germ-free mice, it sensitized them to weight gain and obesity on a high fat diet. Furthermore, delta-valerobetaine administration to normal, conventional mice was able to exacerbate the obesity phenotype in these mice compared to controls. In humans, levels of delta-valerobetaine are higher in obese individuals and correlates with increased visceral adipose tissue as well as severity of hepatic steatosis. Altogether, we show that the microbiome can exert beneficial effects on the mucosal immune response to aid in the reduction of tumor burden but also can exert detrimental effects on fatty acid metabolism resulting in increased obesity. 

Table of Contents

Chapter 1: Introduction (1-22)

            1.1: The Microbiome Revolution (2-4) 

            1.2 The origin of the microbiome (4-6)

            1.2: The gut microbiome and colonic health (7-11)

            1.3: The gut microbiome and mucosal immunity (11-17)

            1.4: Metabolism and Microbes (18-20)

            1.5: Hypotheses (19-21)

            1.6: Statement of Research Objectives (22)

Chapter 2: Lactobacillus rhamnosus GG orchestrates an anti-tumor immune response (23-67)

            2.1: Introduction (25-27)

            2.2: Methods (28-36)

            2.3: Results (37-61)

            2.4: Discussion (62-66)

            2.5: Conclusion (67)

Chapter 3: Microbial metabolite delta-valerobetaine is a diet-dependent obesogen (68-123)

            3.1 Introduction (70-71)

            3.2: Methods (72-86)

            3.3: Results (87-118)

            3.4: Discussion (119-122)

            3.5: Conclusion (123)

Chapter 4: General Discussion (124-

            5.1: Immunotherapy and gut microbiome (125-130)

            5.2: Microbiome-derived metabolites, metabolic disease, and evolution (130-134)

            5.3: The future of gut microbiome research (134-135)

References (136-150)

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