Gut microbiome product delta-valerobetaine controls host metabolism Restricted; Files Only

Liu, Ken H. (Fall 2019)

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Chemical signals produced by the gut microbiome communicate with the liver to regulate systemic energy balance. The research in the dissertation concerns 1) the development and validation of chemical analysis tools suited for identifying novel chemical signals produced by the microbiome and 2) identification and characterization of microbial metabolites which impact energy metabolism in the liver. Chapter 1 serves as an overview of microbiome-host metabolic interactions and provides an experimental framework for in-depth study on this topic. Chapter 2 describes the optimization of a chemical analysis platform suitable for maximizing detection of chemicals in biological samples. Chapter 3 uses the analytical strategy described from chapter 2 to validate the quantification of approximately 200 metabolites and detection of 441 metabolites in biological samples. Chapter 4 describes the discovery of the microbiome-derived mitochondrial metabolite δ-valerobetaine (VB) and the characterization of its activity on energy metabolism in human cells and in mice. Chapter 5 contains brief concluding remarks and future avenues for exploration.

Table of Contents

Chapter 1 : Introduction_______________________________________________________ 1

1.1 - The epidemic of obesity and related metabolic diseases__________________________ 2

1.2 - The microbiome and obesity-related metabolic disorders_________________________ 5

1.3 - Chemical communication between the microbiome and host______________________ 8

1.4 - Gut-liver and microbiome-mitochondria axes_________________________________ 12

1.5 - Multi-omic systems biology approaches for host-microbiome interactions__________ 16

1.6 – Hypothesis____________________________________________________________ 22

1.7 – Statement of research objectives___________________________________________ 23

Chapter 2 : Evaluating strategies for maximizing chemical detection using high-resolution metabolomics (HRM) 29

2.1 Introduction_____________________________________________________________ 31

2.2 Methods________________________________________________________________ 35

2.3 Results_________________________________________________________________ 40

2.4 Discussion______________________________________________________________ 57

Chapter 3 : Reference standardization for quantification and harmonization of large-scale metabolomics 67

3.1 Introduction_____________________________________________________________ 69

3.2 Methods________________________________________________________________ 72

3.3 Results_________________________________________________________________ 76

3.4 Discussion______________________________________________________________ 94

Chapter 4: Inhibition of mitochondrial fatty acid beta-oxidation by the microbial metabolite, δ-valerobetaine     100

4.1 Introduction____________________________________________________________ 102

4.2 Methods_______________________________________________________________ 104

4.3 Results________________________________________________________________ 112

4.4 Discussion_____________________________________________________________ 133

Chapter 5: Conclusions______________________________________________________ 140

5.1 - Summary_____________________________________________________________ 141

5.2 – Preliminary data_______________________________________________________ 144

5.3 – Conclusion___________________________________________________________ 148

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