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The Prebiotic Inulin Beneficially Modulates the Gut-Brain Axis by Enhancing Metabolism in an Apoe4 Mouse Model" (2018)

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The Prebiotic Inulin Beneficially Modulates the Gut-Brain Axis by Enhancing Metabolism in an Apoe4 Mouse Model University of Kentucky UKnowledge Theses and Dissertations--Pharmacology and Nutritional Sciences Pharmacology and Nutritional Sciences 2018 THE PREBIOTIC INULIN BENEFICIALLY MODULATES THE GUT- BRAIN AXIS BY ENHANCING METABOLISM IN AN APOE4 MOUSE MODEL Jared D. Hoffman University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0002-9424-3526 Digital Object Identifier: https://doi.org/10.13023/etd.2018.405 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Hoffman, Jared D., "THE PREBIOTIC INULIN BENEFICIALLY MODULATES THE GUT-BRAIN AXIS BY ENHANCING METABOLISM IN AN APOE4 MOUSE MODEL" (2018). Theses and Dissertations-- Pharmacology and Nutritional Sciences. 24. https://uknowledge.uky.edu/pharmacol_etds/24 This Doctoral Dissertation is brought to you for free and open access by the Pharmacology and Nutritional Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacology and Nutritional Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Jared D. Hoffman, Student Dr. Ai-Ling Lin, Major Professor Dr. Howard Glauert, Director of Graduate Studies THE PREBIOTIC INULIN BENEFICIALLY MODULATES THE GUT-BRAIN AXIS BY ENHANCING METABOLISM IN AN APOE4 MOUSE MODEL _____________________________________ DISSERTATION _____________________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Jared David Hoffman Lexington, Kentucky Director: Dr. Ai-Ling Lin, Professor of Nutritional Sciences Co-Director: Dr. Ming Gong, Professor of Nutritional Sciences Lexington, Kentucky 2018 Copyright © Jared D. Hoffman 2018 ABSTRACT OF DISSERTATION THE PREBIOTIC INULIN BENEFICIALLY MODULATES THE GUT-BRAIN AXIS BY ENHANCING METABOLISM IN AN APOE4 MOUSE MODEL Alzheimer’s disease (AD) is the most common form of dementia and a growing disease burden that has seen pharmacological interventions primarily fail. Instead, it has been suggested that preventative measures such as a healthy diet may be the best way in preventing AD. Prebiotics are one such potential measure and are fermented into metabolites by the gut microbiota and acting as gut-brain axis components, beneficially impact the brain. However, the impact of prebiotics in AD prevention is unknown. Here we show that the prebiotic inulin increased multiple gut-brain axis components such as scyllo-inositol and short chain fatty acids in the gut, periphery, and in the case of scyllo-inositol, the brain. We found in E3FAD and E4FAD mice fed either a prebiotic or control diet for 4- months, that the consumption of the prebiotic inulin can beneficially alter the gut microbiota, modulate metabolic function, and dramatically increase scyllo-inositol in the brain. This suggests that the consumption of prebiotics can beneficially impact the brain by enhancing metabolism, helping to decrease AD risk factors. KEYWORDS: Alzheimer’s Disease, APOE4, Gut Microbiota, Gut-Brain Axis, Prebiotic Inulin, Amyloid β Jared David Hoffman October 23, 2018 Date THE PREBIOTIC INULIN BENEFICIALLY MODULATES THE GUT-BRAIN AXIS BY ENHANCING METABOLISM IN AN APOE4 MOUSE MODEL By Jared David Hoffman Dr. Ai-Ling Lin Co-Director of Dissertation Dr. Ming Gong Co-Director of Dissertation Dr. Howard Glauert Director of Graduate Studies October 9th, 2018 Date ACKNOWLEDGMENTS First, I would like to thank everyone here at the University of Kentucky that has helped me on this journey. To my mentor, Dr. Ai-Ling Lin, I really cannot say enough! I have learned so much as your student, and I thank you for being the best mentor on the planet. I am extremely lucky as you were always there when I needed help and you always provided the best guidance. I’d also like to thank my committee members Drs. Ming Gong, Steve Estus, and Nancy Webb. Thank you for challenging me and helping me improve and grow between each committee meeting. Next, I want to thank Dr. Ishita Parikh for all of her help and support in the lab. Thanks for helping me not get lost in Berlin and the birthday cheesecake. Also, Scott, thank you for your help, support, and expertise in neuroimaging. And thanks to everyone else in the lab and at the University of Kentucky that has helped me. I would like to thank my beautiful wife, Jessie, who has provided me constant support throughout this process, even on the worst of days. Clear eyes, full hearts, can’t lose!! I’d like to thank all my family and friends that have provided me the motivation to keep moving forward: my Dad, Mom, Beth, and grandparents. Grandpa Mahl, thanks for the weekly Sunday 9:30pm calls, even if you did forget a couple times. Grandma and Grandpa Hoffman, thanks for all the help you provided and enjoyment of hearing about my travels. I could not have come even close to finishing this without all of your support. And I’d like to iii thank God for all the opportunities and blessings I have been given. “I can do all things through Christ who strengthens me.” Phillipians 4:13. Lastly, I would like to thank and acknowledge my funding sources during my time here: Graduate School Academic Year Fellowship, Kentucky Opportunity Fellowship Award, and the NIH T32 Fellowship. Without this funding, I would have been unable to do the amazing research that I was able to. iv TABLE OF CONTENTS ACKNOWLEDGMENTS ......................................................................................... iii LIST OF FIGURES ............................................................................................... viii LIST OF TABLES ................................................................................................... ix Chapter 1 Background ...................................................................................... 1 1.1 Dissertation Overview ................................................................................. 1 1.2 Alzheimer’s Disease: Overview .................................................................. 1 1.2.1 Genetic Risk Factors ............................................................................. 3 1.2.2 APOE4 Risk Factors ............................................................................. 5 1.2.3 APOE4 on Host Metabolism ................................................................. 7 1.2.4 APOE Mouse Models............................................................................ 8 1.3 Gut Microbiome: Overview........................................................................ 14 1.4 Gut-Brain Axis ........................................................................................... 19 1.5 Prebiotics: Overview ................................................................................. 21 1.5.1 Inulin .................................................................................................... 23 1.6 Scope of Dissertation ................................................................................ 28 Chapter 2 Methods and Materials .................................................................. 30 2.1 Animals, Caging, and Diet Information ..................................................... 30 2.2 Fecal Bacterial Culture .............................................................................. 31 2.3 Gut Microbiome Analysis .......................................................................... 31 2.4 Plasma Scyllo-Inositol ............................................................................... 34 2.5 Metabolomics Profiling .............................................................................. 36 2.6 Magnetic Resonance Imaging (MRI) ........................................................ 41 2.7 Amyloid-β Staining .................................................................................... 43 2.8 NanoString Array ......................................................................................
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