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A Dissertation Entitled Studies on the Holobiont and Blood Pressure Regulation by Sarah Galla Submitted to the Graduate Faculty

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A Dissertation Entitled Studies on the Holobiont and Blood Pressure Regulation by Sarah Galla Submitted to the Graduate Faculty A Dissertation entitled Studies on the Holobiont and Blood Pressure Regulation by Sarah Galla Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences _________________________________________ Bina Joe, Ph.D., Committee Chair _________________________________________ Matam Vijay-Kumar, Ph.D., Committee Member _________________________________________ Deepak Malhotra, MD, Ph.D., Committee Member _________________________________________ Guillermo Vazquez, Ph.D., Committee Member _________________________________________ Edwin Sanchez, Ph.D., Committee Member _________________________________________ Cyndee Gruden, Ph.D., Dean College of Graduate Studies The University of Toledo May 2019 Copyright 2019, Sarah Lynn Galla This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Studies on the Holobiont and Blood Pressure Regulation by Sarah Galla Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo May 2019 Hypertension, or elevated blood pressure (BP), is very prevalent in the United States with over a third of the population being affected, and is a risk factor for cardiovascular disease, kidney disease, and stroke. BP is a complex, polygenic trait that is regulated by the genome, as well as the environment. Recent studies have found that in addition to the genome, microbiota are also known to regulate BP. Microbiota are composed of microorganisms that live within the body in a symbiotic relationship. The term ‘holobiont’ is used to refer to all of the symbiotic relationships within the body as a unit. In this study, we aimed to determine the role that the host genome, the microbiome, and the interactions between them have in BP regulation. To do this, we performed multiple studies. First, we studied the role of a single gene, the G-protein coupled estrogen receptor (Gper1) on BP regulation by using a previously developed Gper1-/- rat model on the Dahl Salt Sensitive (S) rat background. To understand the function of Gper1, we performed a quantitative proteomic study on endothelial cells, and found 150 differentially expressed proteins. Immune cell migration was one of the most differentially expressed pathways, suggesting a role of Gper1 in immune cell migration. iii To study the role of the microbiome, we gave two hypertensive rat strains, the S rat and Spontaneously Hypertensive Rat (SHR), one of three different antibiotics: minocycline, neomycin, or vancomycin. We found that in the S rat, regardless of the type, antibiotics increased BP. However, in the SHR, two of the antibiotics caused a lowering of BP, while one had no effect. These BP changes were accompanied by changes in bacterial abundance and diversity. Moreover, the S rats had a heightened inflammatory state in their colons, while the SHR did not. This suggested a role of the host immune-microbiome interaction in BP regulation. In addition to adult hypertension, there is an increasing prevalence of pediatric hypertension that has not been well studied. Therefore, we aimed to study if the same mechanisms by which microbiota alter BP in adults were still evident in adolescents. We hypothesized that altering the microbiota during adolescence would affect the development of hypertension. We found that S rats given amoxicillin, the most common pediatric antibiotic, had a reduced BP compared to controls. This reduced BP was associated with microbiotal changes, most notably, a drastic decrease in the Firmicutes/Bacteroidetes ratio, the most common marker of gut dysbiosis. This reduced dysbiosis caused a reduction in both colon and kidney inflammation, that persisted weeks after the cessation of amoxicillin, and caused the noted reduction in BP. Microbiota initially begin to develop at birth and are heavily influenced by maternal factors. Therefore, we hypothesized that maternal antibiotic use during pregnancy and lactation would alter BP. We performed this experiment and found that male S rats whose mother was given amoxicillin had a reduced BP. However, female iv offspring did not have this BP effect. The male offspring had reduced F/B ratios, while the females did not, suggesting a potential link to the sex-specific BP effect. In conclusion, through the use of experiments to study both the host genome and the microbiome, we have found that the genome and microbiome, as well as the interactions between the two, regulate blood pressure. These studies highlight the importance of personalized medicine in the treatment of hypertension, as well as in the prescription of antimicrobials, specifically antibiotics, at any age. v This dissertation is dedicated to my loving husband. Thank you for your continuous understanding and encouragement. You have been by my side every step of the way, and I am incredibly grateful. Also, to my parents, thank you for always supporting me and believing in me even when I did not fully believe in myself. Acknowledgements I am very grateful to my mentor, Dr. Joe, for accepting me into her lab and patiently forming me into the scientist I am today. She allowed me to study more clinically-oriented projects that she knew I would have more interest in as an MD/PhD student. She spent her time teaching me not only valuable lessons in research, but also lessons that are applicable to every area of life. Her constant belief in me has inspired me to further my research career, and I know that she will always be there for me to offer guidance. I would also like to thank my committee members, Dr. Vijay-Kumar, Dr. Malhotra, Dr. Vazquez, and Dr. Sanchez for your support and advice during my graduate school journey. I am also very thankful to our collaborators who have provided me with valuable insight and assistance. Additionally, I would like to thank the Department of Physiology and Pharmacology for all of the help and support I have received. Finally, I would be remiss without thanking my lab mates. To Saroj Chakraborty, Blair Mell, Dr. Xi Cheng, Dr. Ji-Youn Yeo, Dr. Youjie Zhang and Dr. Cam McCarthy, thank you for all of your help and support in the past few years. I would not have been able to accomplish this work without your time, knowledge, and guidance. Thank you for patiently explaining difficult concepts to me and for providing me with great feedback. Everything you have done is greatly appreciated. v Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ..............................................................................................................v Table of Contents ............................................................................................................... vi List of Tables ................................................................................................................... xi List of Figures ................................................................................................................... xii List of Abbreviations .........................................................................................................xv 1 Microbiotal-Host Interactions and Hypertension.....................................................1 1.1 Abstract ..........................................................................................................1 1.2 Introduction ..............................................................................................2 1.3 Gut microbiota, the host genome and hypertension...........................................5 1.4 Gut microbiotal studies using genetic models of hypertension .........................8 1.5 Beyond Gut microbiota, other organ-specific microbiota links to hypertension ........................................................................................................13 1.6 The host as a ‘Holobiont’ .................................................................................14 1.7 The translational value of understanding the host-microbial relationships within a ‘holobiont’................................................................................................16 1.8 Probiotics and Hypertension ............................................................................18 1.9 Conclusion ............................................................................................19 1.10 Summary 21 vi 1.11 References ............................................................................................22 2 Host Genomics and Blood Pressure Regulation ....................................................41 2.1 Introduction ......................................................................................................41 2.2 Methods ........................................................................................................43 2.2.1 Animals and diet ...............................................................................43 2.2.2 Endothelial cell culture .....................................................................44 2.2.3 Protein Identification and relative quantitation by TMT labeling and LC-Tandem MS .........................................................................................45 2.2.4 Data analysis .....................................................................................47
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