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DIETARY TRIMETHYLAMINES, the GUT MICROBIOTA, and ATHEROSCLEROSIS by ROBERT ALDEN KOETH Submitted in Partial Fulfillment Of

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DIETARY TRIMETHYLAMINES, the GUT MICROBIOTA, and ATHEROSCLEROSIS by ROBERT ALDEN KOETH Submitted in Partial Fulfillment Of DIETARY TRIMETHYLAMINES, THE GUT MICROBIOTA, AND ATHEROSCLEROSIS By ROBERT ALDEN KOETH Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Adviser: Stanley L. Hazen, M.D., Ph.D. Department of Pathology CASE WESTERN RESERVE UNIVERSITY August, 2013 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Robert Alden Koeth candidate for the Ph.D. degree *. (signed) Alan D. Levine, Ph.D. (chair of the committee) Stanley L. Hazen, M.D., Ph.D. Jonathan D. Smith, Ph.D. George R. Dubyak, Ph.D. Clive R. Hamlin, Ph.D. (date) 04/16/2013 *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS LIST OF TABLES ................................................................................................ 9 LIST OF FIGURES............................................................................................. 10 ACKNOWLEDGEMENTS .................................................................................. 16 ABSTRACT........................................................................................................ 18 CHAPTER1: Introduction to Dietary Trimethylamines, the Gut Microbiota, and Atherosclerosis ......................................................................................... 20 Cardiovascular Disease and Atherosclerosis............................................. 20 A History of the Gut Microbiota ................................................................... 22 Location and Composition of the Gut Microbiota ...................................... 23 Normal Functions of the Gut Microbiota..................................................... 25 The Relationship Between the Gut Microbiota and Disease ..................... 31 Gut Microbiota Mediated Metabolism of Phosphatidylcholine Promotes Cardiovascular Disease................................................................................ 35 CHAPTER 2: Intestinal Microbiota Metabolism of L-Carnitine, a Nutrient in Red Meat, Promotes Atherosclerosis ............................................................. 47 Authors .......................................................................................................... 47 Abstract.......................................................................................................... 47 Introduction ................................................................................................... 48 Results ........................................................................................................... 51 Metabolomic studies link L-carnitine with CVD ...................................... 51 1 Gut microbiota plays an obligatory role in forming TMAO from L- carnitine in humans ................................................................................... 53 Vegans and vegetarians produce substantially less TMAO from dietary L-carnitine .................................................................................................. 55 Plasma TMAO levels significantly associate with specific human gut microbial taxa............................................................................................. 57 TMAO production from dietary L-carnitine is an inducible trait ............ 58 TMA / TMAO production associates with specific mouse gut microbial taxa.............................................................................................................. 59 Plasma levels of L-carnitine associate with CVD.................................... 60 Dietary L-carnitine in mice promotes atherosclerosis in a gut microbiota dependent manner.................................................................. 62 Gut microbiota dependent formation of TMAO inhibits reverse cholesterol transport ................................................................................. 63 TMAO promotes significant alterations in cholesterol and sterol metabolism in multiple compartments in vivo ........................................ 66 Discussion ..................................................................................................... 68 Acknowledgements....................................................................................... 78 Methods ......................................................................................................... 78 Materials and general procedures............................................................ 78 Research subjects ..................................................................................... 79 2 General statistics....................................................................................... 81 Metabolomics study .................................................................................. 82 Identification of L-carnitine and d9-carnitine preparation...................... 83 Quantification of TMAO, TMA, and L-carnitine........................................ 85 Human microbiota analyses ..................................................................... 86 Mouse microbiota analysis ....................................................................... 87 Aortic root lesion quantification............................................................... 89 Human L-carnitine challenge test and d3-L-carnitine preparation ........ 89 Germ-free mice and conventionalization studies ................................... 92 Metabolic challenges in mice ................................................................... 93 Preparation of bone marrow derived macrophages for reverse cholesterol transport studies.................................................................... 93 Reverse cholesterol transport studies..................................................... 94 Cholesterol absorption studies ................................................................ 95 Bile acid pool size and composition ........................................................ 96 Cholesterol efflux studies ......................................................................... 97 Effect of TMAO on macrophage cholesterol biosynthesis, inflammatory genes, and desmosterol levels................................................................. 97 RNA preparation and real time PCR analysis.......................................... 99 3 CHAPTER 3: Carnitine, a Nutrient Found in Red Meat and a Frequent Additive by the Nutritional Supplement Industry, Can Induce the Human Gut Microbiota to Produce Proatherogenic TMAO...................................... 135 Authors ........................................................................................................ 135 Intro .............................................................................................................. 135 Methods ....................................................................................................... 135 Results ......................................................................................................... 136 Comment...................................................................................................... 136 CHAPTER 4: Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiac Risk.................................................................................................... 139 Authors ........................................................................................................ 139 Abstract........................................................................................................ 139 Introduction ................................................................................................. 140 Results ......................................................................................................... 141 Role of intestinal microbiota in metabolism of dietary phosphatidylcholine ................................................................................ 141 Correlation of plasma levels of trimethylamine-N-oxide with major adverse cardiovascular events............................................................... 143 Correlation of trimethylamine-N-oxide levels with risk in low-risk subgroups ................................................................................................ 145 Discussion ................................................................................................... 145 4 Acknowledgements..................................................................................... 149 Methods ....................................................................................................... 149 Study patients and design ...................................................................... 149 Dietary phosphatidylcholine challenge ................................................. 151 Measurements of choline metabolites ................................................... 152 Statistical analysis for the clinical outcomes study ........................... 152 CHAPTER 5: Intestinal Microbiota Metabolism of L-Carnitine, a Nutrient in Red Meat, Produces TMAO Via Generation of an Intermediate Gut Microbiota Metabolite γ-Butyrobetaine ........................................................ 163 Authors ........................................................................................................ 163 Abstract........................................................................................................ 163 Introduction ................................................................................................
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