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Citrulline and the Intestine

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Citrulline and the Intestine CITRULLINE AND THE INTESTINE THESIS SUBMITTED BY KONSTANTINOS C. FRAGKOS OF THE CENTRE FOR GASTROENTEROLOGY AND NUTRITION DIVISION OF MEDICINE, UNIVERSITY COLLEGE LONDON FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (PH.D.) SUPERVISOR: PROF. ALASTAIR FORBES APRIL 2018 Declaration I, Konstantinos Fragkos, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Konstantinos Fragkos April 2018 2 This thesis is dedicated to the development of greater understanding between health and life sciences and to the opportunity to investigate the complexities of intestinal physiology. 3 Abstract Citrulline, a non-protein amino acid, has been playing an important role in scientific research over the last few years. This thesis explores various aspects of citrulline with respect to intestinal disease, short bowel syndrome and intestinal failure. The first important finding was that citrulline as a term has been used at the end of the 19th century-beginning of the 20th century to describe an extract of the C. colocynthis, used as a subcutaneous laxative. Also, old sources have revealed that citrulline was first described as an amino acid by Koga and Ohtake (1914) and not by Wada (1930a). From the systematic review and meta-analysis, citrulline levels are strongly positively correlated with small bowel length in short bowel syndrome patients and strongly negatively correlated with intestinal disease severity with regards to enteropathies (coeliac disease, tropical enteropathy, mucositis, acute rejection in intestinal transplantation, but not Crohn’s disease). Citrulline cut-off levels have an overall sensitivity and specificity of 80% and citrulline levels compared to controls were reduced by 10 μmol/L. These findings suggest that citrulline is a marker of possible acute intestinal injury or intestinal insufficiency. Next, an original five-by-five cross-over study was designed (Williams design) comparing post-absorptive amino acid concentrations after challenges with citrulline, arginine, glutamine, 3-methyl-hisitidine and placebo. Citrulline was the most potent stimulator for all other amino acids, contrary to beliefs of glutamine challenges. Citrulline challenges could be useful in intestinal failure but also in liver failure where urea cycle pathways including glutamine, arginine and ornithine are implicated. The final study was an investigation of quality of life in short bowel syndrome patients. The quality of life scale is highly reliable in short bowel syndrome patients (Cronbach’s alpha > 0.700) and the main causes of low quality of life are fatigue, diarrhoea/increased stomal output, lack of sleep, gastrointestinal symptoms, and muscle pains. 4 Acknowledgements I am deeply grateful to Prof. Alastair Forbes for his constant guidance on all aspects of my PhD research until today, without whom all my results would be impossible to achieve. I am also very grateful to the following colleagues of Professor Forbes and faculty members at UCL for playing an advisory and guiding role when needed: Dr George Grimble, Principal Teaching Fellow & Honorary Senior Lecturer at UCL; Dr Richard M. Day, UCL Division of Medicine, for helping me with many aspects of lab techniques and supervising certain projects of myself throughout the PhD; Dr Nathan Davies, based at the Royal Free, and Mr Richard Cohen, based at University College Hospital; and finally, Prof. David Sattelle for his help finalising and submitting the dissertation. I am also deeply grateful to my father Christos Frangos, for his constant psychological and monetary – in many instances – support throughout this research path I chose; and my mother Jenny, sister Maria-Roza, nephew Alexandros Dimopoulos, my wife Penelope Makrykosta and my son Orestis Fragkos. Also, acknowledgements are due to all other members of staff, postgraduate research staff and friends who have kindly assisted me with their ideas, discussions, lab assistance or anything else during my research: Prof. Simon Lal, Georgios Bountagkidis, Ioannis Angelopoulos, Nina Parmar, Adeel Hamad, Faris Al-Sultan, Mohammed Eddama, Stephanie Kuku, Bing Wang, Hideo Suzuki, Alistair Windsor, Indira Nathan, Maria Jover-Cobos, Cali Hyde from the Cancer Institute who helped with analyses in the mass spectrometer, Alvin Wong, Peter Berghöfer and other staff at Nycomed, Dr L. Ber from NOW foods (USA), George Kravvas, Bill Batziakas, and last but not least the research participants. 5 Publications and Presentations Arising from this Thesis Publications Fragkos, K.C., & Forbes, A. (2018). A pharmacodynamics study of citrulline challenge testing. In preparation. Fragkos, K.C., & Forbes, A. (2018). Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis. United European Gastroenterology Journal, 6(2), 181-191, doi:10.1177/2050640617737632. Berghöfer, P., Fragkos, K. C., Baxter, J. P., Forbes, A., Joly, F., Heinze, H., et al. (2013). Development and validation of the disease-specific Short Bowel Syndrome-Quality of Life (SBS-QoL™) scale. Clinical Nutrition, 32(5), 789-796, doi:10.1016/j.clnu.2012.12.001. Fragkos, K. C., & Forbes, A. (2011). Was citrulline first a laxative substance? The truth about modern citrulline and its isolation. Journal of Japanese History of Medicine, 57(3), 275-292. Presentations Fragkos, K. C., & Forbes, A. (2017). PWE-101 Citrulline as a marker of intestinal function and absorption in clinical settings: a systematic review meta-analysis. Gut, 66(Supplement 2), A178, doi: 10.1136/gutjnl-2017-314472.347. Fragkos, K. C., & Forbes, A. (2011). Are Citrulline Plasma Levels a Marker of Small Bowel Length and Absorptive Capacity? A Meta-Analysis. Paper presented at the UCL Biomedical Sciences Conference, 28/2-1/3 London, UK. Fragkos, K., Baxter, J. P., Forbes, A., Joly, F., Heinze, H., Jeppesen, P. B., et al. (2011). PP059- MON Development and Validation of a Short Bowel Syndrome (SBS) Specific Quality of Life Scale. Clinical Nutrition Supplements, 6(1), 137, doi:10.1016/S1744-1161(11)70351-9. Fragkos, K. C., & Forbes, A. (2011). PP228-SUN Is citrulline a marker of small intestinal absorption? A systematic review and meta- analysis. Clinical Nutrition Supplements, 6(1), 110, doi:10.1016/S1744-1161(11)70281-2. Fragkos, K. C., & Forbes, A. (2011). OP048 A meta-analysis on the association of citrulline plasma levels and small bowel length. Clinical Nutrition Supplements, 6(1), 20, doi:10.1016/S1744- 1161(11)70048-5. 6 Contents DECLARATION ......................................................................................................... 2 ABSTRACT ............................................................................................................... 4 ACKNOWLEDGEMENTS ........................................................................................... 5 PUBLICATIONS AND PRESENTATIONS ARISING FROM THIS THESIS ...................... 6 CONTENTS ............................................................................................................... 7 LIST OF FIGURES ................................................................................................... 10 LIST OF TABLES .................................................................................................... 14 ABBREVIATIONS .................................................................................................... 16 PREFACE AND OVERVIEW..................................................................................... 20 CHAPTER 1 INTRODUCTION .................................................................................. 24 1.1 History of Citrulline ................................................................................ 24 1.1.1 Early Sources Mentioning the Term “Citrulline” ................................................. 25 1.1.2 The History of Modern Citrulline’s Isolation ....................................................... 26 1.2 Biochemical and Analytical Properties of Citrulline .............................. 28 1.2.1 Citrulline Metabolism ........................................................................................... 28 1.2.2 Intracellular Cycles............................................................................................... 29 1.2.3 Inter-organ Cycle .................................................................................................. 29 1.2.4 Analytical Methods to Quantify Citrulline ........................................................... 30 1.2.4.1 Ion Exchange Chromatography ............................................................................. 31 1.2.4.2 Reversed Liquid Phase Chromatography .............................................................. 31 1.2.4.3 Mass Spectrometry on Dried Blood Spot .............................................................. 31 1.2.4.4 Ultra Performance Liquid Chromatography Coupled with Mass Spectrometry .... 31 1.3 Non-Human Studies of Citrulline and the Intestine ............................... 32 1.3.1 Biochemistry and Developmental Biology of Citrulline ...................................... 34 1.3.2 Clinical Significance of Citrulline ........................................................................ 35 1.3.3 Citrulline Function in Colonocytes ...................................................................... 35 1.4 Summary and Conclusion ....................................................................... 36 1.5
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