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The Role of Bile-Metabolising Enzymes in the Pathogenesis of Clostridioides Difficile Infection, and the Impact of Faecal Microbiota Transplantation

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The Role of Bile-Metabolising Enzymes in the Pathogenesis of Clostridioides Difficile Infection, and the Impact of Faecal Microbiota Transplantation 1 The role of bile-metabolising enzymes in the pathogenesis of Clostridioides difficile infection, and the impact of faecal microbiota transplantation Benjamin Harvey Mullish Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine Imperial College London 2019 Thesis submitted for the degree of Doctor of Philosophy 2 Abstract: The pathogenesis of Clostridioides difficile infection (CDI), and mechanisms of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI (rCDI), remain poorly- understood. Certain bile acids affect the ability of C. difficile to undergo germination or vegetative growth. Loss of gut microbiota-derived bile-metabolising enzymes may predispose to CDI via perturbation of bile metabolism, and restitution of gut bile-metabolising functionality could mediate FMT’s efficacy. Initially, human samples were analysed, i.e.: 1) biofluids collected from rCDI patients pre- and post-FMT (and their donors), and 2) stool samples from primary CDI patients, including both recurrers and non-recurrers. Analysis included: 16S rRNA gene sequencing; liquid chromatography-mass spectrometry for bile acid profiling; gas chromatography-mass spectrometry for short chain fatty acid (SCFA) quantification; bile salt hydrolase (BSH) enzyme activity; and qPCR of bsh/ baiCD genes involved in bile metabolism. Human results were validated in C. difficile batch cultures and a rCDI mouse model. A reduced proportion of the stool microbiota of rCDI patients pre-FMT contained BSH- producing bacteria compared to donors or post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA; a potent trigger to C. difficile germination); TCA levels negatively correlated with bacterial genera containing BSH-producing organisms. Post-FMT stool demonstrated recovered BSH activity and microbial bsh/ baiCD gene copy number compared with pre-treatment (p<0.05), and recovery of SCFA including valerate (p<0.001). Dynamics of stool bile acids/ BSH activity differed in primary CDI patients with and without disease recurrence. In batch cultures, culture supernatant from engineered bsh-expressing E. coli reduced TCA-mediated C. difficile germination relative to supernatant from BSH-negative E. coli. C. difficile total viable counts were ~70% reduced in a rCDI mouse model after administration of BSH-expressing E. coli relative to mice receiving BSH-negative E. coli (p<0.05). These data demonstrate that gut microbiota BSH functionality is a key mechanism influencing vulnerability to CDI and efficacy of FMT. 3 Declaration of Originality: I certify that this thesis, and the research to which it refers, are the product of my own work. Any ideas or quotations from the work of other people, published or otherwise, are fully- acknowledged in accordance with the standard referencing practices of the discipline. Benjamin H Mullish London April 2019 4 Copyright Declaration: The copyright of this thesis rests with the author. Unless otherwise indicated, its contents are licensed under a Creative Commons Attribution-Non Commercial 4.0 International Licence (CC BY-NC). Under this licence, you may copy and redistribute the material in any medium or format. You may also create and distribute modified versions of the work. This is on the condition that: you credit the author and do not use it, or any derivative works, for a commercial purpose. When reusing or sharing this work, ensure you make the licence terms clear to others by naming the licence and linking to the licence text. Where a work has been adapted, you should indicate that the work has been changed and describe those changes. Please seek permission from the copyright holder for uses of this work that are not included in this licence or permitted under UK Copyright Law. 5 Acknowledgements and Dedication: I am very fortunate to have had two supervisors as outstanding as Professors Mark Thursz and Julian Marchesi. They have both been consistently kind, good humoured and motivational, no matter whatever obstacles there were to progress or however spectacular the disasters I presented them with. I particularly remember the challenging times near the start of this project where I had no FMT service, no samples, no funding and no data, and they were totally unwavering in their support of me and belief in this project at all times, which is a testament to the character of them both. I owe them both a real debt of gratitude. I would like to thank Dr Horace Williams for helping me set up the Imperial FMT service, and for joining me in the character-building exercise that was writing the UK FMT guidelines. Other Imperial Consultants have been fantastic role models and hugely supportive throughout, with particular thanks owed to Dr Ameet Dhar and Dr Pinelopi Manousou. I also could not have asked for better collaborators than Dr Jessica Allegretti (Brigham and Women’s Hospital/ Harvard Medical School, UK), Dr Dina Kao (University of Alberta, UK), and Dr Tanya Monaghan (University of Nottingham, UK). The three of them are all inspiring clinician scientists, full of enthusiasm and ideas, and have given me huge amounts of time (and samples!) towards making this project successful. Dr Cormac Gahan and Dr Susan Joyce (from SFI Research Centre APC Microbiome Ireland, University College Cork, Ireland) kindly supplied the engineered bsh-expressing E. coli, and were very helpful throughout in planning the mechanistic studies. In the laboratory at Imperial, my greatest thanks must go to Dr Julie McDonald. Julie has been an amazing lab ‘big sister’ who has been a constantly supportive mentor and brilliant teacher, and I am very grateful for all her support throughout. Other thanks for friendship, assistance and camaraderie in the lab are owed to Grace Barker, Jesus Miguéns-Blanco, Dr Holly Jenkins, Dr Rohma Ghani, Dr Diya Kapila and Dr Fouzia Sadiq. I will miss the strong coffee, vegan baking and post-conference nights out that have helped to keep me sane during my research. Thanks are also owed to Dr Alex Pechlivanis, Dr Isabel Garcia Perez, Dr Zhigang Liu, Dr Jia Li and Jerusa Brignardello, who have all patiently endured many a nagging email or call from me 6 as I have very slowly learned metabonomics. Dr Tom Clarke and Izabela Glegola-Madejska both went beyond the call of duty to help me with the mouse experiments. However, the greatest thanks I owe are to my family and friends; they have bravely survived more conversations about faecal manipulation over the past few years than anyone should rightfully endure. My mother, Sharon, has been – as ever - incredibly supportive throughout, despite having so much on her own shoulders to deal with. She has made so many sacrifices and worked so hard to support my training and my career. Hilary has always been there for me, and has been an amazing source of kindness, endless encouragement, and wise counsel. They are both very cherished. This thesis is dedicated to the memory of my father, David Mullish. Benjamin H Mullish London April 2019 7 Table of contents: Cover page ......................................................................................................................... 1 Abstract .............................................................................................................................. 2 Declaration of Originality ................................................................................................... 3 Copyright Declaration ........................................................................................................ 4 Acknowledgements and Dedication .................................................................................. 5 Table of contents ............................................................................................................... 7 List of figures ...................................................................................................................... 15 List of tables ....................................................................................................................... 18 List of abbreviations ........................................................................................................... 19 Chapter 1. Introduction ............................................................................................ 22 1.1. Overview of Clostridioides difficile infection .............................................................. 22 1.2. Epidemiology of Clostridioides difficile infection ........................................................ 22 1.3. Aetiopathogenesis of Clostridioides difficile infection................................................ 25 1.3.1. Risk factors ................................................................................................... 25 1.3.2. Overview of transmission and pathogenesis ............................................... 26 1.4. Diagnosis of Clostridioides difficile infection .............................................................. 28 1.5. Conventional therapy for Clostridioides difficile infection, and emerging concerns . 29 1.5.1. Overview of therapy .................................................................................... 29 1.5.2. Novel antibiotics .......................................................................................... 31 1.5.2.1. Fidaxomicin ................................................................................... 31 1.5.2.2. Other antibiotics ..........................................................................
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