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A Randomised Trial of the Effect of Omega-3 Polyunsaturated Fatty Acid Supplements on the Human Intestinal Microbiota Gut

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A Randomised Trial of the Effect of Omega-3 Polyunsaturated Fatty Acid Supplements on the Human Intestinal Microbiota Gut Bioavailability of Omega-3 Fatty Acid Formulations and Their Effect on the Intestinal Microbiota Henry Stuart Watson Submitted in accordance with the requirement for the degree of Doctor of Medicine The University of Leeds School of Medicine September 2019 The candidate confirms that the work submitted is his own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. Published work from this thesis are detailed below: Watson H, Mitra S, Croden FC, Taylor M, Wood HM, Perry SL, Spencer JA, Quirke P, Toogood GJ, Lawton CL, Dye L, Loadman PM, Hull MA. A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota Gut. 2018; 67:1974-1983. Watson H, Cockbain AJ, Spencer J, Race A, Volpato M, Loadman PM, Toogood GJ, Hull MA. Measurement of red blood cell eicosapentaenoic acid (EPA) levels in a randomised trial of EPA in patients with colorectal cancer liver metastases. Prostaglandins Leukot Essent Fatty Acids. 2016; 115: 60-66. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. Acknowledgements In compiling my thesis I am grateful for the support and guidance of Professor Mark Hull, who provided invaluable expertise and encouragement during the course of my studies. I am also thankful for guidance of Professor Giles Toogood and the opportunity he provided in allowing me to undertake this period of research. Co-ordination of the randomised cross-over trial was supported by Fiona Croden, Professor Louise Dye and Dr. Clare Lawton at the Human Appetite Research Unit (School of Psychology, University of Leeds). For the purposes of microbiome analysis, the support and guidance of Morag Taylor (Institute of Cancer and Pathology, University of Leeds) was essential. Bioinformatics analysis of microbiome data was performed with the assistance of Dr. Suparana Mitra (Institute of Biomedical and Clinical Sciences, University of Leeds) and Dr. Henry Wood (Institute of Cancer and Pathology, University of Leeds). Liquid chromatography tandem mass spectroscopy was undertaken at the Institute of Cancer Therapeutics at the University of Bradford by Professor Paul Loadman, Jade Spencer and Amanda Race. For the analysis of EPA levels in CRCLM tissue I am appreciative of the work previously carried out by Andrew Cockbain in undertaking the EMT study and the data he provided in helping me undertake my research. I am also immensely grateful to Sarah Perry for her guidance during my time in the laboratory. Abstract Due to their proposed anti-cancer effects, omega-3 fatty acids (O3FA) may have a role to play in both chemoprevention and the adjuvant treatment of colorectal cancer (CRC). Novel O3FA drink formulations may provide a more effective method of delivering O3FA supplementation, although O3FA bioavailability in these preparations compared to traditional capsules has not been ascertained. There is also a lack of research exploring the effects of O3FAs on the colonic microbiota and whether this may have any protective effect on CRC carcinogenesis. This thesis reports the findings of a randomised cross-over trial in healthy volunteers comparing the bioavailability of equivalent doses of O3FA supplementation (2g EPA and 2g DHA daily for 8 weeks) in capsule and drink carton formulations. The trial also explores the effects of O3FA on faecal microbiome profiles. In addition I report the analysis of red blood cell membrane (RBC) EPA levels from the previously reported EMT trial, a Phase II randomised, double-blind, placebo-controlled trial in which patients with colorectal cancer liver metastasis (CRCLM) received EPA (2g daily) prior to surgery. O3FA supplementation provided in a drinks carton supplementation was non- inferior to an equivalent dose of EPA and DHA provided in capsule form. Faecal microbiome profile analysis revealed subtle changes to the colonic microbiota including reversible increases to Lactobacillus and Bifidobacterium. Analysis of RBC samples from the EMT study revealed a positive correlation between RBC membrane and CRCLM tissue EPA levels. Participants with EPA RBC membrane levels of >1.22 also exhibited improved overall survival. This work provides evidence that an O3FA containing drink formulation is of equivalent bioavailability to traditional capsules. Due to their additional nutritional contents they may be of benefit in CRC patients. The effects of O3FAs on faecal microbiome profiles is of significant interest particularly their impact on bacteria associated with anti-CRC effects. Further work is required to elucidate whether O3FAs have a role in CRC chemoprevention or adjuvant treatment via their effects on the colonic microbiota. Chapter 1: Introduction 1.1 O3FAs and colorectal cancer: potential clinical applications……….….1 1.2 Colorectal Cancer…………………………………………………………........2 1.2.1 Epidemiology……………………………………………………….......2 1.2.2 Risk factors……………………………………………………………...3 1.2.3 Aetiology………………….……………………………………………..4 1.3 Omega-3 fatty acids…………….....……………………………………………5 1.3.1 O3FA structure and metabolism………………………………………5 1.3.2 Sources of O3FAs……………………………………………………...9 1.3.3 Chemical forms and absorption of O3FAs…………………………..9 1.4 Bioavailability of O3FAs……………………………………………………...10 1.4.1 Measurement of O3FA bioavailability………………………………10 1.4.2 Factors affecting O3FA absorption and bioavailability……………13 1.4.3 Novel methods of O3FA supplementation………………………….15 1.5 Protective role of O3FAs in inflammation and CRC carcinogenesis…17 1.5.1 Epidemiological studies………………………………………………17 1.5.2 Mechanisms of O3FA anti-neoplastic activity……………………...18 1.5.3 Animal studies exploring the effect of O3FAs on CRC carcinogenesis……………………………………………………………….22 1.5.4 The effect of O3FAs on CRC metastasis…………………………..26 1.5.5 Clinical studies exploring the effect of O3FAs in CRC as a potential method of chemoprevention………………………………………………..27 1.5.6 Clinical studies exploring the effect of O3FAs in CRC as a potential method of treatment………………………………………………………....29 1.6 O3FAs and the gut microbiome……………………………………………..31 1.6.1 The colonic microbiota………………………………………………..31 1.6.2 Microbiome analysis………………………………………………….33 1.6.3 Gut microbiota and CRC……………………………………………..35 1.6.4 Limitations of studies exploring the relationship between the colonic microbiome and CRC carcinogenesis……………………………39 1.6.5 The effects of specific bacteria on CRC carcinogenesis………….40 1.6.6 The effect of O3FAs on colonic inflammation, gut microbiota and CRC…………………………………………………………………………...43 Chapter 2: Aims and hypotheses 2.1 Aims and hypotheses…………………………………………………………47 Chapter 3: A randomised cross-over trial examining the bioavailability of O3FAs in capsules versus an equivalent dose in a drinks formulation and the effects of O3FA supplementation on faecal microbiome profiles. 3.1 Introduction……………………………………………………………………..50 3.2 Overview of study design…………………………………………………….50 3.3 Primary outcome measure…………………………………………………...51 3.4 Secondary outcome measures……………………………………………...53 3.5 Ethical and regulatory approval…………………………………………….53 3.6 Trial design……………………………………………………………………..53 3.6.1 Timing and nature of study visits……………………………………53 3.6.2 Screening visit assessments………………………………………...54 3.6.3 Study visit assessments and sample collection……………………54 3.7 Inclusion & exclusion criteria……………………………………………….54 3.8 Participant Recruitment………………………………………………………55 3.9 Randomisation…………………………………………………………………56 3.10 Sample size calculation……………………………………………………..56 3.11 Adverse events and data monitoring………………..……………………56 Chapter 4: Laboratory methods 4.1 Sample collection and processing for storage…………………………..58 4.1.1 Venous blood………………………………………………………….58 4.1.2 Stool samples………………………………………………………….58 4.1.3 Urine samples…………………………………………………………59 4.2 Microbiome analysis…………………………………………………………..59 4.2.1 Faecal microbial DNA isolation, extraction and recovery………...59 4.2.2 PCR amplification of the 16S rRNA gene…………………………..61 4.2.3 Purification of amplified 16S rRNA PCR product………………….62 4.2.4 Quantification of PCR product……………………………………….63 4.2.5 Library Preparation……………………………………………………63 4.2.5.1 End prep of PCR product…………………………………..63 4.2.5.2 Adaptor Ligation…………………………………………….64 4.2.5.3 Purification of ligated PCR product……………………….65 4.2.5.4 Enrichment of ligated PCR product……………………….65 4.2.5.5 Quantification of the library preparation product………...67 4.2.6 Library sequencing……………………………………………………………67 4.2.7 Bioinformatics microbiome analysis…………………………………………68 4.3 Measurement of RBC membrane PUFA content…………………………68 4.3.1 PUFA extraction from RBC membranes……………………………68 4.3.2 LC-MS/MS……………………………………………………………..69 4.3.2.1 Derivatisation………………………………………………..71 4.3.2.2 LC-MS/MS protocol…………………………………………71 4.4 Statistical analysis…………………………………………………………….72 Chapter 5: Results of the randomised cross-over trial exploring PUFA RBC membrane levels and tolerability of equivalent doses of EPA and DHA in a drink versus capsule formulation 5.1 Introduction……………………………………………………………………..73 5.2 Patient recruitment…………………………………………………………….73 5.3 Baseline characteristics……………………………………………………...74 5.4 Withdrawals…………………………………………………………………….76 5.5 Duration of supplementation and compliance…………………………...76 5.6 Acceptability
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