Thesis

Metabolomics approaches for gastrointestinal disease research and application to clinical trials investigating inflammatory bowel disease and coeliac disease

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Awarding institution
  • University of Strathclyde
Date of award
  • 2025
Thesis identifier
  • T17474
Person Identifier (Local)
  • 202187657
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Abstract
  • Chronic inflammatory diseases of the gut, including inflammatory bowel disease (IBD) and coeliac disease (CoD), present major diagnostic and therapeutic challenges due to their heterogeneous clinical presentation, reliance on invasive biomarkers, and limited specificity of existing tests. Liquid chromatography-based mass spectrometry (LC-MS)-based metabolomics provides a powerful means of characterising small molecule signatures of disease and treatment response. This thesis advances the field by establishing optimised high-throughput LC-MS workflows for gastrointestinal metabolomics and applying them to large-scale clinical cohorts to identify novel disease-relevant metabolic alterations. A monophasic faecal extraction protocol was developed and systemically optimised, ensuring broad metabolite coverage and reproducibility for both untargeted and targeted analyses. Applied to paediatric CoD cohorts, this method revealed three major groups of candidate biomarkers. Firstly, we identified a panel of 12 CoD-specific, non-treatment responsive metabolites spanning bile acids and amino acid derivatives that remain persistently altered despite adherence to a gluten-free diet (GFD). Secondly, we note a group of treatment-responsive metabolites, including amino acid dipeptides and indole and purine related metabolites, which normalised following dietary treatment. Finally, we identified treatment dependent, non-disease-specific metabolites driven by dietary change rather than CoD itself, such as indole-derived compounds and acylcarnitines. In parallel, a rapid LC-MS workflow for urine was developed and systematically optimised to ensure robust application in large-scale clinical studies. Eight individual parameters were sequentially evaluated, spanning across sample preparation, LC and MS elements of the workflow. This iterative workflow produced a high-throughput protocol with a 6.5-minute data collection time, while maintaining peak resolution, reproducibility, and broad metabolite coverage. This optimised protocol was used to analyse 1094 urine samples from IBD patients and healthy controls, representing the largest urinary metabolomics study of IBD performed to date. Finally, a critical review was conducted on the impact of food additives on gut inflammation. This synthesis underscored the dual potential of additives as either inflammatory or therapeutic modulators, reinforcing diet as both a confounder and a therapeutic axis in gastrointestinal disease. Collectively, this thesis provides methodological advancement that strengthens standardisation in LC-MS-based gastrointestinal metabolomics and delivers biological insights into the pathophysiology of disease. This work contributes to the development of non-invasive biomarkers for future clinical translation of metabolomics in gut health.
Advisor / supervisor
  • Rattray, Nicholas J.W.
Resource Type
DOI

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