Bio21 - Theses

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    Metabolomics reveals the relationship between the host and the gut in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
    Armstrong, Christopher William ( 2017)
    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood disorder that likely has a complex etiological mechanism entailing predisposing, triggering, and maintaining factors. ME/CFS patients present with incapacitating long-term post-exertional malaise and a broad array of neurological, immunological and gastrointestinal symptoms. Few studies have looked to detect the basis of the energy depletion and the gastrointestinal symptoms; both are observable by metabolomics. Metabolomics is the study of metabolites, any small organic molecule, including amino acids, sugars, lipids and more. Measuring metabolites in biofluids has been performed for decades, but the development of fast, automated and standardised methods has led to the “-omics” suffix. Previous metabolite studies on ME/CFS have revealed alterations that presented some clues of amino acid and oxidative stress disturbance in ME/CFS. These studies were not using standardised metabolomics techniques and added no gastrointestinal context. In this thesis, the first application of metabolomics to study ME/CFS is described from an initial preliminary study on blood to a larger study on host metabolite changes and their association with gut metabolites and bacteria. All metabolomics research in this thesis was conducted using NMR spectroscopy. The preliminary study was on blood samples from 11 ME/CFS and 10 non-ME/CFS subjects. Glutamine and ornithine were found to be reduced in ME/CFS, and correlations of these metabolites with other metabolites revealed relationships existing between glucogenic amino acids and metabolites that participate in the urea cycle. The second study was on a much larger all-female cohort, 34 ME/CFS and 25 non-ME/CFS participants. Participants donated faeces, urine and blood samples in a timeframe for associations between biofluids to be made. In ME/CFS patients, the metabolite changes indicated a decreased glycolysis (or increased gluconeogenesis) was occurring. We surmised that this was reducing the adequate supply of acetyl-CoA to the citric acid cycle and proposed that amino acids were being increasingly utilised instead, as evidenced by a reduction in blood and urine amino acids. The prominent decrease in blood glutamate and increase in blood aspartate highlighted that aspartate transaminase (AST) might be upregulated to allow amino acids to fuel the TCA cycle. Further evidence for reduced glycolysis was an increase in creatinine, an alternate resource for anaerobic ATP production within muscle. A reperfusion pathway that produces superoxide and results in urinary allantoin accumulation was also observed in ME/CFS patients adding more evidence for increased oxidative stress. In the faeces, Clostridium spp. was increased and Bacteroides spp. were decreased, possibly indicating an alteration in microbes in ME/CFS was towards a scavenging phenotype. The faecal metabolites changes highlighted an increase in fermentation was occurring in the colon of ME/CFS producing SCFA accumulation. Furthermore, the increase in isovalerate suggests that amino acids were increasingly being used for fermentation in ME/CFS patients. We propose that the increasing use of amino acids for ATP production in the host has reduced the production of digestive enzymes, gut bacteria are provided with increased dietary substrate and increased provisions of amino acids in the colon result in increased SCFA and isovalerate via fermentation.