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Exploring the role of tryptophan metabolites in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Development and application of high resolution mass spectrometry methods
Abujrais, Sandy
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]
Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a severe systemic disorder characterized by neurological, gastrointestinal, inflammatory symptoms and fatigue. Disregulation in tryptophan (TRP) metabolism and excessive kynurenine pathway activation may cause these symptoms. Thus, this thesis investigates TRP in ME/CFS. TRP, a key amino acid, regulates nervous system, immune system, endocrine system, and energy metabolism. The main pathway of TRP metabolism is kynurenine, with a minor percentage shuttled towards serotonin biosynthesis, a brain-essential neurotransmitter. Kynurenine metabolism generates kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic).
Our current knowledge of TRP metabolism in ME/CFS is insufficient. Few studies have quantified TRP in ME/CFS, and even fewer have employed high-resolution mass spectrometry, essential for accurate measurements and comprehensive metabolomics. Additionally, many studies disregarded factors like age and sex, which influence TRP metabolite levels. Lastly, preclinical research on the neuroprotective effects of KYN as a potential treatment is notably lacking
To address these research questions, we developed an accurate and comprehensive analytical method using liquid chromatography coupled with high-resolution mass spectrometry. This method quantifies TRP and its metabolites, along with the vitamins B2 and B6, essential for the enzymes in this pathway. Additionally, we measured the oxidative marker hypoxanthine and the amino acids tyrosine and phenylalanine, which compete with TRP to cross the blood-brain barrier, and limit its availability in the brain. We then employed the, TRP method and untargeted metabolomics, to compare the metabolic profiles of ME/CFS patients with those of healthy individuals, considering age and sex. Moreover, the effects of the menstrual cycle on TRP levels were examined by correlating 11 steroids with TRP metabolites. Additionally, the tissue distribution of kynurenine was investigated following both acute and chronic administration in a preclinical model.
The untargeted study found alterations in the vitamin B3, arginine-proline, aspartate-asparagine, L-Adrenaline and S-Adenosyl-L-homocysteine pathways . While, the targeted approach revealed decreased levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in ME/CFS patients. In addition, hypoxanthine and phenylalanine was elevated in ME/CFS patients, suggesting hypoxia and altered amino acid metabolism. The study found strong relationships between TRP metabolites and steroids during the menstrual cycle, suggesting hormones affect this pathway. Preclinical findings showed that kynurenine administration resulted in region-specific effects, with a potential neuroprotective effect in the hippocampus. These studies open avenues for further exploration of TRP metabolism, particularly in relation to ME/CFS and the impact of steroid hormones on this metabolic pathway.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. , p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2437
Keywords [en]
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), liquid chromatography, high-resolution mass spectrometry, tryptophan metabolites, kynurenine, serotonin, neuroprotective compounds
National Category
Analytical Chemistry
Research subject
Chemistry with specialization in Analytical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-536606ISBN: 978-91-513-2207-0 (print)OAI: oai
iVA.org:uu-536606DiVA, id: diva2:1890664
Public defence
2024-09-25, A1:107a, BMC, Husargatan 3, Uppsala, 12:02 (English)
Opponent
Erhardt, Sophie, Professor
Supervisors
Bergquist, Jonas, Professor
Available from: 2024-09-04 Created: 2024-08-20 Last updated: 2024-09-04
List of papers
1. Analysis of tryptophan metabolites and related compounds in human and murine tissue: development and validation of a quantitative and semi-quantitative method using high resolution mass spectrometry
2. Untargeted metabolomics and quantitative analysis of tryptophan metabolites in myalgic encephalomyelitis patients and healthy volunteers: a comparative study using high resolution mass spectrometry
3. Tryptophan metabolites and steroid patterns across menstrual cycle phases in healthy women
4. Potential neuroprotective effects of kynurenine administration in healthy rodents using high resolution mass spectrometry
Exploring the role of tryptophan metabolites in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Development and application of high resolution mass spectrometry methods
Abujrais, Sandy
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]
Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a severe systemic disorder characterized by neurological, gastrointestinal, inflammatory symptoms and fatigue. Disregulation in tryptophan (TRP) metabolism and excessive kynurenine pathway activation may cause these symptoms. Thus, this thesis investigates TRP in ME/CFS. TRP, a key amino acid, regulates nervous system, immune system, endocrine system, and energy metabolism. The main pathway of TRP metabolism is kynurenine, with a minor percentage shuttled towards serotonin biosynthesis, a brain-essential neurotransmitter. Kynurenine metabolism generates kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic).
Our current knowledge of TRP metabolism in ME/CFS is insufficient. Few studies have quantified TRP in ME/CFS, and even fewer have employed high-resolution mass spectrometry, essential for accurate measurements and comprehensive metabolomics. Additionally, many studies disregarded factors like age and sex, which influence TRP metabolite levels. Lastly, preclinical research on the neuroprotective effects of KYN as a potential treatment is notably lacking
To address these research questions, we developed an accurate and comprehensive analytical method using liquid chromatography coupled with high-resolution mass spectrometry. This method quantifies TRP and its metabolites, along with the vitamins B2 and B6, essential for the enzymes in this pathway. Additionally, we measured the oxidative marker hypoxanthine and the amino acids tyrosine and phenylalanine, which compete with TRP to cross the blood-brain barrier, and limit its availability in the brain. We then employed the, TRP method and untargeted metabolomics, to compare the metabolic profiles of ME/CFS patients with those of healthy individuals, considering age and sex. Moreover, the effects of the menstrual cycle on TRP levels were examined by correlating 11 steroids with TRP metabolites. Additionally, the tissue distribution of kynurenine was investigated following both acute and chronic administration in a preclinical model.
The untargeted study found alterations in the vitamin B3, arginine-proline, aspartate-asparagine, L-Adrenaline and S-Adenosyl-L-homocysteine pathways . While, the targeted approach revealed decreased levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in ME/CFS patients. In addition, hypoxanthine and phenylalanine was elevated in ME/CFS patients, suggesting hypoxia and altered amino acid metabolism. The study found strong relationships between TRP metabolites and steroids during the menstrual cycle, suggesting hormones affect this pathway. Preclinical findings showed that kynurenine administration resulted in region-specific effects, with a potential neuroprotective effect in the hippocampus. These studies open avenues for further exploration of TRP metabolism, particularly in relation to ME/CFS and the impact of steroid hormones on this metabolic pathway.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. , p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2437
Keywords [en]
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), liquid chromatography, high-resolution mass spectrometry, tryptophan metabolites, kynurenine, serotonin, neuroprotective compounds
National Category
Analytical Chemistry
Research subject
Chemistry with specialization in Analytical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-536606ISBN: 978-91-513-2207-0 (print)OAI: oai
iVA.org:uu-536606DiVA, id: diva2:1890664Public defence
2024-09-25, A1:107a, BMC, Husargatan 3, Uppsala, 12:02 (English)
Opponent
Erhardt, Sophie, Professor
Supervisors
Bergquist, Jonas, Professor
Available from: 2024-09-04 Created: 2024-08-20 Last updated: 2024-09-04
List of papers
1. Analysis of tryptophan metabolites and related compounds in human and murine tissue: development and validation of a quantitative and semi-quantitative method using high resolution mass spectrometry
2. Untargeted metabolomics and quantitative analysis of tryptophan metabolites in myalgic encephalomyelitis patients and healthy volunteers: a comparative study using high resolution mass spectrometry
3. Tryptophan metabolites and steroid patterns across menstrual cycle phases in healthy women
4. Potential neuroprotective effects of kynurenine administration in healthy rodents using high resolution mass spectrometry
