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Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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Abstract

Dysregulation of the kynurenine pathway (KP) is believed to play a significant role in neurodegenerative and cognitive disorders. While some evidence links the KP to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), further studies are needed to clarify the overall picture of how inflammation-driven KP disturbances may contribute to symptomology in ME/CFS. Here, we report that plasma levels of most bioactive KP metabolites differed significantly between ME/CFS patients and healthy controls in a manner consistent with their known contribution to symptomology in other neurological disorders. Importantly, we found that enhanced production of the first KP metabolite, kynurenine (KYN), correlated with symptom severity, highlighting the relationship between inflammation, KP dysregulation, and ME/CFS symptomology. Other significant changes in the KP included lower levels of the downstream KP metabolites 3-HK, 3-HAA, QUIN, and PIC that could negatively impact cellular energetics. We also rationalized KP dysregulation to changes in the expression of inflammatory cytokines and, for the first time, assessed levels of the iron (Fe)-regulating hormone hepcidin that is also inflammation-responsive. Levels of hepcidin in ME/CFS decreased nearly by half, which might reflect systemic low Fe levels or possibly ongoing hypoxia. We next performed a proteomics screen to survey for other significant differences in protein expression in ME/CFS. Interestingly, out of the seven most significantly modulated proteins in ME/CFS patient plasma, 5 proteins have roles in maintaining gut health, which considering the new appreciation of how gut microbiome and health modulates systemic KP could highlight a new explanation of symptomology in ME/CFS patients and potential new prognostic biomarker/s and/or treatment avenues.

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Data Availability

Data that supports the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

Bahar Kavyani is supported by an International PhD scholarship from Macquarie University. Gilles J. Guillemin is supported by the National Health and Medical Research Council (NHMRC; APP1176660) and Macquarie University. Paul R. Fisher and Sarah J. Annesley are supported by the Mason Foundation (MAS2018F00026 and MASONMECFS051). The authors thank Dr Peter Petocz, School of Statistics, Macquarie University for his assistance with statistical analysis.

Funding

This study is supported by the National Health and Medical Research Council (NHMRC, APP1176660), Macquarie University, and the Mason Foundation (MAS2018F00026 and MASONMECFS051).

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Authors and Affiliations

  1. Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia

    Bahar Kavyani, Seong Beom Ahn, Gilles J. Guillemin, David B. Lovejoy & Benjamin Heng

  2. Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia

    Daniel Missailidis, Sarah J. Annesley & Paul R. Fisher

  3. The Grove Health Pymble, Sydney, NSW, Australia

    Richard Schloeffel

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Contributions

Bahar Kavyani, Benjamin Heng, Richard Schloeffel, Gilles J. Guillemin, and Seong Beom Ahn contributed to conception and design of the study. Experiments and data collection were performed by Bahar Kavyani. David B. Lovejoy, Benjamin Heng, Bahar Kavyani, and Seong Beom Ahn contributed to data analysis. Manuscript preparation and editing were performed by Bahar Kavyani, David B. Lovejoy, Benjamin Heng, Paul R. Fisher, Sarah J. Annesley, and Daniel Missailidis. Samples were collected by Paul R. Fisher, Sarah J. Annesley, and Daniel Missailidis. All authors read and approved the manuscript.

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Correspondence to David B. Lovejoy or Benjamin Heng.

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Ethics Approval

Patient recruitment and sample collection were approved by the Australian National University Human Research Ethics Committee (Reference 2015/193 and the La Trobe University Human Ethics Committee (Reference HEC19316).

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Informed consent was obtained from all participants included in this study.

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The authors affirm that human research participants provided informed consent for publication of data in Figs. 2, 3, 4, 5, 6 and 7 and Tables 1, 2 and 3.

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Kavyani, B., Ahn, S.B., Missailidis, D. et al. Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03784-z

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