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

Bahar Kavyani; Seong Beom Ahn; Daniel Missailidis; Sarah J Annesley; Paul R Fisher; Richard Schloeffel; Gilles J Guillemin; David B Lovejoy; Benjamin Heng

doi:10.1007/s12035-023-03784-z

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 Nov 28. doi: 10.1007/s12035-023-03784-z. Online ahead of print.

Authors

Bahar Kavyani¹, Seong Beom Ahn¹, Daniel Missailidis², Sarah J Annesley², Paul R Fisher², Richard Schloeffel³, Gilles J Guillemin¹, David B Lovejoy⁴, Benjamin Heng⁵

Affiliations

¹ Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
² Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia.
³ The Grove Health Pymble, Sydney, NSW, Australia.
⁴ Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. david.lovejoy@mq.edu.au.
⁵ Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. benjamin.heng@mq.edu.au.

PMID: 38015302
DOI: 10.1007/s12035-023-03784-z

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.

Keywords: Biomarkers; Inflammation; Kynurenine pathway; Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); Proteomics.