Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls, by Nina Groven, Solveig Klæbo Reitan, Egil Andreas Fors, Ismail Cuneyt Guzey in Psychoneuroendocrinology 2021 May 27;131:105287 [doi: 10.1016/j.psyneuen.2021.105287]



  • Quinolinic acid differs between CFS and FM.
  • The neuroprotective ratio kynurenic acid / 3-hydroxykykynurenine is lower in FM compared to healthy controls.
  • The KAT II enzymatic activity (xanthurenic acid / 3-hydroxykynurenine) is lower in FM compared to healthy controls
  • BMI, fatigue and pain are related to kynurenine pathway metabolic concentrations.

The metabolic trap hypothesis suggests that a metabolic problem exists in one or more areas of a person with ME/CFS, with a defect in the IDO2 enzyme of the tryptophan kynurenine pathway being identified as a possible metabolic trap.                                   from MEpedia


Research abstract:


There is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the central nervous system (CNS), because of the neuroprotective or neurotoxic properties of certain metabolites, yet the role of each metabolite is not clear.

The pathology of Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) is currently under investigation, and the overlapping symptoms such as depression suggest that the CNS may be involved. These symptoms may be driven by enhanced neurotoxicity and/or diminished neuroprotection.

However, the kynurenine metabolite status has not been well studied in these two possible related disorders of CFS and FM. The objective of this study was to investigate the metabolites and ratios of the kynurenine pathway in CFS and FM compared to healthy controls and examine the possible correlations with symptoms of anxiety and depression.


In this study, females aged 18-60 were included: 49 CFS patients; 57 FM patients; and 54 healthy controls. Blood plasma was analysed for the following metabolites involved in the kynurenine pathway: Tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid, xanthurenic acid (XA), 3-hydroxyanthranilic acid, quinolinic acid (QA) and picolinic acid.

The concentrations of these metabolites, as well as the ratios of different metabolites indicating enzymatic activity, were compared between the groups. Findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.


QA differed between CFS and FM patients (β = .144, p = .036) and was related to higher levels of BMI (β = .017, p = .002). The neuroprotective ratio given by KA/QA was lower for CFS patients compared to healthy controls (β = -.211, p = .016). The neuroprotective ratio given by KA/HK was lower for FM patients compared to healthy controls, and this lower neuroprotective ratio was associated with increased symptoms of pain. The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (β = -.236, p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (β = -.015, p = .039). Symptoms of anxiety and depression were not associated with the metabolites or ratios studied.


Our study indicates associations between kynurenine metabolism and CFS and FM as well as characteristic symptoms like fatigue and pain. Forthcoming studies indicating a causative effect may place kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

5. Conclusion

CFS patients may have lower neuroprotection due to higher levels of QA and lower neuroprotective ratio (KA/QA) than healthy controls. Fatigue and pain – central factors in CFS and FM – seem to be particularly related to AA, QA, and KAT II activity. Body weight reduction and smoking cessation may be beneficial in chronic fatigue and pain conditions. Kynurenine metabolites and ratios can be promising indicators and targets of diagnosis and treatment of both FM and CSF. However, caution should be taken because of the complexity of the symptoms in these patients, such as fatigue and pain, and their underlying mechanisms, independent of diagnostic groups

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