Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls, 2021, Groven et al

Highlights

• 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.

Abstract

Background
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.

Method
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.

Results
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.

Conclusion
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.

Open access, https://www.sciencedirect.com/science/article/pii/S030645302100161X

 

Here's a presentation of Nina Groven from the department of Mental Health, Faculty of Medicine and Health Sciences, NTNU. She writes: I am looking at the connection between inflammatory processes, CFS/ME and depression to enhance the knowledge about these disorders.

One of the co authors are Egil Fors - famous for his psychosomatic approach to ME and who also coauthored the recently published CBT study by Gotaas et al discussed here

 

The authors previous study was discussed here, Patients with fibromyalgia and chronic fatigue syndrome show increased hsCRP compared to healthy controls, 2019, Groven et al

Selection criteria was Fukuda (in both studies). No mention of PEM. Questionnaires used include HADS and Chalder Fatigue Scale.

These opening sentences, from this paper, suggest a lot, "Kynurenines are suggested to play a central role in psychiatric diseases such as depression (Branchi et al., 2020). Symptoms of depression are frequently accompanying Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) (Groven et al., 2019). Thus, exploring kynurenines also in CFS and FM is of interest."

And finally,
"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."

 

I was going to write a comment asking why these particular authors would be pursuing this particular project, but I see @Andy has already answered the question!

 

Keep in mind the authors made many statistical comparisons and did not attempt to correct for multiple comparisons (despite having a reasonable n=160 sample size) some of the metabolite levels were associated with nicotine use, but this was not reported in the abstract at all.

None of the metabolite levels (not ratios) differed between controls and CFS patients in the adjusted model that considered confounding variables (nicotine use) so I cannot conclude anything interesting from this study.

 

Yep... exactly what I thought after reading it thank you!

 

I'm wondering if Robert Phair and Ron Davis have seen these findings yet. The Kynurenine Pathway is an important part of the "Metabolic Trap"-model they've been working on. The model predicts that kynurenine is missing in some parts of the body/brain, and this could be behind many of the symptoms. So based on my limited understand of these things - doesn't that fit fairly well with the results of this study?

 

This is what Jonas Bergquist in Sweden is trying to find out. He's looking at kynurenine as a treatment option in a trial that's underway.

 

The results of this paper didn’t show any real differences between CFS and controls, so either the kynurenine hypothesis is wrong or it’s only a problem in certain cell types that they didn’t look at in this paper.

 

Come to think of it, I think Phair and Davis mentioned that they think the cells stuck in the metabolic trap are immune cells... It doesn't say which cell types they've gathered in this study, as far as I can see.

 

What is the link between this pathway and fatigue?

 

There is no established link.