Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in ME/CFS 2023, Kavyani et al

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.

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

 

Paywalled, so can't tell how many patients, and what selection criteria.

 

I wonder whether they're testing serum or CSF. If it's serum, it could be showing that levels in the brain cells are higher, due to higher consumption or destruction, and the KYN is higher due to lack of local conversion to the other forms.

 

Edited.
The abstract doesn't provide any numbers, such as cohort size or results data, so it's impossible to judge if it is worth trying to access a paywalled copy: I thought there were guidelines for writing abstracts - though I think the strongest ones are for clinical trials (CONSORT).

 

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Clearly you're not reading enough of the current scientific literature! These non-quantitative/no data abstracts seem to be becoming more common.

 

Exclusive: Researcher has “ceased employment” at university amid investigation and retraction


https://retractionwatch.com/2023/06...university-amid-investigation-and-retraction/

UGHH.

 

Grrr

As someone with ME (=maybe low hepcidin) plus unusually difficult to control haemochromatosis (=low hepcidin) I find it annoying that whenever any study finds a connection between ME and iron either it's not investigated further or behind a paywall (but my inbox is open......)

The finding of low hepcidin in ME here is also unexpected because many ME hypotheses include an element of inflammation - yet inflammation is usually linked to high hepcidin

 

Hi @Ravn, I've quickly messaged you, but please ignore if others have already responded.

 

Thank you

 

. These days I rely heavily on others, to reduce my pain.

 

As Hutan noted I am a coauthor.

This paper is the result of a collaboration where we gave plasma to Macquarie. Bahar (lead author) is a PhD student with an ME/CFS project.

I did review a draft of this paper but I didn't know that it would be paywalled which is why the abstract is not sufficient without the rest of the text. Probably all of the people drafting it who weren't the lead authors/submitters made the same assumption. I might be be breaking some kind of rules with the publisher if I just post the PDF here but if anybody wants the paper please email me at D.Missailidis@latrobe.edu.au and I'll see what I can do.

I hope I can add some context to the scenario with Gilles even though I know very little and am not involved. My understanding is somebody reported him to Macquarie because there was some kind of doctored figure in a paper that he was a collaborating co-author on. I don't think he was even aware of it having happened until the allegation.

Regardless of whatever the truth is, I understand it that Ben Heng has taken over that lab since Gilles resigned. I am not aware of any reasons to doubt the integrity of Ben or Bahar and this paper was done well after Gilles' retirement so I don't think that their work should be judged because of that situation.

 

Thought I'd seen it all - until I looked at ref #32 Van Rensburg S et al (2001) Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities

The data from that 2001 study with its 15 cases and 15 controls and outdated diagnostic criteria is probably just noise (though the unusual constellation in "CFS" cases of low serum iron, low Tf saturation but normal ferritin would have warranted a follow-up study rather than this explanatory attempt: "In trained athletes, sweating during training can result in low Fe levels [9]; hence the excessive sweating experienced by CFS patients may have the same result")

The diagnostic criteria could almost be forgiven, it was 2001. But the patient description... "prone to road rage"

https://www.sciencedirect.com/science/article/abs/pii/S0361923001004786 (it's on, cough, scihub)

Back to the current study.

I haven't looked at all the tryptophan, kynurenine etc findings which make up the main part of the study, just concentrated on the bits related to iron

The relationship between hepcidin and severity is curious but there's huge overlap between groups and underwhelming statistical significance, so I'll be waiting for replication - possibly forever and in vain - before deciding whether to accept the findings as real or just noise

The autors attempt to explain the discrepancy between the unexpected low hepcidin (assuming it's a real finding) in a presumed inflammatory context by hypoxia. To this Raynaud's sufferer that's an interesting take but speculative for now

 

Thanks Trish. I'll be very honest. I need time (that I don't have at the moment) to learn enough about the particular biology and re-aquaint myself with every detail of the results to give you an answer that I'd truly feel happy about. Perhaps I can revisit if the time to do so becomes available. Regardless I would also encourage members to make their own judgments. I have sent the full paper to some folks by email today so please reach out if you would like it.

Wish I had more to offer today but I'm sadly stretched too thin at the moment.

 

That is the key question, especially as so much of this paper is speculation, often about weak findings.

Yet some of the differences in KP metabolites or their ratios are striking.

I now feel better about how much I have been struggling with the biology! I will focus on the key findings and pose some sometimes questions and comments.

Tagging @DMissa, and thanking him for being here and engaging with such good grace. We are a tough crowd.

1. The data/stats
Fig 2 shows lots of impressive differences.
I'm just a little concerned that the legend says "Middle lines and whiskers represent mean and standard deviation(SD) obtained from Mann–Whitney U tests ". These tests yield medians and IQRs so they probably meant they used (parametric) t-tests, but this gives the impression someone might be using a stats package flying a little blind.

Fig 5 shows the correlation of KP metabolites with severity, which is potentially important. The text states a R^2 of 0.49 for 5a (KYN), i.e R of 0.7, which is a strong correlation. The graphed data does not look like it shows a strong correlation - is r^2 =0.49 correct?

2. Findings/discussion
This seems to be

Interesting, esp as the p value looked good and the discussion says a Simmaron study found the same. What about OMF results - did they also look at this ratio when they focused on the IDO metabolic trap?

Odd logic: if IDO-1 is principally induced by cytokines, surely the sign of inflammation are cytokines themeselves. And this study, like most others, finds only evidence of a mild pro-inflammatory shift in blood cytokines. So the cytokine and metabolite data don't seem to quite fit.

But I thought there was was no evidence of cytokines correlating with severity? Again, that would be more direct evidence of inflammation.

Maybe I'm missing something, but I'd like to check on the above before commenting furhter.

Thanks.

 

FWIW, viral infections made my ME symptoms more severe. I think my physically-induced PEM was due to IFN-g increase 24 hrs after exertion.

While baseline severity might not correlate with serum cytokines, the severity might rise with increased cytokines.