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

Sly Saint

Sly Saint

Senior Member (Voting Rights)
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)
 
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).
 
Last edited:
Andy said:
Paywalled, so can't tell how many patients, and what selection criteria.
Click to expand...

Paper said:
Patient and healthy control plasma used in this study were sourced from La Trobe University, Melbourne Australia (HREC approval MQ52020922222899). The ME/CFS patient cohort consisted of 59 patients diagnosed with ME/CFS in line with the Canadian Consensus Criteria. As ME/CFS is known to affect approximately 3 times more women than men, this cohort contained more females (n = 49) than males (n = 10). Symptom severity was graded according to the weighted standing test (WST).
Click to expand...
 
This paper follows on from an earlier literature review by the first author and other co-authors that had a lot of problems.
Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?, 2022, Kavyani

I have yet to have a look at this latest paper, but yes, abstracts need to be better than this one is.

Here's the author list for this 2023 paper:
Bahar Kavyani1 · Seong Beom Ahn1 · Daniel Missailidis2 · Sarah J. Annesley2 · Paul R. Fisher2 · Richard Schloeffel3 · Gilles J. Guillemin1 · David B. Lovejoy1 · Benjamin Heng1

The author list is a very mixed bag including some researchers who understand ME/CFS and are committed to doing right by people with ME/CFS, including a member here, @DMissa.
 
Sly Saint said:
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
Click to expand...
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
 
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.

Jaybee00 said:
Exclusive: Researcher has “ceased employment” at university amid investigation and retraction
Click to expand...

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" :jawdrop:
Van Rensburg 2001" said:
Symptoms. All the CFS patients had psychiatric and somatic symptoms. As for cognitive function: impaired memory, thought processes, and concentration; prone to disorientation/detachment. As for mood disturbances: irritability, anxiety, depression; prone to suicidal ideation. Premorbidly: A-type personality, inclined to do excessive amounts of work. Morbidly: patients were ‘difficult’, avoidant, labile, had poor frustration tolerance and bouts of aggression, or were apathetic, dependent, socially inappropriate/disinhibited, and prone to road rage. A general feature was unusual paraesthesias: ‘burns’ or a ‘numb spot’ (especially on the thigh or foot)
Click to expand...
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
Kavyani 2023 said:
Hepcidin levels were 0.6-fold lower in patients compared to HCs (Fig. 7A). Interestingly, hepcidin levels were lowest in the mild symptomatic group (Fig. 7B) dipping to approximately 0.3-fold relative to healthy controls. However, hepcidin levels then recovered, moving progressively closer to normal in the moderate and severe symptom groups. If confirmed in larger samples, this could suggest that hepcidin dysregulation might be more relevant to early-phase or mild ME/CFS disease processes, raising the possibility that hepcidin expression might have utility as a biomarker of recovery in ME/CFS
Click to expand...
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
Kavyani 2023 said:
Our finding of low hepcidin in ME/CFS patients could point to a homeostatic mechanism for correction of Fe deficiency, as reduced hepcidin expression encourages Fe uptake from the gut for hemoglobin synthesis and red blood cell production. Chronic inflammation generally is viewed as leading to increased hepcidin, which in turn can lead to the anemia of inflammation. Although our findings of KP activation and enhanced expression of inflammatory cytokines provide evidence of systemic inflammation, alternative mechanism/s seem to be involved that lead to reduced hepcidin. Recently, an intriguing new theory suggested that long COVID and ME/CFS could be coagulopathies that induce chronic ischemia–reperfusion injury in tissues with clogged capillaries [63]. The resulting hypoxia could result in the release of poorly liganded Fe, generating damaging reactive oxygen species (ROS). As hypoxia is known to reduce hepcidin, this could be a potential explanation of the reduced hepcidin we found. In support of this idea, hypoxia [64] vascular dysfunction [65] and muscular and cerebral hypoperfusion [66] have been reported in ME/CFS patients. This scenario also ties in with observations of mitochondrial dysfunction and oxidative stress in ME/CFS considering the potential for increased hypoxia to increase ROS, in turn leading to mitochondrial dysfunction [3] and inflammation.
Click to expand...
 
DMissa said:
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.
Click to expand...
Thanks @DMissa for explaining the background to the research. It's really helpful to see it in context. I'm sure it's frustrating for authors for their work to be paywalled, though I guess people working in universities don't notice the problem so much as their universities pay for access to journals.

Do you think the results of this study take us further forward with definite information, or are more of a preliminary possiblity?
 
Trish said:
Thanks @DMissa for explaining the background to the research. It's really helpful to see it in context. I'm sure it's frustrating for authors for their work to be paywalled, though I guess people working in universities don't notice the problem so much as their universities pay for access to journals.

Do you think the results of this study take us further forward with definite information, or are more of a preliminary possiblity?
Click to expand...

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.
 
Thanks for replying @DMissa. No problem. I don't have the energy or knowledge to look at the detail either, so I'll leave it to others to discuss.
 
Trish said:
Do you think the results of this study take us further forward with definite information, or are more of a preliminary possiblity?
Click to expand...
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.

DMissa said:
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
Click to expand...
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
Our first major finding is evidence of persistent KP activation in ME/CFS patients as reflected by increased production of kynurenine (KYN) and increased kynurenine/tryptophan (K/T) ratio. These results indicate enhanced activity of the enzyme/s IDO-1 and/or TDO, which catalyze the conversion of tryptophan (TRP) to kynurenine (KYN).
Click to expand...
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?

As induction of IDO-1 is mediated principally by inflammatory cytokines, these results suggest the presence of ongoing long-term inflammation in ME/CFS patients.
Click to expand...
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.

The fact that increased KYN significantly correlated with symptom severity suggests a potential relationship between inflammation, KP, and symptomology in ME/CFS
Click to expand...
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.
 
Simon M said:
But I thought there was was no evidence of cytokines correlating with severity?
Click to expand...
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.
 
You must log in or register to reply here.
Back
Top Bottom