Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?, 2022, Kavyani

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers. To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP). KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.


Open access, https://link.springer.com/article/10.1007/s00018-022-04380-5

 

Betteridge's law of headlines suggests no.

edit - seriously, the title of the article is a bit misleading given the content that discusses a whole lot of other things.

 

A couple of things.

1) (related) Since I could not see author contributions listed in this paper and I am in the author list, FYI I was asked to write a mitochondrial section for this paper while I was going through a severe period of physical disability last year and early this year - so my contribution is limited to dictating out the mitochondrial section.

2) (unrelated) I had recently said I would stay away from s4me to give people the space to be totally candid in their discussion of work relating to me. Honestly, a lot has changed for me lately. Between the aforementioned health issues, a bit of maturing, and some growth as a scientist, I have come to some realisations:

-fierce motivation to combat misunderstood disability strengthened by my lived experience. I want to participate in and advocate for research + discussion that is genuinely productive. People living through this evil thing deserve decisive action and solutions. Since there so much that I can learn from you folks, it would be more productive for me to absorb your comments than to remain removed. Having seen recent discussion in other threads I'm pretty confident that the chance of my presence won't actually be a barrier to open discourse. If I ever write or do something that isn't great, please don't hesitate. I want to be the most useful scientist I can be. I need your help for that. I'm only at the start of my journey. Many of you have been doing this longer than I've been alive.

 

One of the criticisms of the mitochondrial section is the lack of discussion about whether respirometry, gene expression and proteomics of PBMCs is even relevant atl all. Aside from the comment at the end "If present in cell types or bodily tissues other than immune cells..."

There is no fundamental reason why the metabolic processes in muscle fibres or in the brain during activity has anything to do with the metabolism of PBMCs due to not only being different cell types, but the importance of physiologically relevant microevironments. This is doubly so when the cells have been cultured before testing.
I mean I can understand if one was trying to link a metabolic problem of specific PBMCs (and given the hypothesis in the article - say: microglia and macrophages) with disturbed function and in turn demonstrate specific altered physiological pathology. But no one has gone to those lengths empirically.

But for the article overall, in general, any sort of hypothetical model needs to predict actual physiological dysfunction that coincides with symptom kinetics as well as a demonstrable feedback mechanism for chronic perpetuation. The only thing in the paper along those lines is the claim of "loss of glial cells and neurones" but the actual explanation is rather vague.

While there is some indirect evidence, such as the cited KA/QA ratio, the effect itself was quite weak and probably not a sensitive predictor. Testing CSF might be interesting, but it begs the question as to why such an effect hasn't already been found in prior CSF studies.

Such as the following study from 1992 that tested CSF from CFS patients (why wasn't this cited!?!?!?!?)
"Quinolinic Acid and Kynurenine Pathway metabolism in Inflammatory and non-inflammatory neurological disease"
https://pubmed.ncbi.nlm.nih.gov/1422788/

And in fact they did find increased QA in CSF. Hmm!


Another (uncited) study that tested serum of patients:
"Isoprenoid pathway dysfunction in chronic fatigue syndrome"
https://www.cambridge.org/core/jour...gue-syndrome/169077A0E9F69764D94E1781F552686F

There might be more, but that's it for now.

Also, both seem to be missing from the similar and recently published article that Daniel didn't contribute to:
"The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116917/

 

@DMissa , perhaps you can comment on my hypothesis about dietary niacin causing suicidal moods. I started getting suicidal moods soon after developing ME. I eventually figured out that the severity correlated with both TRP and dietary niacin. So, my hypothesis is that ME causes elevated QA, which causes suicidal moods, and that in the absence of dietary niacin, the cells produce more enzyme to convert QA to NAD, thus reducing QA levels. Taking a niacin tablet would then reduce production of that enzyme, and QA would build up. IIRC, the mood change occurred hours after the niacin tablet (or food); certainly less than a day.

 

Thanks Snowy. I can always count on you for this kind of useful scrutiny. And yes, you are right - there is no intrinsic reason for a link. Multi-system epigenetic changes could be one explanation if a phenotypic pattern is present across multiple body systems/tissue types. Currently pursuing work with other tissue types and also epigenetics work to test this. Once everything is better characterised across the other sample types and epigenetics, etc, we can think in greater detail about physiological implications (If there are any physiological implications!). I would not want to stretch the results from this one sample type towards whole-body physiological conclusions. I think I have tried my best to avoid this in the past.

With regard to specifics, by my own admission - I feel that much of my thinking during my PhD tunnel-visioned too closely on cellular function as I learned all of those details along the way. Working to get better at this and to work now with a greater awareness of physiological context. A lot of this reflection was actually prompted by your comments that I had seen over recent years as well as by others here, so thank you.

Hey there Creekside, thanks for sharing these insights but unfortunately I don't feel qualified to really comment about this.

 

Thank you, Hutan. I am glad to take part in whichever way is appropriate and productive. The driver for why we work in this field should always be community centred... wanting people to get better. I try to osmose this mentality to new students.

I will raise this tomorrow.

I think there is a traditional mentality of keeping things under wraps until final in science. I understand why it is necessary in many cases (eg: non-final data or conclusions, confidentiality/IP, lack of time, etc), but there's probably a balance to be struck here. Perhaps as times change this kind of crosstalk will become more commonplace. It can also be kind of anxiety-inducing at times (well, for me), so maybe that's a factor. I'm really not sure.

I appreciate your kind nature as always. I agree that the crosstalk is very important for productive research and learning. Every avenue for getting this thing figured out as soon as we can should be utilised.

 

I sort of wish that @Hutan would have put a trigger warning thing on her post to force me to read through the entire abstract before I read through her post to see what I would have noticed.

1) yes it’s important to have a concise, well written abstract.

2) Not a defense, but sometimes the abstract is the last thing written — https://harzing.com/blog/2020/06/writing-your-abstract-not-a-last-minute-activity
and doesn’t get the scrutiny the rest of the paper does. Sometimes there are many versions of the abstract depending on the journal word count/format. Maybe an earlier version of the abstract had a lower word count and the author realized s/he could add an additional ~50 words and did this without concurrence of the other authors.

3) The journal itself does have some responsibility for catching typos as the journals have proof readers.

 

Next time one of your colleagues complains about "reviewer #2" being too critical of their paper, remind them that patient reviews of their peer-reviewed manuscript are often much harsher.

 

Wow, that could be so valuable, but as @DMissa notes, trust and non-disclosure would have to be tightly established. I guess we can only stick our hands up and wait to be independently invited to review via a shared Word document or similar. Perhaps we all just need an app - "it's like Uber but for peer review"

 

Sorry to hear you had a tough time @DMissa. Ill health/disability sucks.

But glad to see you back and really appreciate your openness and willingness to engage.

Like others here I got confused reading the paper. The title made me expect a hypothesis paper but the the first half or more was essentially a stand-alone review of the current state of affairs, and there've been a few of those lately. So this part of the paper could have been shortened significantly by referring to one of the recent reviews and/or heavily summarising. All we really need to know from this section is that we don't know much with any certainty and therefore any reasonable and testable hypothesis that may guide future research is potentially useful.

A more concise review section - and one focused primarily on existing KP research - would have given more room to flesh out the KP hypothesis section of the paper.

I've only skimmed that part of the paper so far, partly because I'd run out of reading spoons by the time I got there and partly because I don't have the biochemical knowledge to judge the hypothesis itself anyway. However, I did notice two important things missing.

1) A clear outline of how to test the hypothesis.

2) An explanation of how the hypothesis accounts for delayed PEM. PEM (though not the delay aspect) is mentioned in the review part of the paper (mostly by Daniel ) but there's no mention of PEM at all in the hypothesis section.

Speaking more generally, both omissions have been notable features in other recent hypothesis papers, too. The standard model for ME hypothesis papers seems to be to try and force-fit every finding or observation ever made in ME, no matter how tenuous, into a greater whole - but with the glaring omission of delayed PEM.

Poorly defined PEM may or may not get a vague mention along the lines of 'ROS may explain PEM' (but how? by what mechanism?) but that's about it. This puzzles me. Authors spend a great deal of energy on trying to account in detail for all manner of weak and contradictory 'evidence' in their hypotheses, no matter the quality and reliability of the original studies, yet they ignore the arguably weirdest and most specific phenomenon in ME.

And finally the section on testing the hypothesis typically stretches to little more than a perfunctory paragraph of vagueness.

Ok, so maybe I'm exaggerating a little bit to make my point, but not by an awful lot I don't think.

There's nothing wrong with big picture hypotheses. They're important and necessary. It's equally important and necessary to go back to the detail frequently to check the building blocks are solid and, importantly, to replace them if they're not. We need both. Just like we need people to look at dysfunction at all levels of the organism - and talk to each other about their ideas and findings. Temporary tunnel vision can be a good thing, it helps get the detail right. What needs to be avoided is blindly going down rabbit holes, something that can happen to big picture just as easily as to detail-oriented folks if they don't talk enough to sufficiently many people outside their own echo chamber.

I consider your "tunnel-vision" focus on cellular function to be an important contribution to the overall process @DMissa, don't be hard on yourself. The question 'what sort of mitochondrial dysfunction, if any, is there in ME' is an important one to answer with good data. Once we're on solid ground we can look both up- and downstream. What could cause this type of dysfunction and how can we test if our guess is correct? And the other way, what sort of effects would this sort of dysfunction have at the molecular, cellular, tissue, organ and body level and how can we test for these effects? Do we actually see them in pwME? Clearly, that's too much to ask any one individual researcher to answer. But that's what collaborations are for, including with patients. So thanks again for having the courage to engage Daniel .

Trigger warning plenty more examples to be found in the rest of the paper should you wish to test you proofreading abilities.

 

Probably not.

I wondered why Gilles' Twitter was deleted, this is probably why:

https://www.smh.com.au/national/mac...suspected-research-fraud-20211214-p59hfr.html

Sounds like a guy who just wants his name on papers with no effort whatsoever.

 

Hey everybody. Sorry for the absence, have been overwhelmed with work.

This discussion is important and don't worry about scaring me away or anything.

I have raised the concerns herein with my colleagues with a mind to avoid this in the future.

I hear you all.

Also, regarding the discussion of some kind of formal patient advisory group - we have been discussing it. It's complicated; a formal process, non-disclosure, boundaries, trust, etc would be required. I'm not sure what will be decided in the end but I can at least tell you it's being genuinely weighed up.

I agree and it's part of why I'm here.