If its an unidentified substance then we simple do not know. However absolute amounts in, for example, the peripheral blood might not be very important. This is because local concentrations might be quite high(or low) in some places. Also timing is important. The timing of release of a factor may mean that some periods have a lot released, and some not much. This can alter the body response, and indeed the body looks at changes in some factors, not just amounts. In the worst case, with circadian factors, the body response can be quite different at various times of the day, regardless of the time averaged amount in the peripheral blood. Its a deeply complex story, and requires lots of rigorous investigation.
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Is ME a metabolic problem or a signalling problem?
- Thread starter Trish
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On a large blood protein, while it might result in signal, it might not be a signalling molecule. There might be sensors that detect it and react, such as if its a foreign protein or abnormal.
It might even hide from investigation as its misfolded, and the absolute numbers or concentrations look OK, but nobody is distinguishing between misfolded, unfolded or properly folded proteins. I had this concern with some imported mitochondrial proteins, as if reduced glutathione is low they might not be properly folded in the mitochondria. Many assays tell you total concentrations or amounts of proteins, but do not assess folding.
It might even hide from investigation as its misfolded, and the absolute numbers or concentrations look OK, but nobody is distinguishing between misfolded, unfolded or properly folded proteins. I had this concern with some imported mitochondrial proteins, as if reduced glutathione is low they might not be properly folded in the mitochondria. Many assays tell you total concentrations or amounts of proteins, but do not assess folding.
AliceLily
Senior Member (Voting Rights)
Yes. I had a permanent microbiome change after an infection when I was 20 years old, 1984. The infection was treated and cleared but left me with a completely different makeup. Not normal at all. I personally think that this permanent microbiome alteration set off a much larger problem over time.
So what originally had been a local problem eventually became seriously systemic with ME/POTs ten years later via a flu-like cold onset.
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mariovitali
Senior Member (Voting Rights)
I will second the potential role of glutamate and also add that of excitotoxicity because of impaired Glutamate clearance. Apart from magnesium (which is an NMDA inhibitor as someone mentioned) i would also propose pyridoxal phosphate (Vitamin B6) and FMN to be further investigated (note kynurenine below) :
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517396/
The latest results from the techniques i use also identify a potential central role of Nitric Oxide and its signalling function, i will post more in the "Machine Learning" thread as soon as i have results from the latest algorithmic runs.
jamari
Established Member (Voting Rights)
It's an interesting idea and I heard Ron Davies talking about this. There are alot of patients who are fed by tube or w.e as they're too sick to consume normal food. When they came to testing the microbiome, there wasnt one..
If the microbiome is at the root of the disease, then it is hypothesised that it's not "something in the blood" but "something is missing from in the blood".
I personally think the gut problems in patients is a secondary problem.
My daughter had a minor surgery, it became infected, the hospital gave her several IV antibiotics, and she picked up Clostrium difficile in the hospital (our Canadian hospitals had thousands of deaths from this--and simple bleach kills the bug, but the cleaning here is slovenly), and after 4 months of virulent c-difficile, this nightmare illness struck, virtually over night.
Kitty
Senior Member (Voting Rights)
I've been hesitating to comment, as I feel so lacking in knowledge, but does the 'sickness behaviour' response come into this anywhere?
ME has always felt to me like having a virus, the varying levels of severity representing different points in the arc of the immune response. I can only distinguish between a nasty cold and an ME flare when my nose starts (or fails to start) streaming.
It may be that this response is, or might be, triggered by some of the factors you're discussing – in which case I'll sit down and carry on listening with interest!
ME has always felt to me like having a virus, the varying levels of severity representing different points in the arc of the immune response. I can only distinguish between a nasty cold and an ME flare when my nose starts (or fails to start) streaming.
It may be that this response is, or might be, triggered by some of the factors you're discussing – in which case I'll sit down and carry on listening with interest!
Forbin
Senior Member (Voting Rights)
Interesting. I haven't heard of this before. If a patient were fed intravenously (paraenteral feeding), I could see the gut microbiome being so starved of nutrition that it eventually "disappears."
In enteral tube feeding, on the other hand, nutrients are still delivered to the gut, so I'd be surprised if the entire gut microbiome were to vanish in that case. There do seem to be papers on changes in the gut microbiome during enteral tube feeding, however.
Still, the point is well taken that the disease can't be perpetuated by something in the gut microbiome if there is no gut micobiome.
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Except that it can be filtered out, apparently. I would like to see something on this formally published so we can check the details.
AliceLily
Senior Member (Voting Rights)
Gut symptoms are secondary/downstream for me also but I personally think that there could have been an original problem in the gut for some, a small (?) subgroup where changes in the gut triggered their ME at some further point. If so, I feel for them because they will have even more awful symptoms gut wise than those of us for whom it is secondary.
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boolybooly
Senior Member (Voting Rights)
Both is the right answer IMHO since you ask. What you have to bear in mind @Trish is that most disease symptoms are caused by the immune response to the disease pathogen rather than by the pathogen itself.
The immune system is a complex web of sensors, signalling systems and effectors. Its the effector systems which fight pathogens and make us feel ill but effectors are switched on by signals sent by sensors.
IMHO it is possible that immune dysfunction is an immune response, like running a temperature only different, which has the advantage of changing energy production so it is less favourable for pathogens and lets our cells have an advantage or at least takes an advantage away from pathogens.
So if the metabolic dysfunction is an immune effector system then it is possibly being activated by a signal, possibly a bad signal or a dodgy sensor. Either situation would lead to a signal molecule in the blood which might rapidly transform metabolic processes in a cell which receives the signal. That is the kind of effect you would expect from an immune signal triggering an immune response.
Which is is why discovering the nature of any signal should be the top priority in ME research right now to help untangle the knot of causation and help with discerning subtypes so that future cohorts are better selected and replicability improves.
2c
The immune system is a complex web of sensors, signalling systems and effectors. Its the effector systems which fight pathogens and make us feel ill but effectors are switched on by signals sent by sensors.
IMHO it is possible that immune dysfunction is an immune response, like running a temperature only different, which has the advantage of changing energy production so it is less favourable for pathogens and lets our cells have an advantage or at least takes an advantage away from pathogens.
So if the metabolic dysfunction is an immune effector system then it is possibly being activated by a signal, possibly a bad signal or a dodgy sensor. Either situation would lead to a signal molecule in the blood which might rapidly transform metabolic processes in a cell which receives the signal. That is the kind of effect you would expect from an immune signal triggering an immune response.
Which is is why discovering the nature of any signal should be the top priority in ME research right now to help untangle the knot of causation and help with discerning subtypes so that future cohorts are better selected and replicability improves.
2c
And is there anyone working on this?Both is the right answer IMHO since you ask. What you have to bear in mind @Trish is that most disease symptoms are caused by the immune response to the disease pathogen rather than by the pathogen itself.
Which is is why discovering the nature of any signal should be the top priority in ME research right now to help untangle the knot of causation and help with discerning subtypes so that future cohorts are better selected and replicability improves.
2c
Yes, Davis' group. It's over two years ago now when they detected the "something in the blood" (or more precisely in the serum) factor, which makes ME/CFS cells behave abnormally, but I still haven't heard much updates about it, other than that exosomes might be involved. Right now they seem very committed, perhaps too much, to the metabolic trap hypothesis.
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At one level the problem is simple i.e. because we know some things. E.g. if you review Karl Morten's work then you can see that healthy muscle cells + exosome (fraction) from ME plasma = a change in oxygen consumption (energy production) compared to plasma from healthy people. From this the obvious conclusion is that it's a signalling factor in the blood which causes a change in cellular energy production - metabolic effect.
We know a few other things as well e.g.:
- it's reversible - Ron Davis's plasma switch experiment; and
- there's an increase in the number of exosomes in people with ME i.e. compared to healthy people [Maureen Hanson - presentation at Invest in ME Conference 2019].
However, we don't know precisely what the signalling factor is. Maureen Hanson highlights some candidates in her presentation; also, Bhupesh Prusty highlights some at the end of his presentation [NIH Conference April 2019]. I assume that you need both the compound causing the effect and it's associated receptor e.g. a simple contender would be a microRNA and its associated (target) gene. Hanson doesn't think a single microRNA will be diagnostic for ME (presentation) so possibly this also indicates that the signalling compound is not a single microRNA.
You're aware that Robert Phair's kynurenine samples are in the queue to be analysed on a high sensitivity Mass Spectrometer (hopefully the results will be out for the Symposium). I'd suggested on the mother ship (Phoenix) that they should take the exosome fraction and test it to see if they can identify the cells which are producing the exosomes and look for the signalling compound.
Maybe we should also be cautious here i.e. ask if we really need to know the signalling mechanism. Perhaps it's enough to know whether copaxone, or SS-31, work i.e. improve the activity levels of people with ME. Also, we can answer some questions i.e. who has this switch in cellular energy production - Karl Morten's assessment of cellular energy production is one contender, Ron's nano-needle is another one.
Which reminds me - why do we still not have a test which establishes whether people with ME have this switch in cellular energy production?
Barry
Senior Member (Voting Rights)
I'm non-medical, but interested nonetheless, but this question likely naive.
Why is it obviously a signalling factor in the blood? Could it not be some other non-signalling serum effect inhibiting/blocking the cells' energy processing in some way? And if it is a signalling factor, could it be a) the serum inhibiting the normal cellular signalling, or b) the serum partially superimposing some of its own spurious signals on top of the normal signals?
Note I'm not arguing against what you are saying (I don't have the knowledge for that anyway), just wanting to understand.
No, your question is not naive --- not until we know the answer (which may be some time).
I'm not medical either but Fluge and Mella published this statement "According to this model, ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor, which ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms." [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].
I think you're correct i.e. it could e.g. be some crud [from Bhupesh Prusty? - check out the last slides in his NIH talk (April 2019)], rather than a (specific/deliberate/designed) signalling factor, which causes what Naviaux calls the "cell danger response".
It may be "normal" in the sense that Naviaux described a "cell danger response". However, if it is then it's presumably a currently unknown response -- even relatively recently I seem to have noticed new findings e.g. you can re-set autoimmunity by giving the target sequence in isolation (recent discovery of an existing mechanism).
Why get hung up on what it theoretically is; rather than just chucking it into a mass spectometer and see if that tells you what it is and/or what cells it originates from?
Also why get hung up on not knowing what it is/how it functions? I still recall @alex3619 advice about type 2 diabetes - along these lines- it's possible to diagnose and treat it but the underlying mechanism isn't understood. Why not do the same for ME?
Check out Vicky Whittemore's comments at the Invest in ME Conference 2019 - patients should lobby their elected representatives i.e. for funding for research --- I do a little of that.
That research funding would mean that you could chuck it into a mass spectrometer and possibly find out what it is -- and yes I am being simplistic!
Saz94
Senior Member (Voting Rights)
Some reflections from me on this topic, as I am currently experiencing some worsening as a result of PEM.
It (my current worse-than-usual cognitive state) doesn't feel like a reduction in energy production. It feels like there's some kind of blockage in my brain. So I wonder whether overexertion causes certain chemicals to be produced which then cause this state? (Which then apparently just never leave my brain, if the overexertion was big enough to make me permanently worse?)
Or do they somehow cause some kind of lasting damage in my brain? (I don't think it's that, because I've been able to have flashes of times with better cognition.)
I think inflammation is somehow involved, for me at least, because anti-inflammatories (ibuprofen and curcumin) improve my cognition, and taking an increased amount of them during PEM gets rid of the PEM (well, it did... I can't do this anymore because I've reached the max dosage of both).
When I first started taking curcumin, I remember very clearly that I thought "I don't feel like I have more energy, I feel like a massive blockage in my brain has disappeared, so that I can use my brain more without it being exhausting".
(Incidentally, the curcumin didn't seem to affect my physical capabilities at all, although it did reduce my orthostatic intolerance a little.)
This is obviously not scientific, but from my perception of my experience of ME, it seems like overexertion causes the inflammation in my brain to grow, this will shrink back down to usual level as the PEM passes, unless I am unable to rest adequately, in which case the increased inflammation is here to stay. Unless I take more anti-inflammatory. And if I go too long between doses of anti-inflammatory (for example if I sleep for 12 hours straight), then the inflammation grows bigger, although it then goes back down to normal size once I'm back on track with the doses.
I am not necessarily sold on the inflammation theory, but it is clear that curcumin has some kind of effect on me, and ibuprofen to a lesser extent (I wouldn't have noticed the effect of the ibuprofen if my ME wasn't severe, such that a tiny effect is noticeable). But then, plenty of PWME don't seem to benefit from curcumin, so... it's very confusing.
It (my current worse-than-usual cognitive state) doesn't feel like a reduction in energy production. It feels like there's some kind of blockage in my brain. So I wonder whether overexertion causes certain chemicals to be produced which then cause this state? (Which then apparently just never leave my brain, if the overexertion was big enough to make me permanently worse?)
Or do they somehow cause some kind of lasting damage in my brain? (I don't think it's that, because I've been able to have flashes of times with better cognition.)
I think inflammation is somehow involved, for me at least, because anti-inflammatories (ibuprofen and curcumin) improve my cognition, and taking an increased amount of them during PEM gets rid of the PEM (well, it did... I can't do this anymore because I've reached the max dosage of both).
When I first started taking curcumin, I remember very clearly that I thought "I don't feel like I have more energy, I feel like a massive blockage in my brain has disappeared, so that I can use my brain more without it being exhausting".
(Incidentally, the curcumin didn't seem to affect my physical capabilities at all, although it did reduce my orthostatic intolerance a little.)
This is obviously not scientific, but from my perception of my experience of ME, it seems like overexertion causes the inflammation in my brain to grow, this will shrink back down to usual level as the PEM passes, unless I am unable to rest adequately, in which case the increased inflammation is here to stay. Unless I take more anti-inflammatory. And if I go too long between doses of anti-inflammatory (for example if I sleep for 12 hours straight), then the inflammation grows bigger, although it then goes back down to normal size once I'm back on track with the doses.
I am not necessarily sold on the inflammation theory, but it is clear that curcumin has some kind of effect on me, and ibuprofen to a lesser extent (I wouldn't have noticed the effect of the ibuprofen if my ME wasn't severe, such that a tiny effect is noticeable). But then, plenty of PWME don't seem to benefit from curcumin, so... it's very confusing.
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The brain has the property, if I am recalling this correctly, of shutting down function under low energy. That might mean capacities are partially blocked. The brain does not necessarily decline in function evenly. Cheney was the first to discuss this in respect to ME in that we lose function in ways that resemble heart failure. In short, it seems like the lower our energy the lower our cognitive faculties. There has been woefully inadequate research on this.
The first specific reference that I'm aware of was (December 2016) in this paper by Øystein Fluge and Karl Tronstad "Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome" [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. You might want to check Karl Tronstad's presentation at the Invest in ME Conference this year []. My impression is that Karl states that the regulation of pyruvate dehydrogenase is very complex - which suggests to me that identifying what is changing cellular respiration is not easy.
Check out Maureen Hanson's presentation at the Invest in ME Conference - there's an increase in exosomes in ME. Also, from memory when you remove the exosomes the cells return to normal; however, this is presumably not conclusive i.e. there could be something else that's roughly the same size as exosomes - suggests that it is in the exosomes.
I assume that you can identify the proteins in exosomes using mass spectrometry - potentially thereby identifying the "parent" cells - however, I don't think you could separate out the exosomes causing the problem.
Dr Vicky Whittemore (NIH) at Invest in ME Conference (2019):
"advocacy groups --- that's what makes the difference -
- when they [elected representatives] hear that, from people with the disease -
- advocates -- telling them [elected representatives] what's needed is really what makes the difference"
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