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A map of metabolic phenotypes in patients with ME/CFS (Hoel et al., 2021)

wabi-sabi

Senior Member
Messages
1,458
Location
small town midwest
This was my problem, I was badly hydrated. I don´t like water but I learn it fast.
Yes, this helps on orthostatic intolerance and dysautonomia. Dysautonomia is one of the possible drivers of the lack of oxygen.

The other thing to keep in mind is that these metabolic changes are part of the body trying to survive. They are evidence the body is trying hard under bad conditions. As Whitney has said in one of his blog posts- our bodies are trying so hard to fight for life. We can help them out.
 

Rufous McKinney

Senior Member
Messages
13,249
Studies have shown a tendency to hypercoagulation, or thicker blood, that has trouble getting into capillaries, starving tissues of adequate oxygen.

which is in a sense where my Chinese traditional diagnoses always includes generally, " blood stagnation". Lymph is stagnent, too. CSF also. The body is dried out a type of dryness and it needs moisture.

I have dried out eyes, tongue, throat, lungs (at a minimum). Moistening herbs are really helpful.

the non deforming red blood cells are capable of stagnating at the capillary and end organ level. We also reportedly have more "exosomes"...in our blood stream- waste products, messages and somethings.
 

Rufous McKinney

Senior Member
Messages
13,249
they studied were diabetic or prediabetic. This might be relevant.

confirmed that. (used FIND, confirm rumors)

So where does that put pwME who have prediabetic BS issues. We don't exist?

hard to believe we are largely a group with normal blood sugar.......
 

Murph

:)
Messages
1,799
Just discovered this paper and I'm loving it. We've always thought there must be subtypes. This is a good objective way of defining some - hopefully they are real not a data artefact.

What do they say about the subtypes?

Subtype 1 is moderate and thinner,
subtype 2 is more severe and fatter,
while subtype 3 is mildest and rarest and looks most like the controls.

They worry BMI differences could be driving the metabolic differences between the two major subtypes. An interesting question is whether it could go the other way: are there subtypes of ME that drive fat accumulation and subtypes that drive fat burning? (Of course, the most severe patient I can picture is w.Dafoe, he's not exactly fat!)

One take on the 3 subtypes is they may eventually shake out into:
  • type 1, type 2, and mystery;
  • type 1, type 2, and misdiagnosed;
  • alternatively the different types could be: residual flu viruses, residual enteroviruses, residual herpesviruses (similar metabolcailly to heatlhy controls because everyone has residual herpesviruses in them apparently!)

A long time ago I did a big data analysis on Naviaux's original metabolite paper:
https://forums.phoenixrising.me/thr...nified-me-cfs-theory.55801/page-4#post-931517

https://forums.phoenixrising.me/thr...ic-encephalopathy-cfs-fluge-et-al-2016.48446/ Fluge and Mella have done two similar analyses since. This is their second sample, with some overlapping results and some divergent. I may dive in again. Since 2016 I've learned a whole new statistical software so my ability to cut up the dataset should be a lot better. Plus having three separate analyses to compare means the field is screaming out for a meta-analysis.

ADENOSINE

I remain really fascinated by the role of adenosine in this illness and once again it stands out in their data. However this time Adenosine levels are very high in their plasma readings! Naviaux found it was low. Very odd. I need to see if I can figure out why or if this is all just random red herrings. (Herring very prevalent in Norway, perhaps less so in San Diego! ;))

Anyway, if adenosine is high, it could be important.

I was reminded of an important role for Adenosine a few days ago when I read about it online (https://www.theatlantic.com/science/archive/2018/01/the-mystery-of-sleep-pressure/549473/) - adenosine makes you sleepy! Might be a clue to the fatigue we experience there. But more importantly, adenosine is a product of the breakdown of ATP, and ATP is a molecule cells pump out when they are stressed.

There are many types of cells and many types of stress but one I'm interested in is the physical stress that red blood cells experience when they try to fit through an insufficiently dilated blood vessel. They jostle and distend, making them release ATP. That signal is meant to make the blood vessel dilate in response. What if it doesn't? Do the red blood cells pump out still more? And does the blood get full of ATP which we break down into adenosine, making us sleepy? Could that tie the metabolic data we have here to the circulatory/bloodflow theories going around? Might it also explain that one study that found we were making lots of ATP? This might be where all that energy goes!

I bet there's more insights in there too.
 
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Murph

:)
Messages
1,799
Screen Shot 2022-09-29 at 1.33.10 pm.png

WHAT IS MAKING US SICK?

Above is an interesting table from the supplementary materials. It shows things patient plasma was uniformly low in (left side, under the heading "down") and things they were high in (right side, under "up).

It also shows whether being low or high was positively or negatively associated with four other factors: age, bmi, steps and self-reported functioning (sf36). What you're looking for is something that if you're low in it, makes you feel worse and take fewer steps each day, but isn't associated with age or bmi. Kynurenate is the best example: me/cfs patients are low in it, and the lower we were ,the less steps taken per 24h. it's not correlated with age or bmi so it is hopefully a pure indicator of severity.

DOGS, TRAPS, PROOF

When you go to the wikipedia page for kynurenate you learn a couple of things. One is that it was first discovered in dog urine and is in fact named after dog (Kyn in Greek) urine. But more importantly that it is made by breaking down tryptophan. Does that mean Robert Phair (@HTester) onto something with his tryptophan metabolic trap work? I'm not sure.

There are two main subgroups defined in this work by Fluge and Mella. One has high tryptophan but low kynurenate. That certainly looks like there might be a failure to break down tryptophan, which is I believe the key idea in the metabolic trap hypothesis. (the other subgroup is low in both). It highlights the importance of defining the subgroup in which that trap might apply.

However (one of) Phair's theories is about the IDO enzyme that breaks tryptophan into the intermediate molecule kynurenine. Whereas Fluge and Mella's data shows kynurenine is normal, it is kynurenate which is low.

I know Fluge, Mella and Phair have been at conferences together and I have no doubt Phair has seen this data long before publication. @HTester if you'd like to weigh in here on whether or not this data makes you want to slide down the catabolic chain to look at the breakdown of kynurenine into kynurenate, please do!

WHAT CAN I DO?

While Phair continues his modelling, you might be thinking about how to get better. Can you raise your kynurenate? one answer: Keto diets may raise levels of kynurenate in the brain (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359463/).

If you're looking at ways to lift your levels of kynurenate that are plausibly safe and have anecdotal support in me/cfs - that may, maybe, possibly, be one. This has been studied because epilepsy is associated with low kynurenate and keto diets are good for epilepsy. (it makes me wonder if me/cfs is associated with epilepsy, i must say i've not heard patients mention epilepsy in these pages much.)

Campesterol and also undecenoylcarnitine c111 (no link, science doesn't seem to know anything about this one) show the same pattern as kynurenate: low in patient plasma and the lower you go the less steps you take.

Thyroxine is the opposite: high and the higher you go the fewer steps you take. It is the thyroid hormone. Why is it high? I don't know but the full data shows we are low in the precursor amino acid, tyrosine, so it's not that we have too much of that. Another mystery!
 
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Messages
600
Quote from the paper

There was a particular loss of some phospholipids containing linoleic acid (18:2). This fatty acid is an essential precursor for arachidonic acid, a central messenger molecule linked to inflammation and vasodilatation. The lowering of arachidonic acid derivatives such as 12-HETE and 12-HHTrE further indicate that auto- and paracrine processes may be affected. As further discussed below, some of these effects may be associated with mechanisms likely to be involved in symptoms of ME/CFS.
 

Murph

:)
Messages
1,799
View attachment 49446
WHAT IS MAKING US SICK?

Above is an interesting table from the supplementary materials. It shows things patient plasma was uniformly low in (left side, under the heading "down") and things they were high in (right side, under "up).

It also shows whether being low or high was positively or negatively associated with four other factors: age, bmi, steps and self-reported functioning (sf36). What you're looking for is something that if you're low in it, makes you feel worse and take fewer steps each day, but isn't associated with age or bmi. Kynurenate is the best example: me/cfs patients are low in it, and the lower we were ,the less steps taken per 24h. it's not correlated with age or bmi so it is hopefully a pure indicator of severity.

DOGS, TRAPS, PROOF

When you go to the wikipedia page for kynurenate you learn a couple of things. One is that it was first discovered in dog urine and is in fact named after dog (Kyn in Greek) urine. But more importantly that it is made by breaking down tryptophan. Does that mean Robert Phair (@HTester) onto something with his tryptophan metabolic trap work? I'm not sure.

There are two main subgroups defined in this work by Fluge and Mella. One has high tryptophan but low kynurenate. That certainly looks like there might be a failure to break down tryptophan, which is I believe the key idea in the metabolic trap hypothesis. (the other subgroup is low in both). It highlights the importance of defining the subgroup in which that trap might apply.

However (one of) Phair's theories is about the IDO enzyme that breaks tryptophan into the intermediate molecule kynurenine. Whereas Fluge and Mella's data shows kynurenine is normal, it is kynurenate which is low.

I know Fluge, Mella and Phair have been at conferences together and I have no doubt Phair has seen this data long before publication. @HTester if you'd like to weigh in here on whether or not this data makes you want to slide down the catabolic chain to look at the breakdown of kynurenine into kynurenate, please do!

WHAT CAN I DO?

While Phair continues his modelling, you might be thinking about how to get better. Can you raise your kynurenate? one answer: Keto diets may raise levels of kynurenate in the brain (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359463/).

If you're looking at ways to lift your levels of kynurenate that are plausibly safe and have anecdotal support in me/cfs - that may, maybe, possibly, be one. This has been studied because epilepsy is associated with low kynurenate and keto diets are good for epilepsy. (it makes me wonder if me/cfs is associated with epilepsy, i must say i've not heard patients mention epilepsy in these pages much.)

Campesterol and also undecenoylcarnitine c111 (no link, science doesn't seem to know anything about this one) show the same pattern as kynurenate: low in patient plasma and the lower you go the less steps you take.

Thyroxine is the opposite: high and the higher you go the fewer steps you take. It is the thyroid hormone. Why is it high? I don't know but the full data shows we are low in the precursor amino acid, tyrosine, so it's not that we have too much of that. Another mystery!

This new study by Hanson also finds low kynurenate:

https://www.mdpi.com/1422-0067/24/4/3685

"Kynurenate is part of the tryptophan pathway and is one the metabolites with the most
drastic difference in correlation coefficients between the ME/CFS and the control cohorts"
the paper says. "
The results "attest to a profound dysregulation of this pathway in the ME/CFS patients com-
pared to the controls."