A New Decade of ME Research: The 11th Invest in ME International ME Conference 2016
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Insights into ME/CFS phenotypes through comprehensive metabolomics (Lipkin, Hornig)

Discussion in 'Latest ME/CFS Research' started by Murph, Jul 4, 2018.

  1. Murph

    Murph :)

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    Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics
    Scientific Reportsvolume 8, Article number: 10056 (2018) | Download Citation

    Abstract
    The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls.

    We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.
     
  2. Murph

    Murph :)

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    FULL TEXT https://www.nature.com/articles/s41598-018-28477-9

    Question: Is this finally that analysis that we've been hearing for years Lipkin would do when he had the money? I reckon yes - these samples are four years old!

    Also a note: the title to this thread omits a LOT of impressive names who are listed as authors on this paper. Apologies to them.

    Here's a few key excerpts:

     
    Last edited: Jul 4, 2018
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  3. percyval577

    percyval577 Knight

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    Ive just read the article, a bit complicate written for me. S.3:

    "Among the top plasma biomarkers differentiating ME/CFS patients from controls were

    decreased levels of
    betaine, complex lipids (lysophosphatidylcholine [LPC], phosphatidylcholine [PC]) and sphingomyelin (SM),

    and increased levels of
    triglycerides (TG), alpha-N-phenylacetyl-glutamine, epsilon-caprolactam and urobilin ..."
    Also increased (table2) is phosphatidylethanolamine (PE).

    They could (somehow) come to the result of a dysregulation of the choline-carnetine pathway, as they say on S.3.



    S. 5-6 (results) shows up correlations with fecal bacteria, including "sympton severity".
    S. 6: (discussion). "Plasma levels of 5-MT, a compound related to tryptophan, serotonin and melatonin metabolism, were decreased..." but their data were due to medications of the patients not sufficient.


    S. 7: "ME/CFS is a heterogeneous disorder."
     
    Last edited: Jul 4, 2018
  4. Murph

    Murph :)

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    Re-read it. Six thoughts

    1. They confirm some of the previous metabolomic findings - ceramides and phospholipids.
    2. They find (yet) another subgroup that can confound metabolomic findings - having IBS.
    3. Gut Bacteria matter - they can help identify the disease.
    4. They include 9 men in the 50 patients and 9 in the 50 controls, and this adds no statistical power on the male side, while diminishing statistical power on the female side. Not sure it's worth it.
    5. A treatment idea: They find some possible reasons to take b-vitamins.
    6. These topological maps are interesting to look at but I can't get much out of them in terms of actionable ideas, beyond the fact that the connections look mostly non-random (i.e. There's *something* there.)

    41598_2018_28477_Fig3_HTML.jpg
    Topological data analysis (TDA) revealed altered metabolomic and metagenomic profiles in ME/CFS. The color scheme represents the strength of association with ME/CFS diagnosis (white: strongly associated with control, red: strongly associated with ME/CFS). Each node in a network comprises 1 or more subject(s) who share variables in multiple dimensions. Lines connect network nodes that contain shared variables and subjects. Unlike traditional network models wherein each node reflects only a single sample, the size of a node in the topological network is proportional to the number of variables with a similar profile. (A), (B) and (C) integrate plasma metabolomic, fecal metagenomic and plasma immune profiles, and symptom severity scores using the Jaccard metric to define multidimensional subgroups. Irrespective of the lenses used [(A) neighborhood lenses NL1 and NL2, (B) MDS coordinate 1 and 2, and (C) metric PCA 1 and 2], ME/CFS and control samples formed distinct networks. ME/CFS and control samples also formed distinct networks in TDA based on either fecal bacterial relative abundance or plasma metabolomic data in isolation using a variance normalized Euclidean distance metric with neighborhood lenses (NL1 and NL2). Fecal bacterial relative abundance features (D) were stronger drivers of the network distinction than plasma metabolomic features (E).
     
  5. Neunistiva

    Neunistiva Senior Member

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    I'm not sure if I would call this a subgroup because I had ME/CFS for 6 years and was already mostly bedridden by the time I developed IBS. I accidentally drank a yogurt that has expired and a few hours later I developed IBS that hasn't stopped to this day, 3 years later.

    It wouldn't make sense that I would be categorized into different subgroups just because I got tested pre-yogurt or post-yogurt.

    So I wonder, instead of a being a distinct subgroup, if we don't all just have a predisposition to develop IBS and whether we have it or not just depends on whether we ran into a trigger or not, and then our metabolic profile changes (and probably gut microbiome).

    Did anyone else develop IBS or stop having IBS while having ME/CFS?
     
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  6. jpcv

    jpcv Senior Member

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    @Neunistiva
    I did develop IBS after I became sick with ME/CFS
     
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  7. Neunistiva

    Neunistiva Senior Member

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    How long after?
     
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  8. jpcv

    jpcv Senior Member

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    A few months, I remember that 6 months after my initial symptoms I did a colonoscopy, so at that time I was already having gut disturbances
     
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  9. Learner1

    Learner1 Forum Support Assistant

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    PE would be increased because its not converting to PC? This might affect cell and mitichindrial membranes.

    https://en.m.wikipedia.org/wiki/Phosphatidylethanolamine_N-methyltransferase

    I had a couple of PC IVs recently and felt markedly better after each.
     
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  10. percyval577

    percyval577 Knight

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    I don´t know, I asked myself though.
    Maybe the body wants or wants not to build membranes?
    Accordingly, whats about the free TG´s? whatfor?

    Or can it be understood by a lactate-mechanism?
     
    Last edited: Jul 5, 2018
  11. Learner1

    Learner1 Forum Support Assistant

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    Part of it could be that they're destroyed faster than they can be made, and also that the making of them is slowed down. At least that's the theory my doctors are working with based on some other data points.

    This might have some clues, but it's a little
    dense:

    https://bmccellbiol.biomedcentral.com/articles/10.1186/s12860-014-0043-3

     
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  12. Diwi9

    Diwi9 Senior Member

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    I am also curious if the results are skewed in the IBS group as so many of us take on specific diets to help control symptoms. I don't recall any mention of this in the paper.
     
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  13. percyval577

    percyval577 Knight

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    To me the paper does not look like an attempt to understand anything. It´s even written somehow, well confuse might be said to much.

    Only a lot of different people if Ive grasped it right have paid a lot of effort to the huge amount of investigations and findings announced there, and that´s it.

    So, the findings I would guess to be right (but to be independtly confirmed of course), and any further guesses are still be to figured out.

    Also, one must say that the paper does not dig into manny (possible) subgroups, whatever special there might occure.
    But I guess the databank the findings are steert to can reveal then at some point.
     
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  14. percyval577

    percyval577 Knight

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    Could be, but to be honest it seems to me a baby-step-theory.
    Most often doctors are not the ones who are able to come up with theories and would think in a new direction on their own. And the next patient is already waiting (anyway).
    I know there are a lot of very engaged doctors, doing a lot for the patients even not being paid for. I have met doctors when they go home in the evenning. But all effort they spend will not enable them to come up with a nice theory (new guess).
     
  15. Learner1

    Learner1 Forum Support Assistant

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    Er, why not?
     
  16. Murph

    Murph :)

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    me too
     
  17. SherDa

    SherDa

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    Does this fall under the theory that the pyruvate dehydrogenase enzyme is inhibited? This would result in decreased production of acetyl coenzyme A and acetyl CoA is needed to produce acetylcholine. Without acetylcholine, the nervous system wouldn't be able to function, so it's very vital to life. It only recently occurred to me that the cell membranes act as a reservoir of choline to make acetylcholine. Choline can also be made in the liver from methionine. Carnitine is also made from methionine (plus lysine). Lysine degrades to acetyl CoA and is a ketogenic amino acid that would likely get burned for energy if fat and carbs cannot be burned.

    I'm trying to put the pieces together, but I feel like I'm not quite getting the big picture. My fatigue and brain fog seem to be caused by lack of acetylcholine (central nervous system fatigue/central command fatigue/bonking/whatever you want to call it). However, just taking acetylcholine precursors/cofactors doesn't entirely fix me, just almost entirely. The choline needs to be acetylated by acetyl CoA before it becomes acetylcholine, and I think that's the rate-limiter for me. I believe acetyl CoA is made from lysine and cysteine (which would be derived from methionine if sufficient cysteine is not gotten through the diet). I mean technically every protein made in the human body would require methionine as it is always the start codon. Lysine is a pretty high order amino acid too; it's very vital to human health.

    So low lysine would result in recurrent viral infections (which I had when I got sick). Low methionine could conceivably cause lack of monoamine neurotransmitter production, lack of carnitine, lack of glutathione... (all of which I seem to have). And the low acetylcholine could cause gut problems/dysbiosis. Could it be so simple as a choline/amino acid deficiency for some of us? I can see that my hair and skin are depleted of something, likely cysteine and/or lysine. I could be way off track, but my response to these supplements (acetylcholine support, acetyl CoA support, phospholipid replacement therapy) suggests that I'm not. It's just so hard to tell if it's just a Band-Aid or if I'm discovering my root cause.

    I guess that's a really long way of saying that I'm not surprised they found phospholipid/choline/carnitine aberrations.
     
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  18. SherDa

    SherDa

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    Yes, I would love to know if this affects mitochondrial membranes, especially the inner mitochondrial membrane where the electron transport chain is. A leaky membrane here could result in a lot of oxidative stress?
     
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  19. Murph

    Murph :)

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    Sounds like you understand it somewhat better than most of us! I'd be interested to hear more of your thoughts.
     
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  20. Learner1

    Learner1 Forum Support Assistant

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    I've been in the same boat...we kept solving these amino acid problems til my doctor ordered 40g a day of a custom amino powder.

    These are things that my doctors have been looking at. I think these may be a part of the puzzle, but not sure they'll solve the various immune issues.
    Wonder how Mestinon figures in here? What are you using to support acetyl CoA? Pantethine, BCAAs? And are you using oral or IV phosphatidyl choline, NT Factor, or??
     
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