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A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Fluge, Mella et al

Discussion in 'ME/CFS research' started by Sly Saint, Aug 23, 2021.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    Abstract


    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established.

    We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

    In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

    https://insight.jci.org/articles/view/149217
     
    Ariel, FMMM1, Nellie and 50 others like this.
  2. Midnattsol

    Midnattsol Moderator Staff Member

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    Oh wow, a lot to dig into here! But no time/energy this week :(

    It looks very exciting, although I'm sceptical of how they "controlled" for the diet of the participants. Looking forward to have a more thorough look at the metabolites included in these analyses!
     
    Last edited: Aug 23, 2021
  3. Rain

    Rain Senior Member (Voting Rights)

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    «Our comprehensive evaluation of possible cofounders such as sex, BMI, age, diet, or medication did not indicate that these were main drivers of the ME/CFS phenotypes, but they may contribute to individual variation »
     
  4. Midnattsol

    Midnattsol Moderator Staff Member

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    By looking at xenobiotic compounds (written in supplementary material), many of the other metabolites are also influenced by diet.
     
  5. Hoopoe

    Hoopoe Senior Member (Voting Rights)

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    I benefit from carnitine supplementation. Would this be predicted for any metabolic phenotypes described here?
     
  6. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    Summary based on quotes from the text:

    Based on metabolites tested, ME/CFS were divided into three groups (M1, M2, M3). There was relatively little overlap between the health controls (HC), ME-M1, and ME-M2 clusters, whereas the ME-M3 subset was positioned as a merger phenotype between the 3 others.
    upload_2021-8-23_22-0-57.png
    Overall, the patterns that separated the ME/CFS subsets were dominated by lipid and amino acid metabolites.
    • The ME-M1 metabotype appears to reflect a lipolytic state with increased utilization of both fatty acids and amino acids as energy substrates, possibly due to ineffective carbohydrate catabolism. The ME-M1 subset presented elevated serum levels of free fatty acids (i.e., NEFA) and ketone bodies, despite normal glucose and insulin. This may resemble a context with physiological correlations to glucose starvation and exercise.
    • The ME-M2 metabotype shows indications of disrupted control of lipid metabolism, possibly involving compromised activity of mitochondrial oxidation pathways and consequent effects on lipid trafficking and storage. In the ME-M2 subset, a different metabolic profile was expressed by the elevated serum TAG and insulin mean levels, yet blood glucose was not affected. This may reflect low-grade signs of lipid-induced insulin resistance associated with ectopic peripheral lipid accumulation and inflammatory responses.
    • The ME-M3 subset was found to reflect an intermediate state between the 2 other ME/CFS metabotypes, albeit with some more similarity with the ME-M2 phenotype.

    Both the ME-M1 and ME-M2 subsets convincingly expressed contexts of underlying energy strain, as further supported by the elevation of metabolic stress hormones such as FGF21 and FABP4.

    The following seems to be the main hypothesis:

    "The observed metabolic effects may be associated with tissue hypoxia caused by an underlying pathology related to an autoimmune mechanism. An autoantibody-mediated mechanism may influence, indirectly or directly, the fine-tuned autoregulation of blood flow required to meet the metabolic demands of tissues. Endothelial dysfunction has been shown in patients with ME/CFS (65, 66), and this was also supported in substudies linked to the CycloME and RituxME trials. [...] These findings pointing to vascular dysfunction support that exertion-triggered tissue oxygenation may be impaired, and clearly this would contribute to lowered activity tolerance and involve mitochondrial energy metabolism."​
     
    bobbler, Amw66, Ariel and 46 others like this.
  7. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Another key finding buried in the text:

    Which rules out HPA axis related hypotheses.

    Also:
     
  8. Midnattsol

    Midnattsol Moderator Staff Member

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    While none of the patients had a diagnosis of prediabetes, some of them (eight from Figure 3C) have glucose readings above 6.0mmol/L which is the criteria for prediabetes in Norway. The criteria for diabetes is above 7mmol/L, and two patients are above 8mmol/L while another might be above 7mmol/L. I hope that they are not diagnosed mean that they have been checked out for this, but that might not be the case as sometimes people find out they have a marker for disease by taking part of a study (currently in Norway people taking part in the HUNT study, and also I think the Tromsø Health Study, have been told they have previously undiscovered celiac disease).
     
    sebaaa, alktipping, MEMarge and 12 others like this.
  9. Milo

    Milo Senior Member (Voting Rights)

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    Do you mean A1C? Diabetes is not typically diagnosed from 1 single random glucose. The A1C represents a value that represents the bigger picture and a longer term (last 3 months) of the blood glucose.
     
    Last edited: Aug 24, 2021
  10. Midnattsol

    Midnattsol Moderator Staff Member

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    No, regular glucose. Since it doesn't say HbA1c in the plot or table of clinical values I assume that's what's been measured. The patients can have normal HbA1c values, but that's not clear from the paper. I'm also making the assumption that the blood was sampled when patients were fasted, as that is a requirement when looking at TAG (it says the blood for the clinical test was done following standard procedure. For the metabolomics blood there was a mix of fasted/non-fasted participants).
     
  11. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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  12. Grigor

    Grigor Senior Member (Voting Rights)

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    Hmm, so unlike other researchers. Are these researchers suggesting that this is one condition with different phenotypes?
     
  13. Milo

    Milo Senior Member (Voting Rights)

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    I think it’s inevitable that there will be different phenotypes. I would suggest there are others with different diagnosis.
     
  14. Campanula

    Campanula Established Member (Voting Rights)

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    From what I gather the different phenotypes refer to different strategies of compensating for the energy strain that they describe. So the underlyting energy strain seems to be more fundemental, whereas the compensatory mechanisms the body chooses to use to try to adapt to it, are more diverse. The common mechanism that underlies it all seems to be tissue hypoxia according to their model (according to their previous article in JCI):

    "Endothelial dysfunction with inadequate flow regulation to meet the demands of tissues, reduced venous tone and return, and reduced cardiac output on exertion as well as AV shunting with reduced peripheral oxygen extraction would all result in tissue hypoxia, which we believe may be a common pathomechanistic denominator in ME/CFS" (Bolding mine)
     
  15. tuha

    tuha Established Member (Voting Rights)

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    I really like this hypothes. How difficult it is to prove that there is that problem with tissue hypoxia and endothel dysfunction?
     
  16. Campanula

    Campanula Established Member (Voting Rights)

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    I like it as well. I think blood flow problems are definitely an important aspect of my own illness. Unsure whether autoantibodies are what's behind it though, but I guess we'll see if this pans out in the future?

    When it comes to endothelial dysfunction, there's already been three studies that have discussed this, as far as I know, but I haven't looked into them in detail. Here they are, for anybody interested:

    1. Blausteiner et al.
    2. Scherbakov et al.
    3. Sørland et al.
     
  17. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    Myalgic encephalomyelitis associated with cellular energy strain

    by University of Bergen

    https://medicalxpress.com/news/2021-08-myalgic-encephalopathy-cellular-energy-strain.html
     
  18. Tia

    Tia Senior Member (Voting Rights)

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    A hypothesis that makes sense to a non scientist like me and resonates with my own experiences. Any idea what the 'lack of physical activity' bit in the last line of the article above means? Does it mean that it could be the lack of physical activity in severe patients which could provoke the body to make the metabolic adaptation rather than the other way around? I don't understand.
     
  19. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    Weird my wife takes carnitine (post antibiotic) and my daughter has disabling fatigue.

    Carnitine "transports long-chain fatty acids into mitochondria to be oxidized for energy production" [Wiki] so I'm guessing that if you increasing your dependence on fatty acids [for energy], i.e. due to ME/CFS, and didn't have enough carnitine then yes carnitine supplementation might help - I'm a lay person by the way.

    The GWAS study might help to understand this study (and indeed others) @Simon M
    These studies are telling us outcome but not the underlying cause [I think!] ---- GWAS might help by providing clues to genes which protect and increase risk of developing ME/CFS.

    The references to "endothelial and microcirculatory dysfunction effects on vascular endothelium" made me think of @Snow Leopard
     
  20. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    Yea that's a common concern i.e. how do you get adequate controls to assess the affect of sedentary behaviour?
     

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