1. Guest, the 'News in Brief' for the week beginning 26th September 2022 is here.
    Dismiss Notice
  2. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

Pre-Illness Data reveals Differences in Multiple Metabolites and Metabolic Pathways in Those Who Do and Do Not Recover from IM, 2022, Jason et al

Discussion in 'ME/CFS research' started by Simon M, May 26, 2022.

  1. Simon M

    Simon M Senior Member (Voting Rights)

    Messages:
    649
    Location:
    UK
    Pre-Illness Data reveals Differences in Multiple Metabolites and Metabolic Pathways in Those Who Do and Do Not Recover from Infectious mononucleosis

    https://pubs.rsc.org/en/Content/ArticleLanding/2022/MO/D2MO00124A

    Leonard Jason, Karl Conroy, Jacob Furst, Karthik Vasan and Ben Katz

    Abstract
    Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS.

    4,501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during Infectious Mononucleosis (IM), and at a 6 month follow-up for those who recovered versus (N=18) versus those who went onto develop ME/CFS 6 months later (N=18).

    Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways. The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response. Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%.

    These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.
     
    Last edited by a moderator: May 26, 2022
  2. Andy

    Andy Committee Member

    Messages:
    17,519
    Location:
    Hampshire, UK
    Going by recent papers from Jason, 'severe ME/CFS' just means that the person meets two or more ME selection criteria.
     
    Michelle, merylg, Joh and 15 others like this.
  3. Peter Trewhitt

    Peter Trewhitt Senior Member (Voting Rights)

    Messages:
    2,876
    Great to see these results.

    I had hoped there would be people somewhere doing the same in relation to Covid 19, there was such an opportunity to look at a whole population in the early stages of the pandemic and then follow up over several years.
     
  4. Midnattsol

    Midnattsol Moderator Staff Member

    Messages:
    2,346
    It might be still possible, at least in Norway some of our long-running cohort studies have pre-pandemic blood available for metabolomics. The one I'm most familiar with has focused mostly on lipids though, with blood sampled in 2006-2008.
     
  5. butter.

    butter. Senior Member (Voting Rights)

    Messages:
    155
    This will turn out to b a very important paper. I can already see how people sleep on it and its vast implications. Mitochondrial dysfunction predates what people consider their trigger.
     
    merylg, Forbin, Starlight and 4 others like this.
  6. voner

    voner Senior Member (Voting Rights)

    Messages:
    156
    sous-bois, Forbin, Grigor and 7 others like this.
  7. voner

    voner Senior Member (Voting Rights)

    Messages:
    156
    here is an quote from the paper:

    we selected three major ones including the Fukuda et al. criteria,(15) the Canadian Consensus Criteria,(16) and the Institute of Medicine criteria(17). Those who met more than one case definition (i.e., the Fukuda and either the Canadian and/or Institute of Medicine criteria) were defined as having severe ME/CFS.

     
    cfsandmore, merylg, Joh and 10 others like this.
  8. Andy

    Andy Committee Member

    Messages:
    17,519
    Location:
    Hampshire, UK
    Thanks, as I suspected. I am really concerned about this rebranding of the term 'severe ME'. For patients, and many other people, severe ME denotes a certain, serious, level of impairment; if this attempt to redefine it catches on I can easily see it used by anybody who wants to downplay the severity of a patients suffering.

    "Severe ME? That just means you meet two selection criteria, it doesn't mean you can't work or need those benefit payments."

    And what happens if you are a severe (by the 'old' definition) patient who happens to only meet one definition? Are you then reclassified as moderate? mild? even less deserving?
     
    katrinapears, Michelle, Ali and 17 others like this.
  9. Trish

    Trish Moderator Staff Member

    Messages:
    42,224
    Location:
    UK
    I agree it's a serious problem. Perhaps we need to write to the research team.
     
    ahimsa, Joh, Ariel and 14 others like this.
  10. Mij

    Mij Senior Member (Voting Rights)

    Messages:
    6,274
    I'm curious, is MS defined as serve, moderate or mild?

    I personally prefer relapsing-remitting because we can go from mild, moderate or severe within a week.
     
    merylg, Mithriel, Starlight and 4 others like this.
  11. Hutan

    Hutan Moderator Staff Member

    Messages:
    20,490
    Location:
    Aotearoa New Zealand
    It's open access if you sign up. I think the settings on my computer prevented me from accessing the study via Voner's link.

    Gender skew - not as substantial as is often quoted.
    Edit - it isn't clear to me from the paper if the 18 subjects with 'severe ME/CFS' are all of the people who developed 'severe ME/CFS'.



    This previous paper provides more details about the study (link is to the S4ME thread)
    (11). Jason LA, Cotler J, Islam MF, Sunnquist M, Katz BZ. Risks for developing ME/CFS in college students following infectious mononucleosis: a prospective cohort study. Clin Infect Dis 2021;73:e3740–9.
     
    Last edited: May 27, 2022
    Michelle, merylg, alktipping and 8 others like this.
  12. Hutan

    Hutan Moderator Staff Member

    Messages:
    20,490
    Location:
    Aotearoa New Zealand

    Screen Shot 2022-05-27 at 9.04.12 am.png
     
  13. Hutan

    Hutan Moderator Staff Member

    Messages:
    20,490
    Location:
    Aotearoa New Zealand
    It will be interesting to see if DecodeME finds any genetic issues relating to these metabolites and pathways.
     
  14. Hutan

    Hutan Moderator Staff Member

    Messages:
    20,490
    Location:
    Aotearoa New Zealand
    Re spermine and spermidine:
    This study found that the ME/CFS group had lower spermine, but higher spermidine. It's a very interesting finding.

    Searching the forum, the only mention of spermine and spermidine is a paper about treatment of Covid-19. The two molecules seem to have a role in autophagy.

    There's a 2014 paper about the function of spermine and spermidine:
    This 2014 paper reported that, unlike for spermidine 'there is no known function that is exclusive to spermine', although it is assumed to be important for something, given there is gene for spermine synthase (which produces spermine from spermidine). It sounds as though the effectiveness of the human synthase gene is variable.
    Low spermine creates issues with oxidative stress.
    At the organism level, mutations in the spermine synthase gene can be lethal, and can cause severe problems in animals including Snyder-Robinson syndrome.

    The 2104 paper gives ratios for spermine to spermidine in lymphoblasts of healthy controls and of people with the harmful mutation. It would be very interesting to know what ratio is in people with ME/CFS. Looking at Table 1 above, any change in ratio looks to be subtle, certainly compared with the differences in the ratios of people with Snyder-Robinson Syndrome. I'm not seeing a lot of similarities between ME/CFS and the syndrome:
    Degree of disability isn't well related to the spermine:spermidine ratio, so there are other things going on. Also, the spermine synthase gene seems to be on the X chromosome - meaning that women should be protected somewhat from harmful mutations, which doesn't fit with the gender ratio of ME/CFS.

    Regulation of ion channels

     
    Last edited: May 27, 2022
  15. Midnattsol

    Midnattsol Moderator Staff Member

    Messages:
    2,346
    For this study data was also collected in 2019, but as far as I know metabolomics has not been done. I think it is planned, but when it's only recently been done for the last data collection it could take a while. In response to the pandemic participants were also asked to contribute to an extra set of questionnaires and samples, and they started collecting this extra data from sept. 2021 and it is still ongoing (the cohort is a representative sample from a whole county, and to collect data a team travels around and stays for a number of days at various locations). I don't know if the other longitudinal cohort studies in Norway are doing something similar, they have many things in common but also some differences.
     
    Michelle, merylg, Ariel and 5 others like this.
  16. mariovitali

    mariovitali Senior Member (Voting Rights)

    Messages:
    446
    Michelle, merylg, Hutan and 3 others like this.
  17. Simon M

    Simon M Senior Member (Voting Rights)

    Messages:
    649
    Location:
    UK
    I've got mixed feelings about this study (I've only read the abstract and the comments here, especially from Hutan).

    Strengths
    1. It's a prospective study.

    The great thing about this study is that it collected Baseline data before people developed glandular fever, and then recovered or developed ME CFS.

    2. The study used strict (Bonferroni) statistical correction for multiple comparisons. That decreases the chances that these are chance findings.

    3. The metabolic differences are consistent with (though don't prove) the pro-inflammatory cytokine changes previously found in the same cohort.

    Weaknesses
    1. It's a small study, with only 18 people in each group (recovered/developed "severe" ME/CFS).

    2. As many others have pointed out, there's no good rationale for the study's definition of "severe" as meeting two different criteria. I'm pretty sure this was not specified in the study design. So I'm guessing it popped up when they started data analysis, which is a little concerning.

    It would be interesting to see results for the full recovered versus ME/CFS cohorts.

    3. Are the metabolic differences clinically significant?

    Looking at table 1, the absolute differences in mean metabolite levels are rather small. Is there any evidence that these have any clinical meaning?

    Although spermine does play a role in a pro-inflammatory response, like spermidine, it also plays an essential role in all animal and plant cells. It's a leap to say that these small differences are connected to a difference in cytokine responsiveness and an ability to fight infections.

    That's the nature of metabolites: the role of many of them isn't well understood and they often have multiple roles. That gives researchers a lot of scope to link metabolites to many different biological processes. Whether or not those links are important in the real world.
     
    Last edited: May 29, 2022
    merylg, Michelle, FMMM1 and 15 others like this.
  18. Forbin

    Forbin Senior Member (Voting Rights)

    Messages:
    1,581
    Location:
    USA
    It seems like a large sample size (4,501), so you’d think that the fact that half of the college age participants who came down with infectious mononucleosis (18/36) went on to develop ME/CFS would be a headline in and of itself.

    Even if it were confined to “college age” participants, if that proportion were confirmed, you’d think it would be a pretty big deal.

    [Not that I’m suggesting EBV is the sole cause of ME/CFS].
     
  19. rvallee

    rvallee Senior Member (Voting Rights)

    Messages:
    9,336
    Location:
    Canada
    Somehow news that MS is largely caused by mono barely made the news either. It did get some coverage but considering that this is identifying the cause, you'd think there would be major interest. So no surprise this doesn't get much interest.

    I'm not sure what's going on as this should be major news and maybe lots are happening in secret, behind closed doors, but even in medical news and forums this seems to have gotten very little interest and isn't moving the needle much on anything, as if the idea is so unappealing that most don't want it to be true.

    There's something about medicine and rejecting the germ theory of disease that just continues to plod along, like they have to believe that illness must exactly match injury, if it doesn't, ignore. Only a severe infection can cause severe illness, mild infections must only cause minor, temporary, problems. It's really hard to understand other than from the endless obsession with blaming everything on psychology instead.
     
  20. LarsSG

    LarsSG Senior Member (Voting Rights)

    Messages:
    229
    The two groups of 18 are just the "severe" ME patients and 18 matched controls selected for this specific metabolic investigation. Their previous paper showed 23% meeting any one of the three criteria and 8% more than one criteria at six months. Still a lot, but not 50%.
     

Share This Page