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The Role of Kynurenine Pathway and NAD + Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2022, Dehhaghi et al

Discussion in 'ME/CFS research' started by Andy, Jun 4, 2022.

  1. Andy

    Andy Committee Member

    Hampshire, UK

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness.

    Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS. TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions. The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities. Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS.

    This review discusses the potential association of altered KP metabolism in ME/CFS. The review also evaluates the role of the patient’s gut microbiota on TRYP availability and KP activation. We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS. Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS.

    Open access, http://www.aginganddisease.org/EN/10.14336/AD.2021.0824
    sebaaa, Ravn, Hutan and 5 others like this.
  2. Trish

    Trish Moderator Staff Member

    I can't follow all the details of this paper, but out of curiosity I checked the references given to support the claim that depression and mood disorders are common in people with ME/CFS.

    Only 3 references are given
    [59] Maes M, Mihaylova I, Kubera M, Leunis JC, Twisk FN, Geffard M (2012). IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression. Metab Brain Dis, 27:415-423.
    The other 2 are Crawley studies
    [73] Crawley E, Hunt L, Stallard P (2009). Anxiety in children with CFS/ME. Eur Child Adolesc Psychiatry, 18:683-689. [74] Bould H, Lewis G, Emond A, Crawley E (2011). Depression and anxiety in children with CFS/ME: cause or effect? Arch Dis Childhood, 96:211-214

    Hardly a sound basis for building that part of the hypothesis.

    At a glance the rest seems to be hypothesis built on hypothesis built on assumptions.

    I get the feeling this is written as a preliminary to justify a clinical trial of a nutritional supplement.
  3. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    While of course the quality of a paper should speak for itself, publicity like this around the supervising and correspondence author does create a credibility problem.
    The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS 2019 Kashi, Davis, Phair.
    Jaybee00, cfsandmore, Wyva and 3 others like this.
  4. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    From Gilles Guillemin's Linked In page - just a few recent connections from the list.
    It doesn't seem as though the recent bad publicity has affected the offers of senior roles in organisations developing and selling medicines/supplements.
    Again, certainly not proof that the posted paper is
    but Guillemin certainly has multiple pipelines to fund research and promote products should a nutritional supplement seem to have some scientific foundation.

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    cfsandmore and Trish like this.
  5. Ravn

    Ravn Senior Member (Voting Rights)

    Aotearoa New Zealand
    Haven't read the paper, only looked for a section that declares conflicts of interest, there doesn't seem to be one, which is a bit odd. Sign of a less than stellar journal?

    Supplements to raise NAD+ must be some of the more trialled ones, anecdotally and in a few studies of varying quality, with only the usual mixed results of possibly some minor improvement for some but not others. So...
    cfsandmore, Trish and Hutan like this.
  6. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    Yep, I'd characterise this paper as a naive and biased romp through the ME/CFS literature.
    It covers epidemiology:
    'Differences in laboratory methodologies' causing problems in the estimation of ME/CFS prevalence?

    Umm, the Office of the Privacy Commissioner of Canada is not the first source I would have thought of when wanting an ME/CFS prevalence rate in United Kingdom adults. Possibly that's why they ended up with a figure (13.4%) for 'chronic fatigue' that is vastly different to most estimates of ME/CFS prevalence.

    I was going to go on and provide a link to the forum thread setting out the issues with the Castro-Marrera study of NAD+ supplementation trial that is referenced in the paper, but, as fun as pulling apart the paper is, there are better things to do.

    People with ME/CFS deserve much better research and hypothesising than this. The paper has just created more distracting noise.
    cfsandmore, Ravn, CRG and 2 others like this.
  7. Creekside

    Creekside Senior Member (Voting Rights)

    Decide what figure supports your paper best, then search all available data for the best match?

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