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

[Andy]

Abstract

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

 

[Trish]

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.

 

[Hutan]

• Mona Dehhaghi1, 2,
• Hamed Kazemi Shariat Panahi1,
• Bahar Kavyani1,
• Benjamin Heng1, 2,
• Vanessa Tan1, 2,
• Nady Braidy3,
• Gilles J. Guillemin1, 2,

1. Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, NSW, Australia.
2. PANDIS.org, Australia.
3. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.

* Correspondence should be addressed to: Dr. Gilles J. Guillemin, Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, NSW, Australia. Email: gilles.guillemin@mq.edu.au.

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.

They include neuroscientist Gilles Guillemin, whose name is attached to 25 articles that have been red-flagged for containing potentially doctored images on a research discussion website and scientist Bingyang Shi, who was a co-author of five papers where the journal has acknowledged errors post-publication.
...
In 2019, she raised concerns on PubPeer – a website where scientists discuss published research – about images contained in six papers co-authored by Professor Guillemin, prompting him to ask her whether her investigations were random or targeted. She said in reply that she was reviewing papers by one of his co-authors, who worked at a separate institution, while following dozens of leads across biomedical literature.
...
Then in September this year, science blogger Leonid Schneider exposed more claims against Professor Guillemin after Dr Bik and other anonymous PubPeer reviewers identified unexpected similarities among images contained in a further 17 articles co-authored by him.

 

[Hutan]

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

written as a preliminary to justify a clinical trial of a nutritional supplement.

but Guillemin certainly has multiple pipelines to fund research and promote products should a nutritional supplement seem to have some scientific foundation.


Chief Investigator
ARC Training Centre for Facilitated Advancement of Australia’s Bioactives (FAAB)ARC Training Centre for Facilitated Advancement of Australia’s Bioactives (FAAB)Jan 2022 - Present · 6 mos
https://www.faab.edu.au/rushmore_teams/prof-gilles-guillemin
Expertise in testing the anti-inflammatory, anti-oxidant, neuroprotective, toxicity, immune regulation, activities of natural molecules.

Supported by the $4,997,903 ARC grant over five years, Macquarie’s new ARC Training Centre for Facilitated Advancement of Australia’s Bioactives (FAAB) will bring together Deakin University, the University of SA and Western Sydney University with research universities in the UK, Germany and Brazil, and 14 respected Australian industry partners, to develop products of high molecular complexity that can relieve chronic and acute health problems.

Member of the Scientific Advisory Board
Viome Research Institute Feb 2021 - Present · 1 yr 5 mos

Now, through advancing technology in metatranscriptomics and machine learning models, Viome is utilizing groundbreaking techniques to identify the patterns for optimizing human health and overcoming chronic diseases, cancer, and aging.

Scientific Advisory Board
Patagonian Natural Resources in Translational Biomedicine (PatBio)
Feb 2021 - Present · 1 yr 5 mos


Member of the Scientific Advisory Board
Implicit Bioscience · ContractImplicit Bioscience · Contract Feb 2018 - Present · 4 yrs 5 mos


Chair of the Scientific Advisory Board
Metabrain Research

Metabrain Research is a Biopharmaceutical company developing innovation for Health Industry. We develop preventive and / or therapeutic solutions to cure pathologies linked to metabolic aging (Obesity, Diabetes, NASH, Sarcopenia, Depression and Cog...

 

[Ravn]

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

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...

 

[Hutan]

Yep, I'd characterise this paper as a naive and biased romp through the ME/CFS literature.
It covers epidemiology:

The exact prevalence of ME/CFS remains controversial; however, a large number of studies reported a significant prevalence of ME/CFS among adults [6, 18-20]. This controversy is due to several factors ranging from differences in the laboratory methodologies and the type of population surveyed for definition and determination of the disease [21-25].

'Differences in laboratory methodologies' causing problems in the estimation of ME/CFS prevalence?

According to the Office of the Privacy Commissioner of Canada (OPC), ~27% of adults in the United Kingdom suffer from chronic fatigue which accounts for the prevalence rate of 13.4% in that population

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.

 

[Creekside]

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.

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