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

Andy

Andy

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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
 
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.
 
  • 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.
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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.
Sydney Morning Herald 28 Dec 2021 said:
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.
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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
Trish said:
written as a preliminary to justify a clinical trial of a nutritional supplement.
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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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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.
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Trish said:
I get the feeling this is written as a preliminary to justify a clinical trial of a nutritional supplement.
Click to expand...
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...
 
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].
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'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
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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.
 

Nutritional Aspect of Tryptophan Metabolism​


Nutritional Aspect of Tryptophan Metabolism - PMC

Mammals, including humans, can synthesize the vitamin nicotinamide from tryptophan in the liver. The resultant nicotinamide is distributed to non-hepatic tissues. We have studied the effects of changes in tryptophan–nicotinamide metabolism on niacin ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

"Mammals, including humans, can synthesize the vitamin nicotinamide from tryptophan in the liver. The resultant nicotinamide is distributed to non-hepatic tissues. We have studied the effects of changes in tryptophan–nicotinamide metabolism on niacin nutritional status. The liver plays a critical role in nicotinamide supply. Animal studies showed that the tryptophan–nicotinamide pathway is affected by physiological conditions, the presence of disease, nutrients, hormones, and chemicals."

"The processes involved in the tryptophan–nicotinamide pathway occur in the liver and kidneys. Only the liver has all the pathway enzymes. The kidneys lack several enzymes, such as TDO and kynureninase.13 To determine the tissue that plays a critical role in the biosynthesize of nicotinamide, we created animal models of renal failure and liver injury, and investigated the relationships between tissue enzyme activities and niacin nutritional status.13,14 Rats were fed a diet containing orotic acid, which induces fatty liver.14 In the fatty liver, TDO activity was decreased to 40%, the conversion ratio of tryptophan to nicotinamide to 30%, and liver NAD levels to 60% of the values in control animals. Chronic renal failure was induced by feeding an adenine-containing diet."

"Renal failure led to decreases in liver TDO, liver QPRT, and kidney ACMSD activities, and to an increase in liver ACMSD activity, causing the liver enzymes to suppress the conversion of nicotinamide to tryptophan and the kidney enzymes to enhance it. The renal failure rats showed lower blood and liver NAD levels, and conversion of tryptophan to nicotinamide, corresponding to the changes in liver enzyme activities but not in the kidney enzyme activities. These results show that the liver plays a critical role in nicotinamide supply to peripheral tissues (Fig. 2). Since the kidneys have higher ACMSD activity than the liver, and the rats with renal insufficiency showed higher serum quinolinic acid levels,15 the kidney may have the pathway to eliminate tryptophan metabolites rather than to product nicotinamide."

Has anyone seen studies that would indicate that taking something for fatty liver, maybe something like TUDCA, would improve NAD status in pwME/CFS?
 
Violeta said:
Has anyone seen studies that would indicate that taking something for fatty liver, maybe something like TUDCA, would improve NAD status in pwME/CFS?
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Shouldn't a first step be questioning whether NAD status in PWME is abnormal? Is that something that can't be measured with present technology?
 
Creekside said:
Shouldn't a first step be questioning whether NAD status in PWME is abnormal? Is that something that can't be measured with present technology?
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The Role of Kynurenine Pathway and NAD Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome​




The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PMC

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 ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
 
Violeta said:

The Role of Kynurenine Pathway and NAD Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome​




The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PMC

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 ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
Click to expand...
That is the paper this discussion thread is about.
 
Violeta said:
And maybe I should explain I posted the study again for Creekside's consideration.
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Okay, I skimmed through it, but wasn't impressed. Lots of "may" and "might" and "could" speculation. You could replace many of the factors speculated about with alien modification, curses, and astrological occurrences, without making it less meaningful. It also includes many mentions of studies with findings we're supposed to consider important, yet many of those studies are of poor quality or the findings failed in replication.

All too many papers like this harp on serotonin depletion being a cause of some ME symptoms, talking about TRP metabolism in the gut or liver, yet not mentioning that 90+% of the serotonin in the brain is manufactured in the brain, so shouldn't make much difference in brain levels. FWIW, TRP tablets made my symptoms worse (possibly raising by QUIN levels), yet 5-HTP (an intermediate between TRP and serotonin) didn't.
 
Creekside said:
FWIW, TRP tablets made my symptoms worse (possibly raising by QUIN levels)
Click to expand...

Nutritional Aspect of Tryptophan Metabolism - PMC

Mammals, including humans, can synthesize the vitamin nicotinamide from tryptophan in the liver. The resultant nicotinamide is distributed to non-hepatic tissues. We have studied the effects of changes in tryptophan–nicotinamide metabolism on niacin ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

This is exactly what the paper is talking about.

""The processes involved in the tryptophan to nicotinamide pathway occur in the liver and kidneys."
You would want the liver to convert the tryptophan into nicotinamide.
Taking more tryptophan when that's not happening, yes, will cause problems.
 
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Violeta said:

Nutritional Aspect of Tryptophan Metabolism - PMC

Mammals, including humans, can synthesize the vitamin nicotinamide from tryptophan in the liver. The resultant nicotinamide is distributed to non-hepatic tissues. We have studied the effects of changes in tryptophan–nicotinamide metabolism on niacin ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

This is exactly what the paper is talking about.

""The processes involved in the tryptophan to nicotinamide pathway occur in the liver and kidneys."
You would want the liver to convert the tryptophan into nicotinamide.
Taking more tryptophan when that's not happening, yes, will cause problems.
Click to expand...
Looking at fatty liver as a reason for decreased conversion of tryptophan to niacin.


"The effects of dietary orotic acid on the metabolism of tryptophan to niacin in weaning rats was investigated."
(Orotic acid produced fatty liver)

"The rats were fed with a niacin-free, 20% casein diet containing 0% (control diet) or 1% orotic acid diet (test diet) for 29 d."
(Niacin-free diet to see how much tryptophan is being converted to niacin)

"Retardation of growth, development of fatty liver, and enlargement of liver were observed in the test group in comparison with the control group. The concentrations of NAD and NADP in liver significantly decreased, while these in blood did not decrease compared to the control group."

"The formation of the upper metabolites of tryptophan to niacin such as anthranilic acid, kynurenic acid, and 3-hydroxyanthranilic acid were not affected, but the quinolinic acid and beyond, such as nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, were significantly reduced by the administration of orotic acid. Therefore, the conversion ratio of tryptophan to niacin significantly decreased in the test group in comparison with the control group."
 
Violeta said:
You would want the liver to convert the tryptophan into nicotinamide
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My response to TRP seemed to be due to TRP transported into my brain. Taking BCAAs along with TRP blocked (or reduced and spread out the transport) the effects. So, the liver conversion wouldn't play a role.
 
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