A Metabolic Trap for ME/CFS?

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The article mentions IL-6 and IL-10 being higher in the chronically ill.

Gordon around 16:30 to 20:00 talks about IL-6 and IL-10 being 'running hotter' in CFS patients after infectious mononucleosis, in the video posted above. This guy is really on to something!
Loved the video @Belbyr. Thanks for posting. However in his paper on the work in 2012 he presented this
Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue
Link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480896/
Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-γ also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls.
I'd have to rewatch the video to see it what specific context he mentions IL6 and IL10. From Figure 1 in the paper the effect of IL6 looks small compared to the cytokines 8 and 23

This study by Broderick et al looked at Cytokine signatures in ME/CFS and GWI and found males and females behaved differently. Exercise also changed cytokine expression significantly.
A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome
Link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698072/

Montoyas 2017 study added a correction factor for gender but did not present results separated. IL6 and IL10 were not mentioned in the abstract
Cytokine signature associated with disease severity in chronic fatigue syndrome patients
https://www.pnas.org/content/114/34/E7150

So it seems it's more complicated......................

ETA: In Broderick's 2012 paper he says this and provides examples of differences in other studies.
When comparing this work with results from other studies it is important to remember the type of sample and the specific patient population studied.
In an attempt to address some of these questions, this secondary analysis has focused specifically on a group of female adolescents diagnosed PI-CFS as the result of a uniform and known pathogen, namely EBV.
 
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Tally

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Remember when this article came out recently around Christmas:

https://www.cnn.com/2018/12/17/heal...e-immune-system-trigger-study-intl/index.html
The article mentions IL-6 and IL-10 being higher in the chronically ill.
Please keep in mind that despite what the article or the authors say this study has absolutely nothing to do with CFS. It was a study on hep C patients who developed prolonged fatigue due to interferon-alpha treatment.

It was also a study conducted by King's College London shudder

David Tuller explained it nicely here http://www.virology.ws/2019/01/07/trial-by-error-more-thoughts-on-the-interferon-study/
 

Belbyr

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Please keep in mind that despite what the article or the authors say this study has absolutely nothing to do with CFS. It was a study on hep C patients who developed prolonged fatigue due to interferon-alpha treatment.

It was also a study conducted by King's College London shudder

David Tuller explained it nicely here http://www.virology.ws/2019/01/07/trial-by-error-more-thoughts-on-the-interferon-study/
I understand that, there is correlation as Cort J pointed out.
 

nandixon

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From NOVA article
…..
Presenting a completely different cohort to the ME/CFS study, Gulf War veterans suffering GWI ...... Looking primarily at the immune signalling and detoxification pathways, they were eventually able to achieve 90 per cent accuracy in distinguishing between the groups. As with the post-infectious ME/CFS patients, phenylalanine suppression was found to be the characteristic factor.

In 2012 and 2015 papers Armstrong et al also pointed out phenylalanine was decreased in the blood.
Just making a note here for myself because I didn't read the NOVA article the first time around, and to clarify for others, that “phenylalanine suppression” is referring to suppression of the phenylalanine pathway. Therefore, the patients referred to would likely have been found to have increased blood (serum/plasma) levels of phenylalanine. Whereas most ME/CFS patients, as Armstrong found, are more likely to have decreased levels.

There's probably not a discrepancy though because the (potential) ME/CFS patients in the article are only 24 months out from having had infectious mononucleosis.
 
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@mariovitali

Hi,

I am a very severly affected patient from Austria with a bell scala of 0.

I think you could be onto something.

Liver (high enzymes early on in my disease, gigh bile acids postprandial 2 hours), Gallblader and Digestion (Sibo, Maldigestion, Malabsoprtion and fat stool), muscle wasting, itching and severe PEM are my main issues.

I also have POTS, MCAD and EDS.

So it is most likely only one of many issues, but probably important and maybe actionable.


So what is the status quo?


Thank you!
 

pattismith

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Predicting exactly how it will be impaired is complicated by the enzymology of the first enzyme in the pathway from Trp to serotonin. That enzyme is tryptophan hydroxylase and it has at least two isoforms, TPH1 and TPH2. The dogma is that TPH1 is the peripheral isoform and TPH2 is the brain isoform. So if the dogma is correct, then we'd expect serotonergic nerves in the midbrain to express TPH2 and serotonin-producing cells in the gut to express TPH1. This matters because TPH1 is reportedly substrate inhibited, just like IDO1, and TPH2 is not substrate inhibited.

So with all those reported results taken as facts, we'd predict too much serotonin in the brain and too little serotonin in the gut.

Would this theory fit with the high women/men ratio for ME/CFS?


(Knowing that estrogens increase serotonin by TRPH activation + MAO inhibition, an excess of serotonin in the brain may be more sensitive?)
 

nandixon

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Looks like the IDO trap is something of substance in this article as well.

https://forums.phoenixrising.me/ind...bad-wiring-the-systems-biology-session.59778/
Interesting - In the part of the article that refers to IDO (aka IDO1), which is Dr Keith Kelley's work, on the face of what's presented there (without any additional information) the findings/hypothesis do not appear to be consistent with Dr Phair’s work. Under Dr Phair's metabolic trap hypothesis it is necessary to turn IDO1 back on, whereas Dr Kelley (who apparently is not a ME/CFS researcher per se) would want to turn IDO1 off:

The key message of Kelley’s presentation was that he has uncovered a factor in the brain (Indoleamine 2,3 Diooxygenase – (IDO)) that appears to determine whether several of the symptoms of ‘sickness behavior’ are temporary in nature (as they are supposed to be) or become a permanent part of someone’s life. Because human brain experimentation is ethically limited, most of this work is done by infecting laboratory animals with a pathogen and then exploring what happened in their central nervous systems. This research [has] nothing to do with the pathogen per se and everything to do with finding a ‘switch’ that gets turned [on] and, instead of resetting itself when the pathogen has been cleared, remains turned on, causing sleep problems, fatigue, depression, etc.

IDO seems to be one of the switches that does exactly this…turn it on and you get a lethargic, sick looking mouse. If I understand it correctly, Dr. Kelley has been able to engineer an IDO deficient mouse which showed no signs of illness after it was infected; it didn’t stop running at night, it didn’t seem lethargic…..that mouse just hummed away because the switch that turned on the ‘sickness behavior’ in the brain – had been removed.
…..
Since Dr. Kelley believes these problems are largely immune-based, it wasn’t surprising to see him mention immune agents that he felt might be helpful in fighting inflammation-induced fatigue or pain or depression or other symptoms associated with infections. Dr. Klimas noted that she was trying tumor necrosis factor inhibitors, and there they were right at the top of his list. The list included (262:48)

• TNF inhibitors
• IL-1 receptor antagonists
• Cox-1 and 2 inhibitors
• p38 and JNK inhibitors
• MCP-1 Blockade
Indoleamine 2,3 Diooxygenase Blockers
• IL-17 and IL-23 Inhibitors
• M2 alternative macrophage differentiation
• Antibiotics (Minocycline, doxycycline, polymyxin B)
• omega three fatty acids
• nutraceuticals (resveratrol, luteolin, flavonoids, cucurmin)
• moderate exercise
• behavioral interventions to increase parasympathetic tone

At least six of these are used by some clinicians in some ME/CFS patients (TNF inhibitors, antibiotics, omega three fatty acids, nutraceuticals, moderate exercise, behavioral interventions.
 
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Belbyr

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Good point, my wonder is... is there something our bodies are secretly fighting that flipping this 'switch' would be detrimental. Subgroup maybe? I like how he has moderate exercise and behavioral interventions at the bottom of his list :rofl:
 

pattismith

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Phair found that tryptophan/kynurenine ratio is higher in cells from patients than from controls, does someone know which cells were tested?

Also something that I cannot explain, if the metabolic try trap were to be right, then why IDO1 polymorphism is not found in patients?
 
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JES

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Also something that I cannot explain, if the metabolic try trap were to be right, then why IDO1 polymorphism is not found in patients?
This is explained by the peculiar enzyme kinetics of IDO1. At high tryptophan concentrations IDO1 stops working:

ido-flux.png
 
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nandixon

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Also something that I cannot explain, if the metabolic try trap were to be right, then why IDO1 polymorphism is not found in patients?
Loss-of-function IDO1 SNPs are pretty rare but I suppose you might expect to see some skewing towards patients being somewhat more likely to have those mutations if the metabolic trap hypothesis were correct. (There's also a fairly common gain-of-function IDO1 SNP, rs7820268, that around 10% of the general population is homozygous for and this would need to be accounted for in controls.)

On the other hand, IDO2 SNPs that result in a non-functional IDO2 are extremely common. So the finding of an average of 1.7 damaged copies (alleles) in the severe patients is probably not very significant given that over 40% of the relevant general population (i.e., European-derived ethnic ancestry) already has 2.0 non-functional alleles (i.e., they are either homozygous or compound heterozygous for the IDO2 SNPs).

This is all a moot point though because Dr Phair is no longer sure that the data (measured by mass spectroscopy) from the tracer experiments on the half-dozen severe patients that appeared to show decreased intracellular kynurenine formation is even correct.
 
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@mariovitali @Themos Kalafatis you might be interested in this paper
The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome
TRP Breakdown by KYN Enzymes
The full library of KYN enzymes is only known to be fully expressed in hepatocytes, tumor cells, vascular endothelial cells, fibroblasts, and antigen-presenting cells (APCs), specifically, dendritic cells, monocytes, and macrophages (8, 9). It is critical to note that hepatocytes differ from other cells by the type of the rate-limiting enzyme of the TRP pathway; TRP 2,3-dioxygenase (TDO) is found in the liver, as opposed to indolamine 2,3-dioxegenase 1 or 2 (IDO-1 or IDO-2) which are found elsewhere. Functionally IDO and TDO are similar but are regulated in a very different fashion, resulting in different physiologic roles. Since TDO has a different mechanism for activation and is activated by TRP itself, TDO is almost always continuously activated and expressed; because of this, it is subsequently responsible for 90% of TRP degradation (15). When there is an accumulation of one of the intermediate products of the pathway, this causes inactivation of TDO and a succeeding increase in serum TRP and in TRP availability to the rest of the body.
 
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It seems like gut inflammation and dysbiosis play a big role in the Kynurenine/IDO Pathway. This first quote might explain in part, why researchers can't find a consistent immune cytokine profile in ME/CFS.

Acting through the aryl hydrocarbon receptor, KYN metabolites cause T-cell anergy and apoptosis, proliferation of Treg and Th17 cells, and deviation of the Th1/Th2 response, although the outcome is highly dependent on the microenvironment.

Moreover, new evidence from germ-free mice and human infants shows that gut microbiota and breast milk are key in determining the functioning of the KYN-IDO pathway.
In earlier studies employing a broad metabolomics approach, the composition of gut microbiota was noted to have a profound influence on circulating metabolites; plasma levels of KYN metabolites were affected to a greater extent than levels of other metabolites (96).
Similarly, Desbonnet et al.’s study of antibiotic-induced microbial depletion in mice reported higher circulating TRP levels and reduced peripheral KYN metabolism (92).

Finally, changes to circulating KYN/TRP ratios have been observed following experimental induction of gastrointestinal inflammation via introduction of a parasite and likely altered gut microbiota (100).
 
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