IDO Metabolic Trap Hypothesis Published Today

[knackers323]

Disulfiram is gaining a lot of traction in Lyme disease forums. I wonder if this could be worth testing in the nanoneedle.

What is the mode of action in which it is thought to be helping in Lyme disease?

 

[JES]

What is the mode of action in which it is thought to be helping in Lyme disease?

The idea to use disulfiram seems to have originated from this 2016 paper, in which they tested over 4000 drugs with high-throughput screening to see if they inhibited borrelia. Curiously, the authors discovered that disulfiram was particularly effective at stopping the growth of borrelia in vitro. The catch here is of course that it's in vitro, so we have no idea how this drug will work in vivo yet, but it seems people are reporting strong effects from taking it.

It's possible that the effects people have reported from disulfiram are not from bacterial die-off, but from some secondary effect, as it seems disulfiram affects dopamine and lots of other things as well. But anyway, when the typical treatment in chronic Lyme circles for the last 20 years has been to use antibiotics for several years, at least there is now a potentially more effective drug that won't destroy the microbiome in the process.

 

[FMMM1]

Hi everybody,
Hi Dr. Phair (@HTester)

This is my first post on this forum though I am a member of the forum since 2011.
Sorry for my English, I'm not a native speaker.

I really liked your metabolic trap hypothesis, I've watched the conference talks and read the newly published paper. I'm not a scientist but as other persons with ME/CFS I'm really interested in ME/CFS science and its outcomes.

When I googled articles to find out more about kynurenine pathway, all I get is articles that link the kynurenine pathway and its metabolites to neurodegenerative diseases and to my surprise more commonly its overactive state. Also IDO2 is linked more with its proinflammatory role in some autoimmune diseases in several papers.

The kynurenine pathway and neurodegenerative disease.
https://www.ncbi.nlm.nih.gov/pubmed/25773161
IDO2: A Pathogenic Mediator of Inflammatory Autoimmunity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119657/
IDO2 in immunomodulation and autoimmune disease
https://www.frontiersin.org/articles/10.3389/fimmu.2014.00585/full

On the other side there are papers stating that inhibition of kynurenine pathway or modulating it could be therapeutic in some neurogical diseases:

Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection
https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2012.08487.x
Inhibiting the kynurenine pathway in spinal cord injury: multiple therapeutic potentials?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199950/
Inhibitors of the kynurenine pathway
https://www.frontiersin.org/articles/10.3389/fmolb.2019.00003/full

So my question is: Is it possible that if the theory of metabolic trap is correct, that the trap is not only pathological state but also protective state that acts as emergency brake to not cause bigger damage? But if that is correct, then it is not a good idea to try to open the kynurenine pathway if the chronic trigger is still present.

And my second question and the thing I was missing in the paper: How precisely nonfunctional kynurenine pathway explains ME/CFS symptoms or what is the main possible reason that this pathway is cause of ME/CFS symptoms specifically?

Thank you for your time.

Check out Dr Phairs talks; he mentions a cancer drug which suppressed IDO1/2 (can't remember which) i.e. in order to promote immune activation - kynurenine suppresses autoimmunity. Phair was struck by the fact that these patients, who were terminally ill, refused the drug owing to the severe fatigue. Also, check out Ron Davis's talks; he highlights that sleeping sickness is named after the day/night reversal in sleeping pattern which it causes. The kynurenine pathway is affected (upregulated? https://www.ncbi.nlm.nih.gov/pubmed/28013248 ] in sleeping sickness. So the whole host of symptoms you see in ME appear to be consistent with this hypothesis.

Ron Davis also considers whether ME is a protective state and the risks of turning that state off. This is, I assume, largely hypothetical i.e. since I assume that currently there are no drugs to reduce intracellular tryptophan i.e. turn off the the metabolic trap (if it exists). The drugs which are currently discussed are SS-31 (repairs mitochondrial damage) and Copaxone (similar effect to SS-31 I think - so they may improve quality of life (significantly) but not actually reduce intracellular tryptophan.

If your in the EU then here's a lobby group you may consider joining #MEAction European Union (EU)

Dr Vicky Whittemore (NIH) at Invest in ME Conference (2019):
"advocacy groups --- that's what makes the difference -
- when they [elected representatives] hear that, from people with the disease -
- advocates -- telling them [elected representatives] what's needed is really what makes the difference"

 

[FMMM1]

@HTester; assuming that the metabolic trap theory is correct then people with ME will have a mutation either on:

• IDO2 gene - tryptophan metabolic trap (lets say 75% of the population have this mutation); or
• tyrosine Hydroxylase (?) gene - tyrosine metabolic trap (% population with this mutation ?).

So if you have the genetic data (IDO2 mutation frequency plus tyrosine Hydroxylase mutation frequency):

• in the general population; and
• in population diagnosed with ME.

Then you have an estimate of those who don't have a metabolic trap (misdiagnosis?).

Might be interesting to know what % of the population with ME don't have a metabolic trap.

@Simon

 

[lauluce]

these are certainly exciting times... only 15 years ago the discussion was if ME/CFS existed or not, or if it was a psychological entity or not... today, thanks to the indomitable will of sufferers, advocates and researchers, we are finally at the phase of using the whole might of the human intellect to find real answers as to what in the world has been causing this tragedy that has been called "chronic fatigue syndrome" for more than one hundred years of its documented existence

 

[FMMM1]

Hi everybody,
Hi Dr. Phair (@HTester)

This is my first post on this forum though I am a member of the forum since 2011.
Sorry for my English, I'm not a native speaker.

I really liked your metabolic trap hypothesis, I've watched the conference talks and read the newly published paper. I'm not a scientist but as other persons with ME/CFS I'm really interested in ME/CFS science and its outcomes.

When I googled articles to find out more about kynurenine pathway, all I get is articles that link the kynurenine pathway and its metabolites to neurodegenerative diseases and to my surprise more commonly its overactive state. Also IDO2 is linked more with its proinflammatory role in some autoimmune diseases in several papers.

The kynurenine pathway and neurodegenerative disease.
https://www.ncbi.nlm.nih.gov/pubmed/25773161
IDO2: A Pathogenic Mediator of Inflammatory Autoimmunity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119657/
IDO2 in immunomodulation and autoimmune disease
https://www.frontiersin.org/articles/10.3389/fimmu.2014.00585/full

On the other side there are papers stating that inhibition of kynurenine pathway or modulating it could be therapeutic in some neurogical diseases:

Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection
https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2012.08487.x
Inhibiting the kynurenine pathway in spinal cord injury: multiple therapeutic potentials?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199950/
Inhibitors of the kynurenine pathway
https://www.frontiersin.org/articles/10.3389/fmolb.2019.00003/full

So my question is: Is it possible that if the theory of metabolic trap is correct, that the trap is not only pathological state but also protective state that acts as emergency brake to not cause bigger damage? But if that is correct, then it is not a good idea to try to open the kynurenine pathway if the chronic trigger is still present.

And my second question and the thing I was missing in the paper: How precisely nonfunctional kynurenine pathway explains ME/CFS symptoms or what is the main possible reason that this pathway is cause of ME/CFS symptoms specifically?

Thank you for your time.

I occasionally check out this site
https://followmeindenmark.blogspot.com/2019/06/me-hypotese-metabolic-trap-den.html
There's a post on the metabolic trap here's an extract:
"The question is whether the serotonin system in the brain / brain stem also may be affected in CFS patients? The hypothesis is that there is increased production of serotonin. Robert Phair is also currently see further on this."

Anyone direct me to an explanation of increased production of serotonin in the brain?

 

[maple]

More than 90% of the serotonin in your body is in your gut. From a systems perspective, this could be interpreted as meaning that the serotonin in your gut dominates.

 

[anni66]

More than 90% of the serotonin in your body is in your gut. From a systems perspective, this could be interpreted as meaning that the serotonin in your gut dominates.

Would also implicate hormone balance - seratonin / melatonin/ estrogen

 

[Snow Leopard]

Check out Dr Phairs talks; he mentions a cancer drug which suppressed IDO1/2 (can't remember which) i.e. in order to promote immune activation - kynurenine suppresses autoimmunity. Phair was struck by the fact that these patients, who were terminally ill, refused the drug owing to the severe fatigue.

Most likely IDO1.

"Discovery of IDO1 Inhibitors: From Bench to Bedside"

https://cancerres.aacrjournals.org/content/77/24/6795



Trials:

https://clincancerres.aacrjournals.org/content/early/2019/02/15/1078-0432.CCR-18-2740

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009946/

 

[FMMM1]

Most likely IDO1.

"Discovery of IDO1 Inhibitors: From Bench to Bedside"

https://cancerres.aacrjournals.org/content/77/24/6795



Trials:

https://clincancerres.aacrjournals.org/content/early/2019/02/15/1078-0432.CCR-18-2740

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009946/

Thanks @Snow Leopard don't suppose anyone's identified a drug which increases the activity of IDO1 i.e. so that it is not substrate inhibited (or fixed IDO2)!

 

[FMMM1]

Most likely IDO1.

"Discovery of IDO1 Inhibitors: From Bench to Bedside"

https://cancerres.aacrjournals.org/content/77/24/6795



Trials:

https://clincancerres.aacrjournals.org/content/early/2019/02/15/1078-0432.CCR-18-2740

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009946/

Just noticed this publication "Potent Activation of Indoleamine 2,3-Dioxygenase by Polysulfides" https://www.ncbi.nlm.nih.gov/pubmed/31436417

Looked at it for a few seconds - possibly a way to up-regulate IDO1 i.e. the enzyme which is not broken but is substrate inhibited @Janet Dafoe (Rose49) .

Came across it via this site http://followmeindenmark.blogspot.com/

 

[skandar]

Just noticed this publication "Potent Activation of Indoleamine 2,3-Dioxygenase by Polysulfides" https://www.ncbi.nlm.nih.gov/pubmed/31436417

Looked at it for a few seconds - possibly a way to up-regulate IDO1 i.e. the enzyme which is not broken but is substrate inhibited @Janet Dafoe (Rose49) .

Came across it via this site http://followmeindenmark.blogspot.com/

I think that in order to make IDO1 not substrate inhibited, you would need to modify the 3-dimensional structure of the enzyme. Making more IDO1 ("upregulate") would not remove the substrate inhibition property of the enzyme. Any physical chemists out there, please correct me.

But I have wondered if it is possible to induce a cell to make more IDO2. This would only be helpful if at least one of the alleles of a cell made functional IDO2. This would be either an endogenous compound or a drug that binds directly or indirectly to the regulatory region of the gene to activate its transcription.

 

[FMMM1]

I think that in order to make IDO1 not substrate inhibited, you would need to modify the 3-dimensional structure of the enzyme. Making more IDO1 ("upregulate") would not remove the substrate inhibition property of the enzyme. Any physical chemists out there, please correct me.

But I have wondered if it is possible to induce a cell to make more IDO2. This would only be helpful if at least one of the alleles of a cell made functional IDO2. This would be either an endogenous compound or a drug that binds directly or indirectly to the regulatory region of the gene to activate its transcription.

Yea I meant increase the production of Kynurinine via IDO1. I didn't mean increase production of IDO1; I meant get the IDO1 enzyme to be effective at higher tryptophan concentrations - hadn't realised that up-regulated is only used to describe an increasing in IDO1 concentration. As you poit out incresing amount of IDO1 has no effect if it is substrate inhibited.
Interesting re IDO2 i.e. potentially, if you have a copy of a functional enzyme, as well as a non-functioning one, then there is a potential route to lower tryptophan concentration using the functional copy of IDO2 - hadn't spotted that.

 

[junkcrap50]

Yes, I found the same journal article, but forgot to post on PR. There are already possible polysulfide drugs and polysulfide supplements out there too, which could end up helping. I also came across this article at the time when searching about polysulfides: https://medicalxpress.com/news/2019-04-polysulfide-donors-strongly-suppress-inflammatory.html

Polysulfide donors strongly suppress inflammatory responses
Researchers from Japan have developed a new polysulfide donor: a chemical compound composed of chains of sulfur atoms that can artificially increase reactive sulfur species (chemically reactive molecules containing sulfur) in cells and tissues. This donor is believed to be an excellent candidate for a new anti-inflammatory therapy because it has an extremely high anti-inflammatory effect.
....
A collaboration between researchers at Kumamoto University (Kumamoto, Japan) and Tohoku University (Sendai, Japan) has succeeded in synthesizing a new polysulfide donor by linking multiple sulfur atoms to acetylcysteine, an artificial amino acid. Their experiments revealed that the new donor was able to quickly penetrate into cells and greatly increase the RSS content by transferring extra sulfur atoms to intracellular cysteine and gluthathione.

 

[junkcrap50]

Also bookmarked this in my searching:
https://www.cell.com/cell-chemical-...m/retrieve/pii/S2451945619300376?showall=true

Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock
Highlights
• Cell-permeable, thiol-activable polysulfide donors are developed

• Polysulfide donor treatment increases intracellular polysulfide levels
• Polysulfide donor treatment desensitizes macrophages to TLRs signaling
• Mice are protected from lethal endotoxin shock by polysulfide donor

Summary
Cysteine persulfide and cysteine polysulfides are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. Accumulating evidence has suggested that cysteine persulfides/polysulfides are abundant in prokaryotes and eukaryotes and play important roles in diverse biological processes such as antioxidant host defense and redox-dependent signal transduction. Here, we show that enhancement of cellular polysulfides by using polysulfide donors developed in this study resulted in marked inhibition of lipopolysaccharide (LPS)-initiated macrophage activation. Polysulfide donor treatment strongly suppressed LPS-induced pro-inflammatory responses in macrophages by inhibiting Toll-like receptor 4 (TLR4) signaling. Other TLR signaling stimulants—including zymosan A-TLR2 and poly(I:C)-TLR3—were also significantly suppressed by polysulfur donor treatment. Administration of polysulfide donors protected mice from lethal endotoxin shock. These data indicate that cellular polysulfides negatively regulate TLR4-mediated pro-inflammatory signaling and hence constitute a potential target for inflammatory disorders.

 

[FMMM1]

Yes, I found the same journal article, but forgot to post on PR. There are already possible polysulfide drugs and polysulfide supplements out there too, which could end up helping. I also came across this article at the time when searching about polysulfides: https://medicalxpress.com/news/2019-04-polysulfide-donors-strongly-suppress-inflammatory.html[/QUOTE

I recall that SS-31 is a number of amino acids "randomly" bound - it returns the signal to normal on the nano-needle test. I wonder about this new polysulfide drugs i.e. if it were tested on the nano-needle would it return the signal to normal?

Also, Jarred Younger is looking at micro-glial activation - would this drug cross the blood brain barrier and reduce activation of micro-glia?

 

[Possibly James May]

Things have been unusually quiet for the last two months. @HTester Any updates? Did we hit a roadblock?

 

[Hopeful1976]

Please some news soon. Desperate...

 

[Hopeful1976]

@HTester anything to tell us? Please...

 

[Hopeful1976]

Can I just say @HTester how the gut is implicated in symptoms. I know this. After suffering 25+ years, I can say with certainty that when my gut is bad, m.e symptoms are bad. I had yet another gut flare, started a few weeks ago. Possibly from eating sugary foods (always gets bad after eating sugary foods, so I avoid them usually). Now, after 2 weeks of constant nausea and depressive mood - I am normally fine - bad gut symptoms always correlate with depressed mood, the fatigue, sleeplessness, muscle weakness and fatigue (bruised muscles like I've run a mile) have appeared. Please consider this massive correlation. I know the gut is massively affecting the m.e. I know it 100%. I have to somehow get my gut back under control. It's awful. I have no idea other than bad bacteria overtake and mermiate the gut wall, causing an immune reaction which cause the m.e symptoms? How does your ido2 trap idea fit? How can the ido2 trap fix me?