IDO Metabolic Trap Hypothesis Published Today

JES

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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

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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

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@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

as long as you manage to stay alive, there's hope
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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
 
Messages
472
Likes
758
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?