Stanford Community Symposium 2018: Phair, Metabolic traps, Tryptophan trap

FMMM1 said:
Just found this by accident. Could someone send me a link to the original data/post.

I was wondering if someone had checked the genetic data i.e. to see relationship between IDO2 mutation and incidence of ME/CFS. However, understanding even a small percentage of cases may help to explain the disease mechanism more generally.
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https://s4me.info/threads/stanford-...traps-tryptophan-trap.6033/page-7#post-122456

To explain the 'inner' workings of the forum software a bit, where the forum produces a quote, either via the reply or the multiquote button, it produces a link to the original post and indicates it by a little up arrow
Screen Shot 2019-02-03 at 10.17.16.png
as can be seen in the example above. By using these a number of times I was able to arrive at the post I've linked to above.
 
I didnt read all those threads about possible metabolic problems but is it already sure that there are? For me it makes sense but i have no scientific background. It was already long time before these theories started to appear that i felt that i am not tired but that my body simply doesnt produce enough energie. So i think the metabolisme must to bé involved somehow.
 
FMMM1 said:
Maureen Hanson/Norwegian group is doing/has done a study re-setting the microbiome (faecal transplants); don't think it's that easy to re-set the microbiome
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I agree, faecal transplants, to me, are more topical and will wash away because whatever produces the microbiome composition in the intestines will just keep pumping out an altered composition and the walls will keep returning to the altered state.

We need to find out what is going on in the 'production system that manufactures the microbiome'. Something has been altered, blocked or is producing too much/too little of something in the manufacturing process.

I have a different area of microbiome change, not the gut, but wouldn't be surprised if the same thing that happened to me is affecting the gut in some PwME.
 
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tuha said:
I didnt read all those threads about possible metabolic problems but is it already sure that there are? For me it makes sense but i have no scientific background. It was already long time before these theories started to appear that i felt that i am not tired but that my body simply doesnt produce enough energie. So i think the metabolisme must to bé involved somehow.
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yes, me too. but im tired. much so. since all times.

im wondering, if babiturates like Thiopental could break that trap.

or perhaps less likely something like anti-benzo flumazenil
just cant imagine that there is no way out anymore.
shouldnt be possible such a thing...?

i dont understand this, but would just think, something that ousts the tryptophan in the cells, a more competetive substrate... perhaps a barbiturate or so
 
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IN 2015
http://simmaronresearch.com/2015/03/
THE Pathway???
IFN-y also accelerates tryptophan degradation by activating the indoleamine-2,3 deoxygenase enzyme in the kynurenine pathway – Mady Hornig’s favorite pathway. That pathway produces neurotoxic substances that increase production of the excitatory neurotransmitter glutamate that some researchers believe is in play in both fibromyalgia and ME/CFS. Andrew Miller of Emory University has earmarked the kynurenine pathway in ME/CFS.

Mady was into it about trypofane,

Edit, kynurenine is transformed to kynurenine acid in the muscles, maybe poeple whit ME cant transforme the kynurenine to the harmless kynurenine acid??
 
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i have access to two things:
1) an exercise incline track, lasting a couple of hours
2) leg muscles quickly shutting down to nonfunctional

next time, i will take a "gut abx" in between and see what will change.
i would think, it could help to reduce lactate issues.

could there be any other "self-tests" to narrow down on things regarding muscles ?

anything topical, anything to take... ?
breathing oxygen, breathing co2...
what ?
 
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Recently, dysregulation of the tryptophan-kynurenine pathway possibly via microglial activation has been suggested to be a positive link to suicide and suicide related behaviors. Novel key molecules, especially in the tryptophan/kynurenine pathway, may be discovered by wider analysis of metabolites, lipids and also neuron/microglia-derived exosomes in plasma/serum of suicidal patients.

Novel key molecules, especially in the tryptophan/kynurenine pathway, may be discovered by wider analysis of metabolites, lipids and also neuron/microglia-derived exosomes in plasma/serum of suicidal patients.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381042/

Published online 2019 Feb 13.
Suicide and Microglia: Recent Findings and Future Perspectives Based on Human Studies
Hisaomi Suzuki,1,† Masahiro Ohgidani,2,† Nobuki Kuwano,2 Fabrice Chrétien,3,4Geoffroy Lorin de la Grandmaison,5 Mitsumoto Onaya,1 Itaru Tominaga,1 Daiki Setoyama,6 Dongchon Kang,6Masaru Mimura,7 Shigenobu Kanba,2 and Takahiro A. Kato2,*
 
Comment from Cort in one of his recent blogs on the updated thinking on the metabolic trap:

"Davis has begun to separate out dendritic cells and test them to see if the metabolic trap is present. He brought up an interesting possibility – emphasizing that it was only a possibility – that if the metabolic trap is present, it could lay the groundwork for an autoimmune process to manifest itself. This is because dendritic cells are responsible for shutting down autoimmune producing B-cells."

"If the metabolic trap is present in dendritic cells, it’s probably mucking up their ability to knock out bad B-cells. Furthermore, because the IDO1 pathway plays a role in immune system regulation, it wouldn’t be odd at all for pathogens to take a swing at knocking it out in order to evade capture. That plus a possible genetic predisposition to problems with this pathway could tell the tale in ME/CFS."
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https://www.healthrising.org/blog/2019/05/07/threading-the-needle-nanoneedle-scores-big-in-first-me-cfs-test/
 
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On PR Phair mentions that he has submitted a manuscript on the metabolic trap to a journal. If this is accepted, it might provide a starting point for pharma companies to begin some type of drug discovery.

On the more pessimistic side, I’m pretty sure Phair et al. don’t really have any idea how to unstick the trap.
 
Jaybee00 said:
On the more pessimistic side, I’m pretty sure Phair et al. don’t really have any idea how to unstick the trap.
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Maybe it also depends on what triggers the trap in the first place. If the trap itself is a downstream effect of something else, and if that something else still still persists, then they might still be looking in the wrong place - at a knock-on effect rather than the root cause. But fingers crossed.
 
Trish said:
Thank you Chris Ponting. It's great to have scientists sharing their research findings here.
With respect to this point:

This could presumably be interpreted in two ways:

The biobank data indicate the IDO2 hypothesis is wrong or

The biobank data not matching the 20 severely ill patient study data for IDO2 indicates that a lot of people are self identifying as having CFS when they don't so the data are too contaminated to conclude anything. Given that specialist clinics indicate that many of the people sent to them with CFS don't actually have it, this could be an important factor.
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Really only stating the obvious here; I agree with your comment. I.e. the genetic data would need to be from people who tested positive using a biomedical diagnostic test e.g. the Raman spectroscopy test which measures (high) intracellular phenylalanine (Kara Morten, Cara Thomas and others) or nano-needle ---.


ME Action are lobbying for funding for the development of a diagnostic test and treatments https://www.meaction.net/…/announcing-millionsmissing-2019…/
 
FMMM1 said:
the genetic data would need to be from people who tested positive using a biomedical diagnostic test
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In theory I agree with you, but what if the only diagnostic test available at the time the samples are collected turns out to only identify a subgroup of pwME. Does that mean the rest should not be investigated?

It would be wonderful to have a diagnostic test that clearly differentiated everyone who fits the definitions of ME that include PEM from every other illness but we are a way off that yet, with only small samples tested with the different methods.

Edit: But I do agree that genetic testing using subgroups that show positive on a biomedical test would be ideal.
 
Andy said:
That the data that they have that supports the trap theory is too imprecise for his liking, is my assumption. I'm just reporting what he said to us all as part of his presentation.
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That ties in with other presentations/posts by him and Robert Phair - culture material that everyone uses had a variable amount of tryptophan, Mass Spectometer not precise enough, PBMC's too variable - now narrowed testing to dentritic cells. However 66 out of 66 patients who have given blood samples having IDO2 damaging/loss of function mutations seems to be significant.
 
Andy said:
Just wanted to drop in a note that I made from the recent IiME conference when Ron was talking about the metabolic trap.
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Speculation! I don't necessarily think this is a problem. Another way to maintain a stable disease state [i.e. where cells switch from using glucose, for energy production, to amino acids] would be to maintain the input signal - i.e. the exosome signalling. The fact that those with a defective IDO2 [or tyrosine] gene are worse is inherent in Ron's (wise) selection of very ill people.
 
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