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

Could it also relate to differences in how patients are identified in the UK and USA? Potentially, these 20 patients may represent a fluke?

 

Presuming this is correct, here is another issue. The marker was found from the severe patients study. Supposing its not important for most patients, it might be a marker leading to severity, rather than causative. The biobank will not show this unless the results are stratified for severity. Were they?

 

So far as I am aware only Lipkin and his team did this.

 

OR, given the situation in the UK, the false diagnosis rate is atrocious.

 

It's frightening to think that samples from UK biobank aren't accurate....I'd have assumed they run a tight ship. I wonder what criteria they use?

 

Oh thanks Trish, phew!! I was thinking this sounds like a total dog's dinner!! Thanks for setting me straight.

 

Did I miss an explanation for why the UK biobank was used for this as opposed to the ME/cfs biobank UK?

 

I presume this to mean that if the ME/cfs biobank data was used they'd have to generate such data first? And this would be an added cost?

Otherwise, I appreciate the response but I'm still kinda in the dark as to why that would be preferable.

Not that I really understand much about any of this.

 

I believe this to be correct, the UK ME/CFS Biobank has not analysed their samples in the same way that they UK Biobank has. It's also a numbers game, even if they had the genome data, currently "the UKMEB now has over 600 people participating in the Biobank project – people with ME/CFS, Multiple Sclerosis and healthy controls", whereas the data that Chris Ponting analysed was "from 194,174 females and 167,020 males". The blog notes that one of the limitations of their analysis is that "Only one genomic region was identified, so a much larger study is required with about 20,000 ME/CFS cases to find more.", numbers that, obviously, the UKMEB is currently unable to provide.

 

From the other place- a couple of interesting links re phenylalanine / endocrine system/ trytophan.

https://www.nova.edu/nim/broderick-and-craddock-article-in-intl-innovation.pdf

https://phoenixrising.me/archives/5396

 

I stumbled upon this May 2018 article concerning Tryptophan, the Kynurenine Pathway and IBD (Inflammatory Bowel Disease).

Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis

https://academic.oup.com/ibdjournal/article-abstract/24/7/1471/5001501?redirectedFrom=fulltext

As near as I can tell, the study found that an increase in the ratio of Kynurenic acid to tryptophan was associated with inflammation in uclerative colitis (a form of IBD that seems to show up in some ME patients).

From what little I know about the metabolic trap, I would guess that you'd see a proportional increase in tryptophan in "the trap," as opposed to kynurenine. On the other hand, I believe in this IBD study they tested the serum as opposed to cell contents. Perhaps a build up of tryptophan in the cells lowers its level in the serum, thus increasing the proportion of kynurenic acid to tryptophan in the serum. Of course, this study's findings may have nothing to do with "the trap."

The researcher in the video suggests that additional kynurenic acid may be being generated elsewhere, and mentions the microbiome as a possible location.

 

Cross-linking to @MeSci's post on Carmine Pariente's latest paper 'Persistent fatigue induced by interferon-alpha: A novel, inflammation-based, proxy model of Chronic Fatigue Syndrome', which notes:

This would seem to tie in with the prediction made by @RDP as shown on the slide on the very first page of this thread. Interesting...

 

Very interesting .
Does Phair know of this ? Replication out with a severe illness group?

 

is this on point?
https://www.sciencedirect.com/science/article/abs/pii/S0003986113003627

 

It might be, I have not read the full article. Its certainly looking relevant, but its hard to say, and I would need to have the full article and some very specific questions to review it. I am not sure I have the time/energy though.

 

Only looked at this for a few minutes but what your saying seems reasonable.

If IDO1/2 are not working then intracellular tryptophan will increase while intracellular kynurenine will decrease (Phair). It seems reasonable that intracellular Kynurenic acid will also decrease since it is formed after the IDO1/2 stage [https://en.wikipedia.org/wiki/Kynurenine_pathway].

Fluge/Mella (2016) and Armstrong (2015) showed that amino acids (including tryptophan) were lower in plasma since they were being used as cellular fuel in ME/CFS. So lower plasma levels could indeed reflect higher intracellular levels.

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. Interesting that this group may be highlighting a change to the microbiome resulting in more Kynurenic acid. Wonder if this would give you more kynurenine; bypassing the IDO1/2 stage; an example of nature coming up with a workaround? Wonder if Phair's looked at this study?

Anyway the reason I'm on here is that I think Phair is interested in another potential metabolic trap i.e. substrate inhibited enzyme (operating at lower substrate levels) and a second enzyme operating at higher substrate levels. Anyone know what this second trap is?

 

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.