Community symposium on molecular basis of ME/CFS at Stanford Discussion Thread

[bthompsonjr1993]

Here's the Stanford livestream on you tube. It will be up for a while. Ashley will divide it into individual talks and it will be on OMF website in a while. OMF is already busy raising funds for all those new studies! They are amazing!

https://livestream.com/accounts/1973198/ME-CFS-2018

#mecfs2018

Thank you! So interesting! I hope at some point we may be able to hear Ron or Robert Phair speak about whether Fluge's PDH findings are compatible with the metabolic trap hypothesis.

 

[wigglethemouse]

There is a 2015 thread here on PR about IDO2 with some interesting links
IDO2, Autoimmune Issues, and Cancer

 

[Hopeful1976]

Tryptophan and pregnancy - just been reading about it and how it's need is greater during pregnancy... got me thinking about how so many of us feel better when we are pregnant... are we using up all the tryptophan that is at excessive levels as phair describes that ordinarily is making us feel like crap?....

 

[alex3619]

So can't this test already be used to show that something is wrong?

Its one of the most common tests in several variations right now. However some patients collapse after this test and do not recover in reasonable time ... possibly years. This includes the 2 day CPET and invasive CPET tests.

We already know many things that are wrong. That is not enough. We need to be able to show things that are wrong in tests every doctor can order, or do in the clinic. The hundreds of well validated biomarkers, and thousands in the process of being validated, have not so far had an impact at the general clinical level.

The reason why cellular impedance is possibly useful is its a very cheap test that doctors can do in their own clinic.

I wish the two CPET versions I mentioned were used more often. They should be. The basic technology is from 1949, but the repeat CPET was not demonstrated in ME until 2007.

The first useful test for ME dates back to 1940, though it was not validated till 1995. That is the tilt table test for orthostatic intolerance, a common symptom in ME. Its not diagnostic though. It is however treatable. Yet despite more than half a century the majority of doctors do not use it in ME. This test can have risks though, I went into cardiac arrest in mine.

The next useful test is from 1946, the quantitative EEG. Its in the process of being investigated. I want this test myself as its largely non-invasive.

There are a bunch of other tests too.

Once we establish treatment biomarkers then we need easy and safe tests to monitor treatment. Right now one of those might be a metabolomic panel, particularly if the metabolic trap hypotheses are demonstrated and treatments are made available.

Trying to figure out why the medical profession has ignored more than half a century of advances is complicated, and there is much debate on this.

 

[alex3619]

It can cause the patient to crash

I suspect it works by causing a crash and then measuring the crash. This can be very useful but is not always desirable.

 

[FMMM1]

Thank you! So interesting! I hope at some point we may be able to hear Ron or Robert Phair speak about whether Fluge's PDH findings are compatible with the metabolic trap hypothesis.

Here's an extract from Fluge and Mella's paper [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]:
"Amino acids fueling acetyl-CoA into TCA (category II).
All the 6 amino acids in category II were significantly reduced in nonfasting ME/CFS patients compared with nonfasting healthy controls, with P values of less than 0.001 for Ile, Leu, Phe [phenylalanine], and Tyr and P values of 0.001 and 0.009 for Lys and Trp [tryptophan], respectively (Table 1). The reductions in mean serum levels for all 6 amino acids were highly significant in women with ME/CFS compared with healthy women --".
"Trp" = tryptophan; "Phe" = phenylalanine etc.

So tryptophan, phenylalanine etc. are reduced in the blood plasma of women with ME/CFS compared with healthy controls.

The reverse is true of intracellular levels of phenylalanine in the blood cells Phair studied [PBMCs]; i.e. they are elevated compared with healthy controls. Here are two extracts from the (full) paper below*:
"phenylalanine in -- CFS patient PBMCs were significantly higher than -- healthy controls";
"our results suggest that the increase in cellular phenylalanine may relate to mitochondrial/energetic dysfunction".

If intracellular levels of tryptophan also increased in people with ME/CFS:

• i.e. beyond the point at which IDO1 is substrate inhibited; and
• you have the relatively common (greater than 40% occurrence) mutation of IDO2;

then presumably you'd be stuck in the trap.

I don't know if you can use this method* (Raman spectroscopy) to measure intracellular levels of tryptophan; or at least establish whether they are elevated compared to healthy controls. If you can't use Raman spectroscopy then I wonder if there is another way of measuring intracellular levels of tryptophan?

Exciting stuff. I wonder if we can help to get the necessary funding i.e. to progress this [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1003111].


1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
*2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

 

[sb4]

I'm probably off the mark here but could the increased tryptophan be due, as others have said, to reduced pyruvate dehydrogenase / impaired glucose metabolism. If this is so that means we will have increased amino acid uptake in cells; these will be used in anaplerosis in the TCA cycle however the amino acids that can be converted to pyruvate will build up as pyruvate builds up.

These amino acids will be disposed of however if you have THIS SNP (as described in THIS thread) [I have CT version so 90% reduction in activity] then you will have vastly reduced activity of IDO2 and thus tryptophan will accumulate.

Hopefully getting the system to snap out of this will be a big deal but if what I have said is true then it implies that this won't get to the route problem of what is inhibiting glucose oxidation. Perhaps it's a chicken and egg thing where snapping out of it will fix glucose oxidation.

Anyway it would be interesting to see who else has SNPs on IDO2. Maybe post your results in this thread.

 

[FMMM1]

Tryptophan and pregnancy - just been reading about it and how it's need is greater during pregnancy... got me thinking about how so many of us feel better when we are pregnant... are we using up all the tryptophan that is at excessive levels as phair describes that ordinarily is making us feel like crap?....

Yea from memory, Professor Warren Tate from New Zealand spoke at the 2017 Invest in ME Conference about his daughter who had ME/CFS and was pregnant. He said that some women improve during pregnancy and they were hoping that she would. Interesting that the demand for tryptophan increases during pregnancy.

 

[bertiedog]

I have CT version so 90% reduction in activity] then you will have vastly reduced activity of IDO2 and thus tryptophan will accumulate.

I have this one too.

Pam

 

[Moof]

Anyway it would be interesting to see who else has SNPs on IDO2. Maybe post your results in this thread.

Is the SNP rs10109853? (Sorry, your link goes through to 23andMe, the site asks you to sign in before seeing the info, and I can't find my password!)

If so, I have homozygous TT. I don't know whether that's the version that could potentially reduce ID02 activity, though.

 

[Mary]

We can get a clue from looking at our Krebs cycle which, for most of us, will show a break.

How do you look at your Krebs cycle? What test does this?

 

[Diwi9]

Anyway it would be interesting to see who else has SNPs on IDO2. Maybe post your results in this thread.

I'm CT.

 

[nandixon]

Didn't Dr Chia try using [interferon-gamma]?

Thanks. Yes, he reported his results in at least one publication: The role of enterovirus in chronic fatigue syndrome (note that there appear to be several typographical errors where the greek delta symbol (δ) is used instead of gamma (γ), unless the paper was written in a terribly jumbled fashion).

So far as I can tell Chia never used interferon-γ by itself but always in conjunction with interferon-alpha (hoping to achieve a synergistic or additional effect against suspected enteroviruses).

It appears his initial results with the combination of the two interferons were very good but that all of the patients eventually relapsed:

To date, eight of 14 severely ill patients with detectable enteroviral RNA in their peripheral blood leucocytes have responded to the combination of interferon α and δ [this should probably be gamma (γ), I believe]; six of the 11 totally disabled patients returned to work on a half time or full time basis, but relapse still occurred in most patients after heavy exertion a few months later.

Just prior to that quote a patient is also described who was in remission for 14 months from the combination of interferon-α and interferon-γ. The patient did respond to an additional course of treatment after relapsing.

From other sources, it appears that Dr Chia eventually abandoned using interferon treatments due to many of the patients not tolerating the side-effects.

However, assuming Prof Phair’s metabolic trap hypothesis is correct (and that Chia’s enterovirus findings are anomalous), and assuming it's desirable to attempt to break the trap by upregulating expression of IDO1 (as opposed to other possible strategies such as tryptophan depletion), then presumably only interferon-γ would need to be used because it is the natural direct inducer of IDO1. Interferon-α induces IDO1 but primarily in an indirect manner (including through the generation of interferon-gamma), and with additional side-effects.

 

[Jackb23]

Is it possible to not have significant mitochondrial energy issues and still have the metabolic trap? Reason I ask is because I completed some testing by metabolon and they found everything to be okay with my mitochondria.

 

[aquariusgirl]

I have 43 DNA variations in IDO2 according to Enlis (UTR:4, INTRON: 38).
I am hetero for R 248-W and hetero for R235-W.

Apparently, as Ppojhadski posted, iron is the co-factor. So what happens if your body is sequestering iron as it does during times of infection ....or if you're hoarding iron , if you have hemochromatosis? Is there a link here...?


@alicec what does it mean that I have 43 variations and none of them are protein coding? any thoughts? thanks you

 

[Murph]

However, assuming Prof Phair’s metabolic trap hypothesis is correct (and that Chia’s enterovirus findings are anomalous), and assuming it's desirable to attempt to break the trap by upregulating expression of IDO1 (as opposed to other possible strategies such as tryptophan depletion), then presumably only interferon-γ would need to be used because it is the natural direct inducer of IDO1. Interferon-α induces IDO1 but primarily in an indirect manner (including through the generation of interferon-gamma), and with additional side-effects.

I've been thinking a bit about your idea here. Assuming we can upregulate the genes that express IDO1, would launching more copies of the enzyme into an environment where they will be substrate inhibited help enough?

Looking at the above graph, yes, IDO1 can still make some kynurenine even at high levels of trp. But would it be enough?

Just eyeballing the chart, the flux produced by IDO2 can be 6 times higher than that from IDO1. Is interferon gamma enough to cause a six fold increase in expression of IDO1?

(*I imagine while typing this that somewhere a cellular biologist is head-desking at how overly simplistic I'm being*)

 

[SherDa]

I woke up and saw Ron Davis' and Phair presentations. Did any researcher talk about the effect of leaky gut and / or microbiome and whether or not it plays a role ?

I would love to know this too given the impact the gut microbiome has on the kynurenine/tryptophan/serotonin pathways. It's been a few months since I've read up about it, but I think it was Bifidobacterium infantis that downregulates the IDO enzyme and maybe lactobacillus upregulated it? I'm not sure if it was discovered whether these occurred via IDO1 or IDO2. Sorry, I can't remember the details and won't have time to read about it for a couple days (too much homework to do!)

 

[Sushi]

How do you look at your Krebs cycle? What test does this?

The NutraEval shows this. I'm sure that there are other tests that do as well though I'm not sure which ones.

 

[Mary]

The NutraEval shows this. I'm sure that there are other tests that do as well though I'm not sure which ones.

Thanks, I had that done several years ago, will dig up my records

 

[ljimbo423]

Is it possible to not have significant mitochondrial energy issues and still have the metabolic trap? Reason I ask is because I completed some testing by metabolon and they found everything to be okay with my mitochondria.

Can I ask what your 3 worst symptoms are? Just wondering if they might be more related to the neuro-inflammation Jarod Younger talked about at the symposium.