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

adambeyoncelowe said:
So what does this mean? Is it likely this is a side-effect of long-term amitriptyline use (or similar)? If not, would long-term use of these drugs worsen the problem?
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In terms of reduced 5MT levels, yes, it seems to be a side effect, and, yes, it would seem to have the possibility of worsening the problem (or at least as I understand it).
 
I have a possibly dumb question about the trap

After watching Phair's presentation plus reading about it on a blog (https://paolomaccallini.com/2018/10/08/is-it-a-trap/) I think I understand the concept of the metabolic trap.

What I don't understand is how it gets started. I get that there has to be an excess of tryptophan for the trap to spring, but where does all that tryptophan come from in the first place? What is the mechanism that gets us from the trigger, let's say EBV for example, to having too much tryptophan? Surely it's not just eating too much chicken soup – contains tryptophan – when ill with glandular fever ;)!

Incidentally, the blog contains a list of the snps (rs numbers) Phair looked at; 3 of them can be looked up on 23andMe. @nonstopflu
 
Ravn said:
I have a possibly dumb question about the trap

After watching Phair's presentation plus reading about it on a blog (https://paolomaccallini.com/2018/10/08/is-it-a-trap/) I think I understand the concept of the metabolic trap.

What I don't understand is how it gets started. I get that there has to be an excess of tryptophan for the trap to spring, but where does all that tryptophan come from in the first place? What is the mechanism that gets us from the trigger, let's say EBV for example, to having too much tryptophan? Surely it's not just eating too much chicken soup – contains tryptophan – when ill with glandular fever ;)!
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I had the same question after watching Phair's presentation. I don't have a biology background - so it's quite possible that I'm wrong about this (and consequently I'm very happy to be corrected...) - but I think the explanation is that there are actually three enzymes which degrade tryptophan down the kyneurenic pathway. The third enzyme is tryptophan 2,3-dioxygenase (TDO), which is mentioned in the blog post you linked to. TDO exists mostly in the liver and when we're healthy it does the bulk of the work converting tryptophan to kyneurine. When we get ill and our immune system is activated, TDO seems to be inhibited and IDO (which is found in tissues other than the liver) activity is simultaneously dramatically uprated. So as I understand it Phair's theory is that the tryptophan levels start to rise when we get ill because TDO is down-regulated - and IDO is then supposed to take over but can't.
 
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Ravn said:
What I don't understand is how it gets started.
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I think this is a reasonable question. I find it hard to see how this theory can give the right system dynamics and after all that is what Dr Phair is supposed to focus on. At least the illness should flip into energy shortage and out, if it varies at all. My impression is that ME is not 'on-off' like that.
 
Jonathan Edwards said:
I think this is a reasonable question. I find it hard to see how this theory can give the right system dynamics and after all that is what Dr Phair is supposed to focus on. At least the illness should flip into energy shortage and out, if it varies at all. My impression is that ME is not 'on-off' like that.
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Is that always the case? Cannot some systems simply latch into a self-limiting static state, stuck a long way off from where the normal control point would be? Especially if some aspect of self regulation has gone awry? Maybe flipped into positive feedback? Certainly true of physical systems, and one of the things that has intrigued me the last couple of years is how biology has so much self-regulation integral to it. Needless to say, as you know, I've no medical knowledge, but this aspect also intrigues me.
 
Trish said:
No idea. It seemed that the metabolic trap was affecting the other pathway from tryptophan to kynurenine, not the pathway from tryptophan to serotonin, though I guess there could be a link.

The particular biological pathway he highlighted was based on a genetic variant of the IDO2 gene observed in the severe ME CFS study patient's genomes. His idea was that since ME sometimes occurs in outbreaks, there must be a common genetic variant that predisposes a lot of people to develop ME. He looked for common genes that occurred more often in the study group and found this particular gene where there are several mutations possible that mean a pathway from tryptophan to kynurenine is disrupted if the tryptophan level rises too high.

There is another gene for making kynurenine from tryptophan, so having one disrupted is not normally a problem as both pathways combine to produce enough kynurenine.

But if the tryptophan level rises too high, the pathway under study here switches to producing less kynurenine, more tryptophan builds up, and makes the situation worse, so the biochemistry is trapped in an unhealthy steady state. Hence metabolic trap.

I don't know why I've tried to explain all that. I hope I've got it right. I found it absolutely fascinating. I wonder whether @Chris Ponting has looked at this gene.

And the key point for patients that Ron Davis emphasised about this research is not to try messing about with our levels of any of the chemicals involved such as tryptophan. He says that could be very dangerous.
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Is there a written primer on any of this anywhere?

Edit: I realise that Robert Phair's presentation (which I'd not had a chance to look at until now) is a good primer in its own right. Also @paolo's blog.
 
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Stewart said:
I had the same question after watching Phair's presentation. I don't have a biology background - so it's quite possible that I'm wrong about this (and consequently I'm very happy to be corrected...) - but I think the explanation is that there are actually three enzymes which degrade tryptophan down the kyneurenic pathway. The third enzyme is tryptophan 2,3-dioxygenase (TDO), which is mentioned in the blog post you linked to. TDO exists mostly in the liver and when we're healthy it does the bulk of the work converting tryptophan to kyneurine. When we get ill and our immune system is activated, TDO seems to be inhibited and IDO (which is found in tissues other than the liver) activity is simultaneously dramatically uprated. So as I understand it Phair's theory is that the tryptophan levels start to rise when we get ill because TDO is down-regulated - and IDO is then supposed to take over but can't.
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As I understand it the actual trap hypothesis is more concerned with IDO1 inhibition than TDO (plus of course the IDO2 fault) but if what you say about TDO is correct, @Stewart, that could certainly be one way to explain the initiation of the trap, which is exactly what my question was. For this we would have to assume that a viral or other ME triggers could downregulate TDO causing tryptophan to increase for long enough to spring the IDO1/IDO2 trap. Is this possible/plausible? @mariovitali (you seem to know a lot about the liver)?

Further trying to answer my own question: what else could cause high tryptophan in the first place, before the trap has sprung and locked us into a vicious circle?

Logically there are two main considerations, too much tryptophan entering, and tryptophan not being broken down fast enough.

1/ Too much tryptophan enters the system:
  • Tryptophan is an essential amino acid so diet has to be assumed to be the main source of it. To me it seems unlikely that all ME patients were consuming excessive amounts of tryptophan foods at the time of their triggering infection, or other trigger happening.
  • Can tryptophan be synthesised by the microbiome? And if so, in sufficient quantities to cause a problem? I have no idea but it would be surprising given tryptophan's essential amino acid status.
2/ Tryptophan does not get broken down fast enough:
  • Could there be another cause for IDO1 to be downregulated, other than the excess tryptophan levels accounted for in the trap? E.g. could a viral infection downregulate IDO1?
  • Could one or more of the other tryptophan pathways be downregulated, i.e. the kyrunenine via TDO pathway (as discussed above) and/or the serotonin pathway? Could either of those be downregulated by a viral infection or other trigger?
  • Presumably none of the above, IDO1, TDO or serotonin are downregulated by additional mutations or these would have been found already?
Ok, so I didn't answer my own question, just expanded it into many more. Oh well.
 
paolo said:
Thanks for mentioning my blog post. I searched for a way to better understand the trap hypothesis and I found the mechanical analogy.
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You're welcome @paolo. I do enjoy your blog and often find it helpful when trying to get my head around a complex ME issue. Though in this particular case your mechanical analogy didn't work for me, too abstract for my way of thinking maybe? But I'm sure it's just perfect for somebody else; we all think and comprehend differently. In any case, the rest of your explanation was very clear.
 
Jenny TipsforME said:
I’ve written a blog post about my attempt to understand https://tipsforme.wordpress.com/2018/10/13/understanding-the-ido-metabolic-trap-hypothesis
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You ask a lot of good questions in your blog @Jenny TipsforME, so good I'd like to highlight just a few here.
What about varying severity steps up and down
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This had entered my mind, too. The way the hypothesis was presented I could understand how it could explain switching into – or out of – ME mode, a sudden on/off switch. Sure, this happens sometimes but often there are changes from one level of severity to another, sometimes sudden, sometimes gradual, and the trap didn't seem to explain those events.
IDO1 is subject to substrate inhibition — the enzymatic reaction stops when there is too much substrate (tryptophan). The substrate is competing with each other to get to the active site of the enzyme. So much fighting to get in, the enzyme just sits there waiting for something “to get in its belly!”… meanwhile, substrate level (tryptophan) continues to rise and rise.” Phair
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In fact, doesn't that sound as though ME should be a progressively deteriorating condition, according to this hypothesis? What stops the trap, for most patients, from becoming an ever worsening vicious circle?
If you correct low kynurenine will correcting that reset ME
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There was some talk somewhere of testing this. But wouldn't that be intervening at the wrong end of the trap? I can see how adding some extra kynurenine into the system could potentially alleviate downstream effects of having too little kynurenine but how would that fix the excess tryptophan that triggered the trap in the first place? Plus whatever havoc the excess tryptophan is creating in the serotonin pathway?
If you watch the presentation on the IDO Trap, the message not to attempt to hack the kynurenine pathway ourselves is loud and clear.
However, it would be really useful to get more clarity about things we might already be taking or doing. Are there things we should stop? Or should we carry on as normal?
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Quite!

If I sound skeptical about the trap it's just because there are so many parts I still don't understand. I would love for the hypothesis to be true simply because it seems to offer hope for better and faster treatments than other hypotheses. And I do have a couple of the mutations so would have a good argument to receive said hypothetical treatment... {and here Ravn disappeared into daydream land}.

Edit: typo
 
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Cortisol seems important as ( as far as i can tell and i coukd be wrong) it has no " nested control" system as Barry has previously described- perhaps because it is a key player in fight or flight, and hence survival.

It also impacts hundreds of other genes and processes , ( including adrenaline ) if it goes " rogue" , merry hell may break loose.

Factor in common SNPs and feedback loops on many other proceses may be affected.

This is Sunday morning wittering so please feel free to disregard if it sounds weird.
 
The fascinating part of the presentation was the analsis of what the enzymes did.

There are probably many other genes where function overlaps and it is simply assumed that others within the " group" compensate.

Given what has been found - what if they don' t

What are the most common of such gene groups and what actually happens

What happens when there is a complete absence ' eg GTSM1. I understand that this particular one is commonly missing. Could it be part of the perfect storm ?
 
Barry said:
Is that always the case? Cannot some systems simply latch into a self-limiting static state, stuck a long way off from where the normal control point would be?
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Yes, indeed. It could get to a new place and stay there. Or it could maybe flip flop between states. You see that with paroxysmal atrial tachycardia. But PWME are not in one of two states. They go up and down in various steps and often fairly gradually as I understand it. And there does not seem to be a positive feedback loop here, just a rate shift that could create a bottleneck.
 
Jim001 said:
I dont recall Phair mentioning the TDO enzyme. Was it just implied?
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Robert Phair didn't mention TDO or even imply it. I apologise if I gave the impression he had - that wasn't my intent. I came across the role of TDO while reading up on kyneurine after watching Phair's presentation and I've tried to make sense of how it would it would fit with his metabolic trap hypothesis.

It seems pretty clear (to me at least) that we don't have the full picture yet of the metabolic trap theory yet. Phair's talk at the Stanford symposium was obviously limited by the time available, and it focussed almost exclusively on the tryptophan-kyneurine pathway. We know from public comments by Phair and Ron Davis that they are looking at a number of different metabolic traps, so it seems that the theory is almost certainly a lot more complex than the talk may have implied.
 
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I am not really well enough to look into this but it was my understanding was that most of our tryptophan was derived from bacteria in our guts.

doing a quick pubmed search I saw this https://www.ncbi.nlm.nih.gov/pubmed/30054537
Gut microbiota modulation accounts for the neuroprotective properties of anthocyanins.
"Here, we demonstrate that the blackberry anthocyanin-rich extract (BE) can modulate gut microbiota composition and counteract some of the features of HF-diet induced dysbiosis. In addition, we show that the modifications in gut microbial environment are partially linked with the anti-neuroinflammatory properties of BE. Through fecal metabolome analysis, we unravel the mechanism by which BE participates in the bilateral communication between the gut and the brain. BE alters host tryptophan metabolism, increasing the production of the neuroprotective metabolite kynurenic acid."

So this may link into some of the odd gut related improvements and declines some of us (me) see in ME/CFS. I have been mostly horizontal and fogged in this year after taking a couple of courses of antibiotics in an attempt to get rid of b. hominis.
 
It just occurred to me that I have been supplementing with bifidobacterium longum and bifidogenic foods all year and b longum makes tryptophan https://www.datapunk.net/substrata/display.pl?216816+S

I have been following the path I knew to be cargo cult science - see what a healthy gut looks like in someone without ME/CFS and try to copy it. But it may be the case that our versions of healthy pre-ME/CFS guts were unlike those who do not have these SNPs. If Phair turns out to be right about the metabolic trap.
 
richard7 said:
BE alters host tryptophan metabolism, increasing the production of the neuroprotective metabolite kynurenic acid.
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I've only read the abstract which I interpret - in/correctly? - as not referring to tryptophan synthesis but only to tryptophan metabolism, i.e. the conversion of – presumably dietary - tryptophan into other metabolites such as kynurenic acid.

Does the article itself say anything more? It's too long for my current energy level to read.
 
This potential ME-trigger-to-tryptophan route is mighty confusing.

On the one hand stressors and infections can upregulate IDO and TDO, potentially causing tryptophan to decrease.
On the other hand certain infections (unfortunately the usual ME suspects were not tested in this study) are thought to cause hypoxia conditions in the liver and this in turn to downregulate TDO, potentially causing tryptophan to rise.
Immune-mediated catabolism of tryptophan by tryptophan 2,3-dioxygenase (TDO) may also impair serotonin synthesis, by decreasing levels of the precursor. TDO is up-regulated by increased cortisol levels due to stress. [...]
During the onset of an infection or immune response (i.e., the presence of a danger signal) and the subsequent release of proinflammatory cytokines—including IFN-γ—many cell types react with robust IDO synthesis and tryptophan catabolism.
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https://www.sciencedirect.com/topic...-molecular-biology/tryptophan-2-3-dioxygenase
Negative Impact of Hypoxia on Tryptophan 2,3-Dioxygenase Function
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https://www.hindawi.com/journals/mi/2016/1638916/
 
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