IDO Metabolic Trap Hypothesis Published Today

anni66

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We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1. This could be combined with excess Trp in the diet, which some of you know is my hypothesis for how so many athletes and body builders have contracted ME/CFS.

In the Australian Dubbo study of infections, I think it was 9% had ME/CFS symptoms 6 months post-infection. These tended to be those who had the most severe infections, so we're thinking that's the immediate cause of increasing cellular Trp.

Then, of course, after cellular Trp increases beyond the critical point (defined in the paper), you can be cured of the precipitating infection, but you are still in the IDO metabolic trap.
Have genetic impacts on NO therefore been looked at?
 

bread.

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We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1. This could be combined with excess Trp in the diet, which some of you know is my hypothesis for how so many athletes and body builders have contracted ME/CFS.

In the Australian Dubbo study of infections, I think it was 9% had ME/CFS symptoms 6 months post-infection. These tended to be those who had the most severe infections, so we're thinking that's the immediate cause of increasing cellular Trp.

Then, of course, after cellular Trp increases beyond the critical point (defined in the paper), you can be cured of the precipitating infection, but you are still in the IDO metabolic trap.


Hello Dr. P.,

what an honour to have you here with us. Congratulations for publishing this paper!

Do you think that people with a non sudden onset and a continous deteoriation also fit your model?

What about the high number of EDS patients (like myself) in the severly ill subset? You wrote that NO is a strong inhibitor of IDO, to my knowledge NO will rise in a state of hypoxia in any given cell.

We do know that there is a hypoxic state in muscles and nerve tissue in me/cfs. Could this be the reason for mitochondrial damage and/or increased oxidative stress? What else could account for the low energy state (it is not fatigue) and does your theory account for that?

I am sure it does - but I do not see it from reading the paper?


I think Dr. Birch found genetic issues for NO metabolism in a subset of me/cfs patients.

Infections will dramatically increase NO in tissues. High NO would also explain POTS and a chronic compensatory sympathetic state.

EDS and it laxitys in any given structure but also the high numbers of Small Fiber Neuropathy seen in this syndrome seem to be a very good predisposition for a hypoxic state, hence a high NO state, especially with exertion.

The main question will be what drives what, and how much of the damage accumulated is reversible?

THANK YOU.


@HTester
 
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We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1.
Hypothesizing on why did I get SO MUCH WORSE in the last 14 months. I've had: chronic Eppstein Barr...for most of my life, but managed to work for 35 years. But I got MUCH WORSE...and had two bouts of severe intestinal flu (I assumed) (maybe Norovirus, I thought). Emergency Room last summer I thought I was gonna die.

Here is some research that NO can increase substantially in infectious gastroenteritus. (the ER wrote that on my bill). This is an opportunity for IDO1 to have been impaired here, and maybe my tryptophan levels went way up to more decimating levels.

https://academic.oup.com/jid/article/180/2/542/883252

For what is worth, we have nitric oxide saliva test strips...and my husband who does not have ME turns them magenta and I barely register any color at all. I do not recall when I did that test and so its not correlated with when I had the intestinal illnesses.

I did not have food poisoning, I know that.
 
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This could be combined with excess Trp in the diet, which some of you know is my hypothesis for how so many athletes and body builders have contracted ME/CFS
@HTester
Thanks for your important work! I am thrilled you are working on this disease.
I was an collegiate athlete (Division I) and beyond, but never had a high protein diet, including when I contracted this dreadful disease (age 36). Yet, I too wonder why so many former athletes have ME/CFS.
 
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When I got sick, I was playing high school football and hammering the protein and work out supplements. I remember I started N.O. right before I got sick. I was dumb for doing all of that stuff.

Fatigue is not a big problem for me but full body pain, GI issues, and POTS are killer.
I also got sick after a few months of heavy protein consumption trying to gain muscle.

Also had mono right before that which I’m sure didn’t help.
 

aquariusgirl

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I am wondering if Phair, Davis & co find a way to reverse the trap, if there's a risk of IRIS from the unresolved infections?

Also, I believe I read where one suggested treatment was injecting kynurenine into the spine ? Sorry don't have a source. It could be the cancer researchers who are looking at that. Any thoughts on that @HTester?

Finally, (lame anecdote alert) is there any way embryonic stem cells could affect the levels of intracellular trytophan? I am puzzled by the case of a family of 7 who recovered from chronic lyme after getting embryonic stem cells when every other therapy failed.
 
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Hello Dr. P.,

what an honour to have you here with us. Congratulations for publishing this paper!

Do you think that people with a non sudden onset and a continous deteoriation also fit your model?

What about the high number of EDS patients (like myself) in the severly ill subset? You wrote that NO is a strong inhibitor of IDO, to my knowledge NO will rise in a state of hypoxia in any given cell.

We do know that there is a hypoxic state in muscles and nerve tissue in me/cfs. Could this be the reason for mitochondrial damage and/or increased oxidative stress? What else could account for the low energy state (it is not fatigue) and does your theory account for that?

I am sure it does - but I do not see it from reading the paper?


I think Dr. Birch found genetic issues for NO metabolism in a subset of me/cfs patients.

Infections will dramatically increase NO in tissues. High NO would also explain POTS and a chronic compensatory sympathetic state.

EDS and it laxitys in any given structure but also the high numbers of Small Fiber Neuropathy seen in this syndrome seem to be a very good predisposition for a hypoxic state, hence a high NO state, especially with exertion.

The main question will be what drives what, and how much of the damage accumulated is reversible?

THANK YOU.


@HTester
Bread you described what i feel is happening but didn't have the ability to put into words.
 
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Hypothesizing on why did I get SO MUCH WORSE in the last 14 months. I've had: chronic Eppstein Barr...for most of my life, but managed to work for 35 years. But I got MUCH WORSE...and had two bouts of severe intestinal flu (I assumed) (maybe Norovirus, I thought). Emergency Room last summer I thought I was gonna die.

Here is some research that NO can increase substantially in infectious gastroenteritus. (the ER wrote that on my bill). This is an opportunity for IDO1 to have been impaired here, and maybe my tryptophan levels went way up to more decimating levels.

https://academic.oup.com/jid/article/180/2/542/883252

For what is worth, we have nitric oxide saliva test strips...and my husband who does not have ME turns them magenta and I barely register any color at all. I do not recall when I did that test and so its not correlated with when I had the intestinal illnesses.

I did not have food poisoning, I know that.
the same thing happened to me last year...Terrible gastroenteritius ...i felt deathly ill, the POTS and high blood pressure issues went haywire as did the sympathetic nervous system. I didn't think i would survive . It was terrifying.
 
Also, I believe I read where one suggested treatment was injecting kynurenine into the spine ? Sorry don't have a source. It could be the cancer researchers who are looking at that.
@aquariusgirl,

The most recent statement with Dr. Davis talking about Kynurenine injections into the spinal fluid is the April 2019 Research Update, Bedside Chats with Ben. Looking on clinicaltrials.gov the only intervention with L-Kyurenine is a recently completed phase 1 trial to see if "L-Kynurenine induces vasodilation in the cerebral vessels and trigger headache in healthy individuals". I don't know if this is the clinical trial Dr. Davis was referring to in the talk with Ben, due to the trial being administered intravenously and he explicitly said he wanted to inject it into the spinal fluid.

Most likely the next major update on the trap will be at the Stanford Symposium on September 7th. In Dr. Davis's latest video (Harvard Symposium) he mentioned that he's in a holding pattern to have access to the high sensitivity mass spectrometer. It kind of seemed that once the testing was done on the mass spectrometer they would know if the metabolic trap was just a hypothesis or something worth working on treatments for.
 

lauluce

as long as you manage to stay alive, there's hope
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I wonder the following: if the intracelullar concentration of tryptophan is so high in ME, could then the extracellular concentration get actually very low as tryptophan is taken by the cell from the outside?
And beyond that point, once the extracellular concentration has fallen, could that lead to a lower production of tryptophan products such as serotonin in the brain, which is made from blood circulating typtophan? could this lead to further symptoms?
 
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Hip

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Viral infections are communicable, but they don’t last long (days to weeks). The disease itself is noncommunicable, and can often show symptoms months after the viral infection.
Many viral infections clear up after a few weeks, but others can stick around as a low-level chronic infection that lasts indefinitely. Enterovirus is one of the ME/CFS-triggering viruses which can stick around indefinitely, and numerous studies have found chronic enterovirus infections in the muscles, stomach and brains of ME/CFS patients.

ME/CFS is found at around 10 times the normal prevalence in the spouses/partners and children of ME/CFS patients (ref: here), so that does not sound like a disease which is entirely noncommunicable.
 
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We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1. This could be combined with excess Trp in the diet, which some of you know is my hypothesis for how so many athletes and body builders have contracted ME/CFS.

In the Australian Dubbo study of infections, I think it was 9% had ME/CFS symptoms 6 months post-infection. These tended to be those who had the most severe infections, so we're thinking that's the immediate cause of increasing cellular Trp.

Then, of course, after cellular Trp increases beyond the critical point (defined in the paper), you can be cured of the precipitating infection, but you are still in the IDO metabolic trap.
Mr. Phair, I think you are really onto something here. I took a preworkout supplement called N.O. Xplode every day. The N.O., of course, stands for nitric oxide. I talked to Jameson Hill, and he was taking the same supplement daily. I just know our nitric oxide levels had to be really high.

Plus the incredible amounts of protein I was eating every day had to have raised my tryptophan levels! I ate 2 lbs of chicken breast a day, drank 0.75 gallons of milk daily, ate 6 egg whites for breakfast each day, and consumed a lot of protein powder after each workout. I went to bed one night perfectly healthy, and I woke up the next morning with CFS.

I just feel that what you are saying lines up PERFECTLY with my experience. I know you are onto something, you give me such great hope! Please never quit investigating!
 
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Mr. Phair, I think you are really onto something here. I took a preworkout supplement called N.O. Xplode every day. The N.O., of course, stands for nitric oxide. I talked to Jameson Hill, and he was taking the same supplement daily. I just know our nitric oxide levels had to be really high.

Plus the incredible amounts of protein I was eating every day had to have raised my tryptophan levels! I ate 2 lbs of chicken breast a day, drank 0.75 gallons of milk daily, ate 6 egg whites for breakfast each day, and consumed a lot of protein powder after each workout. I went to bed one night perfectly healthy, and I woke up the next morning with CFS.

I just feel that what you are saying lines up PERFECTLY with my experience. I know you are onto something, you give me such great hope! Please never quit investigating!
This scenario sounds so similar to me.

I woke up one morning with ME/CFS and the process/timeline in which it happened lines up with how I imagine the “trap” to occur/set in.

I would eat 12 eggs and 0.5kg of bacon every morning and Around 1-2kg of meat throughout the day to fuel my training. At the West Australian Institute of Sport I was instructed to consume around 24,000kj worth of food a day, which I mostly consumed as meat. I also slept only 4-6 hours a night to get in the necessary study in for senior year/college admissions, so I would require about 400mg of caffeine (minimum) to get me through. I had regular infections and colds from the lack of sleep/gung-ho attitude to life and I believe this tipped me over the edge.

My years of cardio training has allowed me to become in tune with my body. I certainly feel that I don’t ever go into the “aerobic zone” anymore, as if my muscles are stuck in the anaerobic zone of energy production. After little exercise (walking), I have continuous fascicultations throughout my legs; something I never had prior even after literal hours of non stop cardio.

While I know this is an oversimplification of the energy pathways (I have looked at all the threads regarding them), I thought it be best to describe my physical feeling in a way that I always previously thought of it.

I hope this hypothesis proves consistent as it certainly does to my own situation.

All the best @HTester, you have inspired me to go from aerospace engineering to biomedical.

Thank you from Australia,


Jordan
 
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Many viral infections clear up after a few weeks, but others can stick around as a low-level chronic infection that lasts indefinitely. Enterovirus is one of the ME/CFS-triggering viruses which can stick around indefinitely, and numerous studies have found chronic enterovirus infections in the muscles, stomach and brains of ME/CFS patients.

ME/CFS is found at around 10 times the normal prevalence in the spouses/partners and children of ME/CFS patients (ref: here), so that does not sound like a disease which is entirely noncommunicable.
The children correlation is easily explained by genetics. And the spousal correlation can be explained by common exposure to the kinds of viruses that trigger ME/CFS.

Like I said, the initial virus that causes ME/CFS is probably communicable. But there is zero evidence that the disease itself is communicable.
 

bread.

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Many viral infections clear up after a few weeks, but others can stick around as a low-level chronic infection that lasts indefinitely. Enterovirus is one of the ME/CFS-triggering viruses which can stick around indefinitely, and numerous studies have found chronic enterovirus infections in the muscles, stomach and brains of ME/CFS patients.

ME/CFS is found at around 10 times the normal prevalence in the spouses/partners and children of ME/CFS patients (ref: here), so that does not sound like a disease which is entirely noncommunicable.


hey!

would you be interested in writing a „pr primer for enteroviruses in relation to me/cfs“? Maybe that would help to build up pressure from within the community!

what is the latest? why is nobody seriously working on this? etc.

I do believe that me/cfs is a very complex heterogenic, polygenetic plus environmental trigger (multiple, in a add on fashion) secondary mitochondriopathy disease (and this is also just a subset probably), but if that is not the case I believe Enteroviruses should be on the forefront of what should be looked into.
 

Hip

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Like I said, the initial virus that causes ME/CFS is probably communicable. But there is zero evidence that the disease itself is communicable.
If the viruses that are thought to cause ME/CFS are communicable (which they are), then that means the disease is also communicable.

Although with enterovirus, this is associated with several diseases, including: type 1 diabetes, Parkinson's, ALS, sudden heart attacks, mitral valve prolapse, Sjogren's, Crohn's, and is a known cause of viral myocarditis. So you may catch enterovirus from an ME/CFS patient, but the disease you develop may not be ME/CFS, but may be one of these other diseases. But there is also a chance you will develop ME/CFS.

I've seen this for myself: the Coxsackie B4 virus which appeared to trigger my ME/CFS spread over several years to more than 30 friends and family, and lots of the above diseases suddenly appeared in these 30+ people. See this post for all the details of the diseases my virus triggered as others caught it from me.



I believe Enteroviruses should be on the forefront of what should be looked into.
I've a big interest in enterovirus, and have helped write several MEpedia articles on this virus.