Metabolic Trap, wouldn't we suffer from serotonin abnormality?

[taniaaust1]

Its hard to find info on symptoms of high serotonin not serotonin Syndrome.

This website says:

• Shivering
• Muscle stiffness
• Confusion
• Restlessness
• Agitation
• Rapid heart rate
• Sweating
• Loss of coordination
• Twitching muscles

https://www.naturalstacks.com/blogs...#Symptoms-of-high-levels-of-serotonin-include

While we do have some of those symptoms we don't have others and our main symptoms aren't really described by this

If I crash badly, I can go into ALL those above symptoms. This caused a doctor who saw me in a very crashed state one time to actually phone an ambulance as he thought I had Serotonin syndrome. Note I wasnt on any drugs which give that but the doctor I do not think he believed me and he became convinced that was what was wrong with me and would not believe me that just a bad ME crash causes me those symptoms.

"Serotonin syndrome symptoms usually occur within several hours of taking a new drug or increasing the dose of a drug you're already taking. Signs and symptoms include:

• Agitation or restlessness
• Confusion
• Rapid heart rate and high blood pressure
• Dilated pupils
• Loss of muscle coordination or twitching muscles
• Muscle rigidity
• Heavy sweating
• Diarrhea
• Headache
• Shivering
• Goose bumps

Severe serotonin syndrome can be life-threatening. Signs and symptoms include:

• High fever
• Seizures
• Irregular heartbeat
• Unconsciousness "

The only things on that list I did not have on that day I was at the doctors while in a very bad ME rash was I did not have diarrhea and I was conscious though I did feel like I was about to pass out. I even had the issue with my pupils going on and they were not responding properly.

 

[pattismith]

interferon gamma increases IDO1 expression, which lowers intracellular tryptophan and fight bacterial and virus (low intracellular tryptophan directly starves intracellular chlamydia and stop them to grow up and proliferate).

"IFNG : This gene encodes a soluble cytokine that is a member of the type II interferon class. The encoded protein is secreted by cells of both the innate and adaptive immune systems. The active protein is a homodimer that binds to the interferon gamma receptor which triggers a cellular response to viral and microbial infections. Mutations in this gene are associated with an increased susceptibility to viral, bacterial and parasitic infections and to several autoimmune diseases."


So if this metabolic trap is correct, I suppose alteration in the IFNG gene would be a predisposition to ME/CFS.

 

[FMMM1]

interferon gamma increases IDO1 expression, which lowers intracellular tryptophan and fight bacterial and virus (low intracellular tryptophan directly starves intracellular chlamydia and stop them to grow up and proliferate).

"IFNG : This gene encodes a soluble cytokine that is a member of the type II interferon class. The encoded protein is secreted by cells of both the innate and adaptive immune systems. The active protein is a homodimer that binds to the interferon gamma receptor which triggers a cellular response to viral and microbial infections. Mutations in this gene are associated with an increased susceptibility to viral, bacterial and parasitic infections and to several autoimmune diseases."


So if this metabolic trap is correct, I suppose alteration in the IFNG gene would be a predisposition to ME/CFS.

Re-written:

I've been exchanging posts with @nandixon regarding this [https://forums.phoenixrising.me/ind...otonin-abnormality.61946/page-2#post-1012575]. Here's nandixon take:
"Some subsets of PBMCs apparently aren't affected by INFg with respect to expression of IDO1, though. Lymphocytes are one example if I remember correctly. (I can't remember whether dendritic cells, which may be more important in this context, are or not.)"

I assume that @nandixon is correct i.e. INFg increases IDO1 expression. Cells which respond in this way will clear more tryptophan.

I was wondering if in practice this gives rise to a trap in some cells and not in others. I.e. some cells will have high levels of tryptophan (since they can't clear it with IDO1) i.e. enough to spring the trap; and others won't reach this point (since they can clear it with IDO1). Keep in mind that you seem to need the relatively common mutation on IDO2 [40 percent + of the population] i.e. to spring the trap.

Maybe this contributes to the "messiness" of ME/CFS data i.e. some people are effected to a different degree due to INFg.

Answer is just to get the scientists to test it i.e. OMF tested 6 people they (and others) can test more.


Consider writing to your elected representative i.e. to request funding for ME/CFS research including the development of a diagnostic test.
I've written to the European Union Committee on the Environment, Public Health and Food Safety (ENVI) requesting that they lobby for funding for research into ME/CFS including the development of a diagnostic test [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1003111].
Currently the ENVI Committee is lobbying for increased funding for research into Lyme disease and the development of a diagnostic test.
In 2016 the European Commission [European Union civil service] said [regarding Lyme disease] that "Both basic research and the development of new diagnostics, treatments and vaccines for Lyme borreliosis are funded by EU research and innovation framework programmes. The total EU contribution to such projects since 2007 amounts to EUR 33.9 million [US dollars]" [http://www.europarl.europa.eu/doceo/document/E-8-2016-008631-ASW_EN.html].

ME/CFS received no funding from the European Union [http://www.europarl.europa.eu/doceo/document/E-8-2017-006901-ASW_EN.html].

 

[pattismith]

In the perspective of a potential serotonin syndrome, Ambroxol may be beneficial, this study was released some months ago:

In vitro pharmacology of ambroxol: Potential serotonergic sites of action
Significance
Together, these studies indicate that ambroxol may exert its beneficial properties via antagonism of the 5-HT3 serotonin receptor and/or inhibition of serotonin uptake (5-HT transport: SERT), in addition to its reported effects at the sodium channel and guanylate cyclase.

 

[pattismith]

interferon gamma increases IDO1 expression, which lowers intracellular tryptophan and fight bacterial and virus (low intracellular tryptophan directly starves intracellular chlamydia and stop them to grow up and proliferate).

"IFNG : This gene encodes a soluble cytokine that is a member of the type II interferon class. The encoded protein is secreted by cells of both the innate and adaptive immune systems. The active protein is a homodimer that binds to the interferon gamma receptor which triggers a cellular response to viral and microbial infections. Mutations in this gene are associated with an increased susceptibility to viral, bacterial and parasitic infections and to several autoimmune diseases."


So if this metabolic trap is correct, I suppose alteration in the IFNG gene would be a predisposition to ME/CFS.

sorry to quote myself but here what has been found about IFNG, CFS patients would be high IFNG producers!

However I wonder of this finding is significant, I would like to know more about polymorphism for the IFNGR1, because impairment of this receptor leads to impaired INF gamma activity


Clin Exp Rheumatol. 2006
A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles.

Abstract
OBJECTIVE:
In the past two years we have developed a biological bank of genomic DNA, cDNA, serum and red blood cells of Italian patients with certified CFS from the two Italian referral centers for the syndrome. Recent studies have shown an imbalance in cytokine production in disease states similar to Chronic Fatigue Syndrome (CFS), such as sickness behavior, both in animals and in humans. However we notice that serum cytokine concentrations are often inconstant and degrade rapidly. With this in mind, we investigated cytokine gene polymorphisms in 80 Italian patients with CFS in order to ascertain whether in this group of patients it is possible to describe a genetic predisposition to an inflammatory response.

METHODS:
We analyzed the promoter polymorphisms of IL-10, IL-6 and the IFNgamma 874 T/A polymorphism in intron 1 with a PCR-SSP method (Cytogen One Lambda Inc. Canoga Park, CA, U.S.A) in 54 patients and TNF-308 G/A and -857 C/T promoter polymorphisms with a PCR-RFLP method (in 54 and 80 patients respectively).

RESULTS:
There is a highly significant increase of TNF -857 TT and CT genotypes (p = 0.002) among patients with respect to controls and a significant decrease of IFN gamma low producers (A/A) (p = 0.04) among patients with respect to controls.

CONCLUSIONS:
We hypothesize that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults of unknown nature.

 

[JaimeS]

So I wonder if it's 'just' the serotonin receptors 'adapt' (potentially causing a functional depression without actual depression), but other receptors could have adapted like this also in ME CFS, such as KDM mentioned?

After the 6 mo to a year we may all be deficient in everything. But the receptors do get more sensitive and/or more numerous over time, and so your body behaves as though everything's pretty normal. This means shifts up and down in hormones and neurotransmitters have more drastic consequences, though -- every tiny tick up and down is a huge percent difference compared to a normal person's.

That's interesting -- that's the first time I've thought of this as a mechanistic explanation why pwME have trouble coping with changes in anything.

 

[JaimeS]

In the perspective of a potential serotonin syndrome, Ambroxol may be beneficial, this study was released some months ago:

In vitro pharmacology of ambroxol: Potential serotonergic sites of action
Significance
Together, these studies indicate that ambroxol may exert its beneficial properties via antagonism of the 5-HT3 serotonin receptor and/or inhibition of serotonin uptake (5-HT transport: SERT), in addition to its reported effects at the sodium channel and guanylate cyclase.

I was actually thinking of 5-HT3 blockers as treatments for ME awhile back. My reaction to serotonin was so dramatic that I was thinking about this therapeutically for awhile. Cortisol blockers, too.

 

[JaimeS]

A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles.

New
In one case 80 pts, in one case 54.

:thumbdown:

Genetics needs more. Don't care what the p values appear to be.

 

[bertiedog]

Because of chronic migraines, sometimes almost daily I have used the Triptans to help to get me out of pain. I do respond quite well to them as long as I only use them occasionally otherwise I get rebound migraines. For the other migraines I just take paracetamol and a bit of codeine and basically have to put up with the pain until the attack wears off after 48 hours or so.

My understanding is that the Triptans work by stimulating serotonin so was wondering if this fits in with the new theory? I also know that the Triptans cause vasoconstriction which helps with a migraine attack.

Also I have got some SNPs that might interfere with the production and removal of serotonin. At the moment I cannot remember what they are as I have had some huge stress in the past 24 hours as my Beagle has developed seizures but can look them up sometime.

Pam

 

[JaimeS]

My understanding is that the Triptans work by stimulating serotonin so was wondering if this fits in with the new theory?

?!?!?

What I hear is that serotonin *blockers* help with migraine -- that's the mechanism behind feverfew. If I take a pill of that and go to sleep, when I wake up, my migraine is gone.

Citation: https://www.ncbi.nlm.nih.gov/pubmed/17163262

This would be far from the first time that supposed agonists and antagonists to a receptor end up with similar action. If something is not a 'perfect fit' to the serotonin receptor, it can block 'real serotonin' from binding, but still induce a (milder) serotinergic effect than true serotonin would do.

A conventional blocker could end up having the same result.

 

[JaimeS]

Also I have got some SNPs that might interfere with the production and removal of serotonin.

I'm also a "slow processor" so the serotonin I do make hangs around longer than average.

 

[sb4]

So one of the bodies responses to infection is to inducr interferon gama which activates TDO in order to starve the pathogen of Tryptophan. So what happens if our b-cells (or whatever cells) are the ones that don't have TDO yet have problems with IDO2 and are infected? Unlimited supply of Tryptophan for pathogen?

 

[Martin aka paused||M.E.]

Sorry if answered elsewhere but what would happen if one with high levels of serotonin would take SSRI?

 

[andyguitar]

It could make you very ill @MartinDH

 

[andyguitar]

To cut a long story short consider this. Can elevated levels of Serotonin in the brain cause inflammation? If yes could that inflammation cause the symptoms of ME/CFS by way of defective signaling in the brain? Next question. If this is the case how long would it take for the inflammation to go? Few hours, few months, few years?

 

[Wishful]

TRP elevates my ME symptoms, but 5-HTP--which converts to serotonin but not kynurenines--doesn't. Elevated kynurenines are more likely involved in ME.

 

[FMMM1]

So one of the bodies responses to infection is to inducr interferon gama which activates TDO in order to starve the pathogen of Tryptophan. So what happens if our b-cells (or whatever cells) are the ones that don't have TDO yet have problems with IDO2 and are infected? Unlimited supply of Tryptophan for pathogen?

Really don't know much about this but intracellular tryptophan is presumed to be high i.e. based on a limited number of people with ME/CFS. Plasma/serum tryptophan may be high or low i.e. may not be related to intracellular levels. If your pathogen doesn't have access to intracellular tryptophan then I'm not clear whether it would have access to high/low tryptophan.

 

[FMMM1]

TRP elevates my ME symptoms, but 5-HTP--which converts to serotonin but not kynurenines--doesn't. Elevated kynurenines are more likely involved in ME.

Really don't know much about this. If you listed to Ron Davis talk, and Phair's talk, (OMF Conference 2018) then I think kynurenine is low i.e. because IDO1 & IDO2 aren't converting tryptophan to kynurenine.

Maybe this will help:
Stanford Community Symposium 2018: Phair, Metabolic traps ...

https://www.s4me.info › ... › ME/CFS News and Research › BioMedical ME/CFS News
7 Nov 2018 - 20 posts - ‎10 authors
That means that the original clue identifying IDO2 doesn't really ... Data was shown for tryptophanand kynurenine, but if the biological ..... tryptophan isn't being removed by the normal route to byconversion to N-formylkynurenine. .... Also, the lower limit of detection (LOD) for these mRNAs isn'tlow enough

 

[sb4]

Really don't know much about this but intracellular tryptophan is presumed to be high i.e. based on a limited number of people with ME/CFS. Plasma/serum tryptophan may be high or low i.e. may not be related to intracellular levels. If your pathogen doesn't have access to intracellular tryptophan then I'm not clear whether it would have access to high/low tryptophan.

Yeah, this is what i am saying though. If the cells that have the IDO2 problem and tryptophan problem (so the ones that are missing TDO) also have the pathogen inside them then that could be double trouble if the pathogen feeds off of Tryptophan as it appears many pathogens do.

 

[FMMM1]

Yeah, this is what i am saying though. If the cells that have the IDO2 problem and tryptophan problem (so the ones that are missing TDO) also have the pathogen inside them then that could be double trouble if the pathogen feeds off of Tryptophan as it appears many pathogens do.

Yea see what you mean. If you Google "intracellular tryptophan" then you see a bunch of stuff on pathogens. Problem is everything gets degraded, including pathogens inside cells, and their DNA/RNA?(whatever it is i.e. their genetic signature) ends up in the bloodstream. When Ron Davis's group went looking for pathogens (i.e. their genetic signature in blood) they found nothing. Check out Ron's talk at the 2017 Community Symposium. Ron's done the same talk a number of times; he doesn't entirely rule out something lurking somewhere e.g. trypanosomes. Google "trypanosomes me cfs" and you'll find some stuff re Ron's gene expression findings.