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Indoleamine 2,3-dioxygenase

Messages
69
I want to discuss the Tryptophan pathway as it is related to CFS and see if there's any interest. I'll keep this fairly short.

Fructose.

I want to first discuss the role of fructose in the Tryptophan pathway as it relates to those with CFS. An estimated 25-30% of the general population have issues with fructose malabsorption, estimates of 45-70% in those with CFS. You will need to take this with a grain of salt as I have, these appear to be claims. But in IBS and Crohns it is a certainty you will experience issues metabolizing fructose. The best idea here is to ask yourself how you do with fruit I suppose.

A common thread between those with CFS is a high prevalence of digestive issues, either earlier on in their condition or ongoing.

In those with Fructose Malabsorption, fructose (especially in high fructose corn syrup) won't digest properly in the gut, and will ferment. This has a significant impact on gut health.

Why it's relevant to CFS?

"Fructose malabsorption (breath DH2 production>20 ppm) was detected in 35 of 50 individuals (70%). Subjects with fructose malabsorption showed signifcantly lower plasma tryptophan concentrations and significantly higher scores in the Beck depression inventory compared to those with normal fructose absorption. Conclusions: Fructose malabsorption is associated"

In these studies, Tryptophan was found to be significantly decreased in serum, and depression was noted indicating impaired Tryptophan to Serotonin conversion.

But Kynurenine was unchanged.

Tryptophan metabolism follows two pathways, both equally important.

1. TRYPTOPHAN>5-Hydroxy-tryptophan>5-Hydroxy-tryptamine (serotonin)>Melatonin
2. TRYPTOPHAN>N-formyl-kynurenine>kynurenine>2,amino,3(3-oxoprop-enyl)-fumaric acid>quinolinate>niacin

Indoleamine 2,3-dioxygenase.


IDO along with tryptophan,2,3-deoxygenase are responsible for the conversion of Tryptophan to n-formyl-kynurenine.

IDO & TDO are the rate limiting steps for conversion.

"Generating mice deficient for tryptophan 2,3-dioxygenase and comparing them to the wild type, the group found that the tryptophan 2,3-dioxygenase-deficient mice showed increased plasma levels not only of tryptophan, but also of serotonin and 5-HIAA in the hippocampus and midbrain."


Overactive IDO enzyme activity has been heavily implicated in chronic fatigue syndrome. During times of increased immune function and resultant interferon-y release, IDO becomes overactive, putting a great deal more emphasis on kynurenine synthesis. This is how our body protects itself during acute illness, but research has shown chronic illness to keep IDO active. This is important for two reasons.

1. Patients with elevated kynurenine, and overactive IDO function (Huntingtons, alzheimers, parkinsons, lyme, mononucleosis etc.) Adopt identical symptoms to those of us with CFS. During treatments with interferon-a, patients also develop what is usually temporary CFS symptoms (they claim it's horrible, yet laugh at us and call us malingerers not realizing it's a life sentence for us).
2. Through constant up regulation of IDO by interferon, this enzyme will eventually remain elevated, regardless of viral status.

The body will respond to an upregulation of IDO by releasing more interferon, this will cause further inflammation.

When the gut becomes inflamed, there is a drastic change in our microbiome.

L.Reuteri is only found in 9-30% of people, 30% being now antiquated. The administration of therapeutic dosages of Reuteri were shown very effective in mitigating liver damage in high fructose fed rats. Reuteri has not been investigated much in its role on fructose metabolism, but may well coincide with fructose intolerance given the estimated prevalence.

What reuteri is also able to do, is increase serotonin and normalize faulty kynurenine processing, these are in therapeutically relevant doses. 5-100 Billion CFU strain probiotics are not therapeutic, 50-100 could be fine for the average Joe. But actual treatment is in the 500 billion-3.6 trillion daily dosage. I haven't been able to find anyone on here who has maintained a week of this standard.

Another relevant compound I see nothing about is the IDO inhibitor rosmarinic acid taken in therapeutically relevant doses. I find this interesting as it points to a lack of trial and error on a large scale with treating IDO up regulation or kynurenine, I also see very little KYN testing going on.

This is something for people to look into I believe, and take very seriously.
 

alicec

Senior Member
Messages
1,572
Location
Australia
Based on the single study you linked done in 2000, which doesn't appear to have been repeated or expanded on in subsequent years, I see there are lots of claims on internet sites that fructose malabsorption causes depression through interfering with tryptophan uptake - ie less tryptophan is available for metabolism by either of the two pathways you go on to describe.

Even if this is true (and the evidence is pretty thin) I don't follow what this has to do with the claims about increased IDO activity in CFS.

Kynurenic acid is one of the metabolites tested on OATS. Lots of people on PR have had these tests. Some have reported elevated values, some haven't as far as I recall.
 
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Messages
69
Based on the single study you linked done in 2000, which doesn't appear to have been repeated or expanded on in subsequent years, I see there are lots of claims on internet sites that fructose malabsorption causes depression through interfering with tryptophan uptake - ie less tryptophan is available for metabolism by either of the two pathways you go on to describe.

Even if this is true (and the evidence is pretty thin) I don't follow what this has to do with the claims about increased IDO activity in CFS.

I didn't claim it was the cause. I'm saying that consuming fructose will cause gut inflammation in those who cannot properly metabolize fructose.

https://books.google.ca/books?id=K1LxBwAAQBAJ&pg=PA75&lpg=PA75&dq=fructose kynurenine&source=bl&ots=V_2WmKRjxS&sig=ZFwbSQqAFO2WfAKMOagK76cOEgA&hl=en&sa=X&ved=0ahUKEwi8iZOznJfWAhVhsVQKHf5SB6MQ6AEIQzAG#v=onepage&q=fructose kynurenine&f=false

What I meant, was that of fructose malabsorbers, a significant decrease in serum tryptophan was noted, without significant kynurenine decrease, indicating that emphasis had shifted towards kynurenine, in the absence of tryptophan depression increased (serotonin is made from tryptophan and plays a role in mood), and kynurenine stayed relatively the same.

In this study, a small subset of people had increased levels of Kynurenine and decreased tryptophan. Indicating a gradient, those who were already of poor health had a greater immune response to the fructose, with decreasing Tryptophan.

Kind of like how some people get CFS and most don't.
 
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Messages
69
Based on the single study you linked done in 2000, which doesn't appear to have been repeated or expanded on in subsequent years, I see there are lots of claims on internet sites that fructose malabsorption causes depression through interfering with tryptophan uptake - ie less tryptophan is available for metabolism by either of the two pathways you go on to describe.

Even if this is true (and the evidence is pretty thin) I don't follow what this has to do with the claims about increased IDO activity in CFS.

Kynurenic acid is one of the metabolites tested on OATS. Lots of people on PR have had these tests. Some have reported elevated values, some haven't as far as I recall.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911177/

http://simmaronresearch.com/2015/03...ctivation-may-drive-chronic-fatigue-syndrome/

https://books.google.ca/books?id=HXMGAQAAQBAJ&pg=PT878&lpg=PT878&dq=kynurenine cfs&source=bl&ots=fHLMTuIrjc&sig=ZT5YAyxw1r8nMYe_2eWNpqSVf80&hl=en&sa=X&ved=0ahUKEwjGg7SKoJfWAhXilVQKHak3C84Q6AEIXjAJ#v=onepage&q=kynurenine cfs&f=false

https://books.google.ca/books?id=aTEWod9MDvIC&pg=PA90&lpg=PA90&dq=kynurenine cfs&source=bl&ots=i5i2Ovtgdr&sig=osMTav-QYhEmn0sME9GHgZsrKnA&hl=en&sa=X&ved=0ahUKEwjGg7SKoJfWAhXilVQKHak3C84Q6AEIWjAI#v=onepage&q=kynurenine cfs&f=false

http://brainfoggedphd.blogspot.ca/2016/08/everyones-favourite-pathway-kynurenine.html
 
Messages
69
I didn't see you edited your post to remind me that kynurenic acid is generally tested for.

Well kynurenic acid is not kynurenine. And has nothing to do with the destructive pathway I'm talking about, kynurenic acid helps to offset the damage done as kynurenine goes through the kynurenine hydroxylase path.

when IDO is excessively upregulated by if-y, kynurenic acid loses priority.
 
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Messages
69
jeez @Thewonders92 calm down.


This thread reminds me of this video by rostenberg:
https://www.youtube.com/watch?time_continue=3&v=VIgDRzis7o8

Yeah got a bit hot headed, I don't do well with confrontation and helping people out of this nightmare is very important to me.

I apologize either way, and I'll just make use of ignore from now on. Not that my emotional temper tantrum will do much to validate my opinion now, but I want to leave it up to defend my stance on the theory.
 
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alicec

Senior Member
Messages
1,572
Location
Australia
I'm not trying to dismiss you nor do I think I am superior to you.

I was simply trying to understand connections you made that weren't obvious to me.

I realise that kynurenine and kynurenic acid are not the same thing but the latter is the product of the former so measuring it (along with quinolinic acid, another OAT metabolite which is further downstream in the pathway) does give some indication of flux through the pathway.

I realise also that I posted in a hurry and should have taken more time to explain what I meant about kynurenic acid.

Apart from that, actually I appreciate your prodigious capacity to delve into often obscure nooks and crannies and make connections that others might not make.

On occasions I haven't followed these connections or haven't thought some of them are valid and have said so. Isn't that what the forum is for?
 

wastwater

Senior Member
Messages
1,267
Location
uk
I may have a deletion of GMDS and saw it connected to fructose and mannose
I saw something called mannose binding lectin deficiency that can be common and effect immunity especially early in life causing problems with upper respiratory tract infection that I did have a lot of

I wonder what percentage of pwme have this deficiency
 
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