Glutamine, Glutamate & Glutathione

Arnie Pye

Arnie Pye

Senior Member (Voting Rights)
Some time ago I read that L-Glutamine was required by the gut to help healing and that it could be supplemented, and it helped lots of people with gastritis and other gut problems. I bought it in a powder form and started taking it.

I've seen recommendations for people to take anything from 20g - 40g L-Glutamine powder per day. I stuck with just 5g - 10g per day though.

To begin with, and for several months, it helped a lot. But then I gradually started getting worse, and had bouts of pain more severe than I ever started with, so I gave it up.

I have since tried to work out what might have gone wrong. I've tried understanding the relationship between Glutamine, Glutamate & Glutathione, because I thought it might be relevant, but failed completely. My chemistry and biochemistry knowledge is a big fat zero. And of course the problem I had may be nothing to do with glutamate or glutathione, or it could be a problem with the glutamine and something else I was taking.

Can anyone help with a link that explains what glutamine does in the body and what it gets converted to for people who don't have much in the way of background knowledge?
 
Don't feel bad, even scientists find it complex, as they are quick to point out in the paper below :nerd:

Neither do I have expertise in this subject, but there are a few pearls in this paper which might help clarify how you may have shifted to converting glutamine back into glutamate, which is an excitatory neurotransmitter and probably best avoided by us.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556573/

Again from my place of ignorance I am getting the sense that glucose metabolism is messed up in PwME on many levels.
 
I'm pretty sure it's glutathione we want, isn't it? Comment from brain dead and clueless, too tired to Google it, over here losing brain cells by the second.
 
Allele said:
Don't feel bad, even scientists find it complex, as they are quick to point out in the paper below :nerd:

Neither do I have expertise in this subject, but there are a few pearls in this paper which might help clarify how you may have shifted to converting glutamine back into glutamate, which is an excitatory neurotransmitter and probably best avoided by us.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556573/

Again from my place of ignorance I am getting the sense that glucose metabolism is messed up in PwME on many levels.
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I think so too. I'm taking it again - about 1 level tsp or 3g a day at the moment. I think - but can't be sure - that I need less of it now, being 64. I used to take about 10g a day. Different people of different genders probably need different amounts too. If only I knew how much of various things I needed! I felt as though I had got it just right for a couple of years, then it all went haywire again.
 
As said above, glutamine often gets converted to glutamate, which is involved in pain signaling. I don't tolerate even small amounts of it.
 
Glutamate (or glutamic acid; glu) and glutamine (gln) are closely related amino acids which readily interconvert. The difference between them is that the glu side chain ends in a carboxylic acid group (COOH) while the gln side chain ends in an amide group (CONH2).

Both amino acids are non-essential, meaning that humans can synthesise them, but under some conditions, our bodies can't keep up the supply of gln and it becomes conditionally essential.

Glu is converted to gln by incorporation of ammonia. This reaction is a key element in control of this toxic byproduct of metabolism in many parts of the body and gln acts as a carrier for transport of ammonia generated in the periphery back to the liver for removal in the urea cycle. Conversely when the reverse reaction occurs ammonia becomes available for use in biosynthetic processes such as purine synthesis.

Thus glu/gln plays a central role in mammalian nitrogen flow.

Another central reaction involving glu/gln is transamination, the interchange of an amino group between an amino acid and an alpha keto acid. This can be used in biosynthetic reactions so glu forms the basis for the synthesis of other amino acids such as proline, citrulline and arginine.

Alternatively, it can be used catabolically with the most relevant reaction gln > glu > alpha keto glutarate which then feeds directly into the Kreb's cycle for energy production. Other amino acids can be converted to glu by this same process and thus this serves as a major route for energy production from amino acids.

Glucoenogenesis is closely linked to the Kreb's cycle and is an important source of glucose for energy use under some circumstances. See this thread for a more detailed explanation. This particularly relevant in the gut and kidney where gln becomes the source for gluconeogenesis.

In fact glu/gln is far and away the most important source of energy in the gut and most dietary glu/gln is used in the gut for just this purpose, as shown in this study. Supplementary gln would boost this process and has been shown to have positive effects on gut integrity.

As others have indicated glu/gln plays other roles in the body, most notably in the brain where glu functions as an excitatory neurotransmitter and a precursor to the inhibitory neurotransmitter GABA.

The blood brain barrier is essentially impermeable to glu but gln can cross, albeit slowly.

Possibly long term supplementation has increased uptake of gln into the brain which in turn has influenced levels of glu. However I'm not aware of any studies showing that gln supplementation influences gln uptake in the brain. In fact one study in very ill patients given gln parenterally found that it didn't.

The study linked above is not helpful in this respect, it is simply looking at how best to characterise the complicated and very tight control of gln/glu and hence GABA balance within the brain.

Nevertheless the phenomenon of sensitivity to gln is not uncommon. I have experienced it myself. We can hypothesise that it somehow affects glu activity in the brain but we don't know how.

Another possibility is that gln is involved in regulating nitric oxide production. I haven't seen any studies linking gln supplementation and effects on NO but it is a possibility.

Finally you mention glutathione (GSH). Gln supplementation can certainly stimulate GSH production, as was found in the study I linked above about glu metabolism in the gut. I can't see how this could have any adverse consequences though.
 
Not sure if it's useful but glutamic acid is fairly easy to obtain via the diet and occurs in a variety of foods (notably eggs, meat, dairy products and soy protein). It is easy to digest from these foods. As mentioned it isn't an essential amino acid, because it can be synthesised in the body, but digestion from protein rich food is a far more efficient way of getting it.
 
I ran out of time and energy yesterday to go into more detail about the proposition that sensitivity to gln supplements is because of effects on glu in the brain.

It's an attractive notion, but not only is there no evidence for it, but also it is hard to see how it would work.

The study I linked above, almost all dietary glut was used in the gut. Very little made it through the other side to enter the general circulation. Other studies show that for gln, the general circulation donates gln to the gut, not the other way round - ie dietary gln needs to be topped up to supply the needs of the gut.

Studies have shown that a large dose of gln to the gut just results in less uptake from the blood, though there is still some.

This reduction in transfer of gln from the blood to the gut, however, would be a drop in the ocean and is unlikely to affect the general gln pool.

Gln is the most abundant amino acid in the blood where it is maintained at high concentrations by high input from muscle. It is also the most abundant one in the intracellular free amino acid pool and is estimated to comprise about a half the the whole body pool of amino acids.

Even if gln supplementation did somehow perturb the general blood pool, it is even more difficult to see how this would affect glu in the brain.

To control the excitotoxic potential of glu in the brain, it is strictly kept inside cells, to be released momentarily when neurons fire, then quickly and efficiently removed by astrocytes.

There is a complex two compartment system to control this tightly so neurons which release and respond to glu don't absorb it. Instead it is taken up by astrocytes which convert it to gln. Gln is then released and is taken up by neurons which convert it to glu as needed.

The blood brain barrier excludes glu from the blood to maintain this low extracellular concentration of glu in the brain.

There is movement of gln in both directions across the BBB but this is tightly controlled and the net movement is from the brain to the blood.

There is no way that small changes in gln in the blood, which happen all the time, are going to perturb the very tightly controlled glu/gln system in the brain.

Particularly with reports of adverse effects from small doses of gln, such as from @adreno, it seems much more likely to me that the adverse effects are generated locally. Possibly they arise from some metabolite of gln or perhaps from some perturbation of the regulatory properties of gln.

I've never been able to find a satisfactory explanation.
 
alicec said:
Particularly with reports of adverse effects from small doses of gln, such as from @adreno, it seems much more likely to me that the adverse effects are generated locally. Possibly they arise from some metabolite of gln or perhaps from some perturbation of the regulatory properties of gln.
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Could it be ammonia?
 
I was recommended to try liposomal glutathione supplements from someone on PR a while ago. But they were so expensive I didn't bother.

Would this be better for those sensitive to the powder, though?
 
adreno said:
Could it be ammonia?
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It could be. Conversion of gln to glu for further energy use by the gut does generate a lot of ammonia but this is carried directly to the liver for disposal via the portal vein and doesn't affect systemic ammonia.

Still maybe if one already had some problems dealing with ammonia there could be some consequence.
 
arewenearlythereyet said:
Not sure if it's useful but glutamic acid is fairly easy to obtain via the diet and occurs in a variety of foods (notably eggs, meat, dairy products and soy protein). It is easy to digest from these foods. As mentioned it isn't an essential amino acid, because it can be synthesised in the body, but digestion from protein rich food is a far more efficient way of getting it.
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Haven't read to the end so will delete if double up.

If my protein and fat digestion is not functioning well (much of it goes straight through),
does this mean I don't get glut... this stuff?
(Bad brain day, gone out to lunch, will understand you when it comes home. No need to dumb down answer but keep short is good).

Edit: I meant to ask if anyone knows if the "easy to digest" thing is significantly reduced by a rapid digestion and protein and fat malabsorption.
 
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Subtropical Island said:
Haven't read to the end so will delete if double up.

If my protein and fat digestion is not functioning well (much of it goes straight through),
does this mean I don't get glut... this stuff?
(Bad brain day, gone out to lunch, will understand you when it comes home. No need to dumb down answer but keep short is good).

Edit: I meant to ask if anyone knows if the "easy to digest" thing is significantly reduced by a rapid digestion and protein and fat malabsorption.
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Basically if working properly most of the protein will be hydrolysed with the HCL in your stomach, assisted by pepsin and other enzymes to very short chain peptides and amino acids by the time the nutrients exit your stomach. Some proteins are easier and quicker to hydrolyse than others ( eg globular proteins in milk and eggs). High fibrous protein foods (e.g collagen foods like meat) are slower. I don't know about protein surviving normal digestion beyond the duodenum....this seems odd to me. The environment in the stomach is pretty aggressive so scale wise think of a vat of concentrated HCL dissolving stuff...it's not gentle. i think low stomach acidity is a factor in digestive problems but I don't think it would result in whole protein surviving the process. Not sure if that's what you are saying?
 
arewenearlythereyet said:
Basically if working properly most of the protein will be hydrolysed with the HCL in your stomach, assisted by pepsin and other enzymes to very short chain peptides and amino acids by the time the nutrients exit your stomach. Some proteins are easier and quicker to hydrolyse than others ( eg globular proteins in milk and eggs). High fibrous protein foods (e.g collagen foods like meat) are slower. I don't know about protein surviving normal digestion beyond the duodenum....this seems odd to me. The environment in the stomach is pretty aggressive so scale wise think of a vat of concentrated HCL dissolving stuff...it's not gentle. i think low stomach acidity is a factor in digestive problems but I don't think it would result in whole protein surviving the process. Not sure if that's what you are saying?
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Edited to remove personal queries and stick to the point: Not sure myself.
My thought is that if protein can make it through then some of the other nutrients will be similarly challenged in getting absorbed. You make me realise that the question why might that even happen needs to be answered first: is it not being broken down or is it appearing later in the tract etc.
 
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Subtropical Island said:
Not sure myself. Had stool tests with protein and fat in them. Have blood tests with markers for malabsorption and dehydration despite excellent inputs (checked by nurse, doctor, nutritionist and ...). Clinical diarrhoea (frequency and consistency) for a year now.
My thought is that if protein can make it through then some of the other nutrients will be similarly challenged in getting absorbed. But you make me realise I need to do more than make my doctor aware of this (as I have), focus on an excellent diet and trialing a few supplements (I have both ...and found indications that occasional sublingual B12 and magnesium supplementation might help) and learn more myself. I have no problem with milk and eggs I don't think. Hmmm... I need to identify which phase is malfunctioning: luminal, mucosal, post-absorptive (https://emedicine.medscape.com/article/180785-clinical#b5)
Thanks, will add to do list. (Happy for any shortcuts you can give though).
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No worries I wish you luck with the diet nutrition side of things. Also the amount of junk science you will have to sift through is a pain. I have struggled with this recently myself due to failing memory and being out of touch for a year due to being made redundant (I worked in the food industry).

Here is what I have found so far with some of my own speculation.

I think some poor nutrient absorption can definitely happen for various reasons and stomach acidity can be linked.

The only things that seem based on reliable evidence are that:

low stomach acidity can be related to:

If stomach acidity is low it can cause malabsorption of essential vitamins and minerals (low B12 absorption being one of the key markers, but also iron, magnesium, zinc and possibly calcium although that is contentious) and reduce the production of pepsin causing a less efficient protein digestion. CHO digestion is much more robust since we start digesting these as soon as we eat and acid even on its own can digest starch without amylase (generally). This is unlikely to be black and white so we are probably still producing a hell of a lot of stomach acid ...its just not quite enough to be our normal efficient.

We then go into a whole host of speculation from there on in and a lot of confused messages and confused thinking starts creeping in. I have lost count of the times I have read "nutritionists" or their like starting off with the above and then carrying on explaining how maple syrup is better than sugar or that bacteria can pass through the gut wall or that whole food groups are bad foods etc etc.

I think its safe to assume that low stomach acidity can be a problem and this may affect how efficiently we digest food and possibly have knock on effects further on. We know that Pepsin production is activated by HCL secretion as well as the acid denaturing the tertiary structure of the protein to allow the enzymes access to the peptide bonds etc. We also know that the pancreas and liver responds to a variety of signals following acid and pepsinogen secretion to allow their secretions to be timed correctly. This means that inefficient acid production can have a knock on effect for fat protein and CHO digestion in the duodenum.

Diarrhea is associated with irritation of the gut lining, infection, chronic illness, stress and interestingly high histamine (i.e. lots of things)
Bloating is associated mainly with the production of gas by bacteria in the gut

So something must be explaining the symptoms further down. In terms of bloating this could be an excess of nutrients (short chain peptides, short chain saccharides etc) causing changes in gas producing gut bacteria, but as with everything gut biome there is a lot of speculation due to lack of information. Diarrhea could be so many things its difficult to attribute it to diet when you have a chronic illness.

My gut issues (same symptoms as yours...the alternating diarrhea and constipation is a drag), have reduced a lot over the last 12 months. During that time I have been doing some things that may have had an effect:

diet: reduced carbs and sugar consumption (150g or below a day), moderate protein (50-100g), higher fat (50% of calories)
Supplements: B12, folate, B complex and zinc
Meal sizes: have reduced these to smaller meal sizes but more nutrient dense foods.

Of course this is totally anecdotal and there could be something else happening. I have gone from having 3-4 episodes of diarrhea a day ( and bloating and random constipation) to one or two episodes a month by doing the above. I used to get constant reflux symptoms but now rarely get these.

I still eat a varied diet just control the food groups and meal sizes a bit better than i did before. I am mild moderate so this may be a factor in terms of still being to move around more which I think also helps stimulate gut motility etc. Its possible that the supplementation with folate and B12 alone reduced high histamine and stopped diarrhea that way? Its equally possible that I'm entering a different phase (I am worse off cognitively and OI wise than I was a year ago?)

There seems to be little but theories to go on. I hope you find something that improves your symptoms and hope this hasn't been too preachy ...I don't really know how it worked but I'm sticking to my regime like some sort of voodoo just in case it has had an effect.

Edited to remove beta blockers...that's wrong they create more Stomach acid if anything not less.
 
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arewenearlythereyet said:
No worries I wish you luck with the diet nutrition side of things. Also the amount of junk science you will have to sift through is a pain. I have struggled with this recently myself due to failing memory and being out of touch for a year due to being made redundant (I worked in the food industry).

Here is what I have found so far with some of my own speculation.

I think some poor nutrient absorption can definitely happen for various reasons and stomach acidity can be linked.

The only things that seem based on reliable evidence are that:

low stomach acidity can be related to:

If stomach acidity is low it can cause malabsorption of essential vitamins and minerals (low B12 absorption being one of the key markers, but also iron, magnesium, zinc and possibly calcium although that is contentious) and reduce the production of pepsin causing a less efficient protein digestion. CHO digestion is much more robust since we start digesting these as soon as we eat and acid even on its own can digest starch without amylase (generally). This is unlikely to be black and white so we are probably still producing a hell of a lot of stomach acid ...its just not quite enough to be our normal efficient.

We then go into a whole host of speculation from there on in and a lot of confused messages and confused thinking starts creeping in. I have lost count of the times I have read "nutritionists" or their like starting off with the above and then carrying on explaining how maple syrup is better than sugar or that bacteria can pass through the gut wall or that whole food groups are bad foods etc etc.

I think its safe to assume that low stomach acidity can be a problem and this may affect how efficiently we digest food and possibly have knock on effects further on. We know that Pepsin production is activated by HCL secretion as well as the acid denaturing the tertiary structure of the protein to allow the enzymes access to the peptide bonds etc. We also know that the pancreas and liver responds to a variety of signals following acid and pepsinogen secretion to allow their secretions to be timed correctly. This means that inefficient acid production can have a knock on effect for fat protein and CHO digestion in the duodenum.

Diarrhea is associated with irritation of the gut lining, infection, chronic illness, stress and interestingly high histamine (i.e. lots of things)
Bloating is associated mainly with the production of gas by bacteria in the gut

So something must be explaining the symptoms further down. In terms of bloating this could be an excess of nutrients (short chain peptides, short chain saccharides etc) causing changes in gas producing gut bacteria, but as with everything gut biome there is a lot of speculation due to lack of information. Diarrhea could be so many things its difficult to attribute it to diet when you have a chronic illness.

My gut issues (same symptoms as yours...the alternating diarrhea and constipation is a drag), have reduced a lot over the last 12 months. During that time I have been doing some things that may have had an effect:

diet: reduced carbs and sugar consumption (150g or below a day), moderate protein (50-100g), higher fat (50% of calories)
Supplements: B12, folate, B complex and zinc
Meal sizes: have reduced these to smaller meal sizes but more nutrient dense foods.

Of course this is totally anecdotal and there could be something else happening. I have gone from having 3-4 episodes of diarrhea a day ( and bloating and random constipation) to one or two episodes a month by doing the above. I used to get constant reflux symptoms but now rarely get these.

I still eat a varied diet just control the food groups and meal sizes a bit better than i did before. I am mild moderate so this may be a factor in terms of still being to move around more which I think also helps stimulate gut motility etc. Its possible that the supplementation with folate and B12 alone reduced high histamine and stopped diarrhea that way? Its equally possible that I'm entering a different phase (I am worse off cognitively and OI wise than I was a year ago?)

There seems to be little but theories to go on. I hope you find something that improves your symptoms and hope this hasn't been too preachy ...I don't really know how it worked but I'm sticking to my regime like some sort of voodoo just in case it has had an effect.
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Thanks for all of this. I found myself giving a really long rambling reply with lots of personal details and then realised this is not the members only section. And I don't want to hijack the thread.
But very useful, and in many ways relevant to me. Will try again with my reply when my brain is one notch more functional (editing myself is not currently working right and I need to rest).
 
arewenearlythereyet said:
i think low stomach acidity is a factor in digestive problems but I don't think it would result in whole protein surviving the process. Not sure if that's what you are saying?
Click to expand...

Without details.. :D it is possible that whole protein passes the gut to the outside.
 
arewenearlythereyet said:
The only things that seem based on reliable evidence are that:

low stomach acidity can be related to:
Click to expand...
If I may add - and hopefully correctly, since I'm not an expert - you als need Chloride for HCl (stomach acid) and, if my searches were correct, Vitamin B6.
 
MeSci said:
Don't a lot of us produce too much acid?
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I had (and probably still have) low stomach acid for a long time, though it's better for a few weeks now. It's a big problem. I don't know how common it is. The symptoms of low and high stomach acid are in many points similar (just my experience) so that most would maybe say they have too much stomach acid although they don't.
 
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