Elevated Energy Production in Chronic Fatigue Syndrome Patients

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Tuha

Senior Member
Messages
638
Jonathan Edwards said:
I am afraid that there may be a very mundane explanation for both the Naviaux and this result without any conflict. Both might relate in different ways to low levels of activity. The mononuclear cells may behave differently simply because in ME they are not being shunted off to overworked muscle to do some repairs. The average age of monocytes in ME and healthy blood may be different. All sorts of explanations are possible - with nothing to do with the root cause of ME. What I think we need are studies where ME patients are matched to controls not just by age and gender but also by average daily actometer scores, calorie intakes and sleep schedules.
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Certainly ME patients have often small daily activity. Personally I have to rest often during the day but I walk every day at least one hour. So in my case you cannot say that I am deconditioned. Still especially my legs hurt every day because of elevated lactic acid. This was also confirmed in the hospital where they measured my lactat level and it was already elevated before exercise and after exercise it went only slowly down. Is this not a sign that in ME patients is somehow involved the metabolisme and it is not due to inactivity? Does this lactat problem support somehow Naviaux´s findings? I know that similar lactat problems have many patients.
 
Ben H

Ben H

OMF Volunteer Correspondent
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1,131
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Hi guys,

This is directly from Dr Hanson on the study vs Naviaux etc:

"I don't think there is any contradiction. As you mentioned, it is comparing apples and oranges. Lawson et al measured ATP in PBMCs, while both Naviaux and my lab measured plasma ATP. It is also possible the blood was handled in different ways after collection. There is no need to be concerned about anyone's data yet."

Which is really helpful! What a brilliant lady and researcher!


B
 
C

ChrisArmstrong

Messages
67
Hi all,

I was actually asked about this just recently in regards to it contradicting our research and came to read up on it. We found an increase in glucose and decrease in glycolysis end-products that suggest a glycolysis inhibition of some kind.

It actually doesn't contradict our research or the Naviaux study findings and it brings a lot of valuable information to support the general theme of what might be going on here.

Proliferating cells (immune cells) use glycolysis to proliferate, they actively stop pyruvate from glycolysis entering the mitochondria in a process called the warburg effect. The reason for this is glycolysis provides about 5 times the amount of energy over time and metabolite flux through glycolysis promotes the metabolite flux through pentose phosphate pathway (this is where you make nucleotides for DNA replication). By stopping the entry of glucose into the mitochondria to make ATP it upregulates the use of amino acids and lipids for ATP production (possibly why we see a global decrease in blood amino acids and lipids). This process is called glutaminolysis, the purpose is when glutamine enters the TCA cycle, it must remove two of it's ammonia groups, it does this by transferring them to other carbon bodies and this transfer expands the variety of non-essential amino acids available in the cell. You need a variety of amino acids to build new proteins for replication an glutaminolysis provides this.

So the authors of the paper should be aware that this is exactly what one would expect to be occurring in an immune cell.

So how does this relate to the hypometabolism in the blood? Well the hypometabolism may actually be caused by these immune cells functioning this way because proliferation takes a lot of metabolites, cofactors, vitamins and minerals to occur. Blood is very different to the cell and individual cell types are different from each other. Chronic immune activation may be what leads to the hypometabolism state.

I spoke about this in a recent webinar but starvation and sepsis are two acute disorders that show the same metabolic anomalies we are observing in the blood metabolome and this work actually adds to them. Sepsis and starvation may provide a very good model to shed light on this illness because they are well studied in clinical work. What is found in starvation for example is a reduction of amino acids and lipids in the blood but also with an increase in glucose (hyperglycemia). The logic is that the body maintains glucose high in the blood so it can be readily used by the brain and muscles to find food, the same occurs in sepsis except the high glucose is used to give immune cells the ability to proliferate to fight infection. Both states maintain a low level energy through out the rest of the body by slowly breaking down proteins and lipids to fuel TCA cycle in mitochondria.
 
Kati

Kati

Patient in training
Messages
5,497
ChrisArmstrong said:
Hi all,

I was actually asked about this just recently in regards to it contradicting our research and came to read up on it. We found an increase in glucose and decrease in glycolysis end-products that suggest a glycolysis inhibition of some kind.

It actually doesn't contradict our research or the Naviaux study findings and it brings a lot of valuable information to support the general theme of what might be going on here.

Proliferating cells (immune cells) use glycolysis to proliferate, they actively stop pyruvate from glycolysis entering the mitochondria in a process called the warburg effect. The reason for this is glycolysis provides about 5 times the amount of energy over time and metabolite flux through glycolysis promotes the metabolite flux through pentose phosphate pathway (this is where you make nucleotides for DNA replication). By stopping the entry of glucose into the mitochondria to make ATP it upregulates the use of amino acids and lipids for ATP production (possibly why we see a global decrease in blood amino acids and lipids). This process is called glutaminolysis, the purpose is when glutamine enters the TCA cycle, it must remove two of it's ammonia groups, it does this by transferring them to other carbon bodies and this transfer expands the variety of non-essential amino acids available in the cell. You need a variety of amino acids to build new proteins for replication an glutaminolysis provides this.

So the authors of the paper should be aware that this is exactly what one would expect to be occurring in an immune cell.

So how does this relate to the hypometabolism in the blood? Well the hypometabolism may actually be caused by these immune cells functioning this way because proliferation takes a lot of metabolites, cofactors, vitamins and minerals to occur. Blood is very different to the cell and individual cell types are different from each other. Chronic immune activation may be what leads to the hypometabolism state.

I spoke about this in a recent webinar but starvation and sepsis are two acute disorders that show the same metabolic anomalies we are observing in the blood metabolome and this work actually adds to them. Sepsis and starvation may provide a very good model to shed light on this illness because they are well studied in clinical work. What is found in starvation for example is a reduction of amino acids and lipids in the blood but also with an increase in glucose (hyperglycemia). The logic is that the body maintains glucose high in the blood so it can be readily used by the brain and muscles to find food, the same occurs in sepsis except the high glucose is used to give immune cells the ability to proliferate to fight infection. Both states maintain a low level energy through out the rest of the body by slowly breaking down proteins and lipids to fuel TCA cycle in mitochondria.
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In regards to sepsis, there such a thing called post-sepsis fatigue syndrome, notably people who were very, very sick following sepsis (on life support) and pulled through but have not made a full recovery enough to work or function well enough. These folks are also advocating for research of their 'syndrome' (I hate the word syndrome)
 
C

ChrisArmstrong

Messages
67
Kati said:
@ChrisArmstrong thank you for your SolveCfs talk, I have watched it today and made screen shots of the presentation. i am wondering if it's ok to post screen shots on this forum (new thread) considering you may have unpublished findings? Let me know!
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Yes by all means do. It will be posted on youtube soon enough. I didn't get time to go over questions but if we post it on here then I figure I can answer queries here.

And yes there is post-sepsis syndrome. Sepsis is a much more acute disorder and with it can come extreme long-term damage even after recovery. Long-term damage outside of the illness may be structural changes that occurred because of it. All these disorders need more research.

The sepsis model is different in ME/CFS as we expect it's a low-level slow sepsis. We think it's due to a change of bacteria in the gut and increased translocation into the blood but it could also be due to any chronic external stress factor the immune system can handle (eg mould, autoimmune food intolerance). The idea is that the immune system can handle the insult but as it's constantly being supplied to the body externally it will constantly be draining resources from the body to do it. We think the gut is the place you could get a consistent external factor triggering the immune system, it is likely external because if it was internal then the immune system should have cleared it (however there are many bugs or viruses that can stay hidden internally).

The added component is that we don't think you necessarily need a bacteria dysbiosis initially. The proteins that are first degraded to fuel global ATP production are the proteins in the gut. We think it's possible that you could have an initial trigger infection that could persist long enough for chronic immune activation and subsequent chronic starvation to ensue. This starvation could take proteins from the gut and change the gut morphology, which then changes the bacteria types and may promote pathogenic bacteria that create more work for the immune system. This creates a negative feedback loop that maintains the disorder.

Coming out of hypometabolims is the answer but it's complex. You can come out of starvation hypometabolism because all the cofactors, minerals and vitamins aren't yet depleted to the same level as we suspect in ME/CFS. Refeeding syndrome is a real issue with coming out of starvation, food metabolites entering the blood will be absorbed by cells and take minerals from the blood with it which actually has devastating consequences. They find magnesium, phosphate, potassium, calcium to be supplemented significantly in refeeding and this is usually given by drip (side-step the gut). Coming out of ME/CFS may be more difficult because the marcomolecules (carbohydrate, protein, fat) need to be introduced with all the cofactors, minerals and vitamins. It might be a bit like trying to put up a picket fence held together by rope that has blown down, if only a few pickets fall and the rest stand then you can pick them up and it will stand, if the whole fence falls down and you pick only a few pickets up then it will fall back down, you need all the pickets to be pushed up at once to correct it.

Edit - this actually probably belongs in its own thread. Sorry for derailing this topic.
 
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Kati

Kati

Patient in training
Messages
5,497
ChrisArmstrong said:
Yes by all means do. It will be posted on youtube soon enough. I didn't get time to go over questions but if we post it on here then I figure I can answer queries here.

And yes there is post-sepsis syndrome. Sepsis is a much more acute disorder and with it can come extreme long-term damage even after recovery. Long-term damage outside of the illness may be structural changes that occurred because of it. All these disorders need more research.

The sepsis model is different in ME/CFS as we expect it's a low-level slow sepsis. We think it's due to a change of bacteria in the gut and increased translocation into the blood but it could also be due to any chronic external stress factor the immune system can handle (eg mould, autoimmune food intolerance). The idea is that the immune system can handle the insult but as it's constantly being supplied to the body externally it will constantly be draining resources from the body to do it. We think the gut is the only place you could get a consistent external factor triggering the immune system, it has to be external because if it was internal the immune system would have cleared it.
Click to expand...

i exchanged a convo with this person who had the post-sepsis syndrome and she seemed to have a different set of symptoms than mine, but still, many similarities considering the spectrum of vague but disabling symptoms which are typically not expllained by a regular lab service.

Thank you for your work. It is truly fascinating. I will post my screen shots in a moment and will tag you when the new thread is posted so you will be notified. Thank you for engaging here, your contribution is appreciated.
 
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C

ChrisArmstrong

Messages
67
Kati said:
i exchanged a convo with this person who had the post-sepsis syndrome and she dseemed to have a different set of symptoms than mine, but still, many similarities considering the spectrum of vague but disabling symptoms which are typically not expllained by a regular lab service.

Thank you for your work. It is truly fascinating. I will post my screen shots in a moment and will tag you when the new thread is posted so you will be notified. Thank you for engaging here, your contribution is appreciated.
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Yes this is something that needs to be highlighted. The broad biochemistry is similar but ME/CFS is obviously a different disorder, we use the findings to form a model of a new pathogenesis. ME/CFS is it's own thing and the chronic nature of it will make it more similar to chronic disorders than acute ones in symptom expression.
 
L

lansbergen

Senior Member
Messages
2,512
ChrisArmstrong said:
We think the gut is the only place you could get a consistent external factor triggering the immune system,
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Not the airways?

ChrisArmstrong said:
it has to be external because if it was internal the immune system would have cleared it.
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As I understand it the immune system can not clear the infection I suspect.

And as it stays in the environment for decades reinfection can occur frequently

There are many strains and when they tried to eliminate the infection with a breeding program a more virulent strain stroke in animals that were supposed not to be susceptible[/QUOTE]
 
Seven7

Seven7

Seven
Messages
3,446
Location
USA
I keep insisting, is something in the gut mess not allowing the food to be processed like in normal plp (why we are so deficient as in starvation). I wonder if there is a way to measure what comes off of digestion to find the problem in the chain.
 
C

ChrisArmstrong

Messages
67
lansbergen said:
Not the airways?

As I understand it the immune system can not clear the infection I suspect.

And as it stays in the environment for decades reinfection can occur frequently

There are many strains and when they tried to eliminate the infection with a breeding program a more virulent strain stroke in animals that were supposed not to be susceptible
Click to expand...
[/QUOTE]

Yes true, this is also very possible. Poor wording on my part (have a bad habit of speaking in absolutes when talking casually). We just think it's likely, this is our level of thinking but it could be internal. I will change that wording as we definitely keep an open mind about it.
 
C

ChrisArmstrong

Messages
67
J.G

J.G

Senior Member
Messages
162
ChrisArmstrong said:
Coming out of ME/CFS may be more difficult because the marcomolecules (carbohydrate, protein, fat) need to be introduced with all the cofactors, minerals and vitamins. It might be a bit like trying to put up a picket fence held together by rope that has blown down, if only a few pickets fall and the rest stand then you can pick them up and it will stand, if the whole fence falls down and you pick only a few pickets up then it will fall back down, you need all the pickets to be pushed up at once to correct it.
Click to expand...
In this context, might it make sense for Rituximab responders to supplement heavily during treatment with vitamins, minerals and cofactors (such as those that Naviaux et al. 2016 found depleted) to make sure the fence stands firmly by the time B-cells come back online?

A supplementation package shouldn't be difficult to put together - a precedent in KPAX002 already exists (no endorsement given) - and might ultimately arbitrate between relapse or long-term remission. It could even be highly tailored to the variability of metabolite depletion in each individual patient (which if I read Naviaux correctly is quite high).
 
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