Kati
Patient in training
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Thank you so much will share on twitter. Canadian government needs to get educated.
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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.
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.
Question: Could this all fit with an auto-immune process rather than an external triggering factor?
Answer: Yes it could. Anything that keeps a chronic immune activation going could lead to the hypometabolism. The different triggers and genetic pre-dispositions all make this more complicated and bring about the variations in symptom expression.
Hi Chris, I have so many questions, here are a few:
There are seemingly 2 kinds of ME patients, those who gain a lot of weight from onset and those who have much trouble maintaining their weight. Does it have to do with metabolic impairment discussed here, glycolysis and the TCA cycle?
Second question is would there be different metabolic pathway problems under the umbrella of ME in which the metabolic profile shows variation?
Thirdly: do you see metabolomics as biomarkers that would be used in the mainstream medicine, and would it be accepted. Would mito clinicians make sense of this?
Lastly: are these results in the realm of nutrition or is it more complicated than popping glutamine supplements?
That bolded part is a typo. Sorry. Typed "body of" twice.Can you clarify the bolded part? Thanks!
GG
I guess we have to prove the hypothesis before we start recommending anything at this stage. Rituximab destroys B cells, if this hyptohesis is correct then it should remove the drain on energy metabolism and should help ME/CFS in that regard as well as limiting the ROS. As Naviaux stated it may not be as simple as supplementing the cofactors that are lost, studies need to focus on studying how to bring people out of hypometabolism.Posted this in the Lawson et al thread, but since the discussion is migrating I'll add it here as well.
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 picket 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).
@ChrisArmstrong You mention refeeding syndrome on one of your slides. I recently went through having a PEG placed and being refed after a very long period of severe dietary restriction, malabsorption and resulting malnutrition. The doctor was anticipating that I would get refeeding syndrome but it didn't eventuate. Could the mitochondrial problems in CFS prevent refeeding syndrome from happening?
It seems to make sense as unlike a "healthy" person I wouldn't be able to switch back suddenly to making normal levels of ATP, depleting my phosphate stores (and other nutrients) in the process.
Well this is a hypothesis at this point. Generally the body is trying to maintain normal metabolism. Energy metabolism doesn't just require macromolecules (carbohydrates, fats, protein), it also requires cofactors, vitamins and minerals. It's common that people might be depleted of iron and vitamin b12 and this produces fatigue, this is an example of how a mineral or cofactor can cause fatigue. There should be ways to support the body and we will be looking into the best way to do this. In the cases i suggested above, people feel fatigue even if it's just iron or b12 they lack. What we invisage is more likely in ME/CFS is that it's many if not all cofactors, minerals and vitamins that are reducedIs having to eat frequently a possible consequence of these metabolic problems? What is the body trying to achieve, and is there a way to support it?
Well the same mitochondrial pathways that occur in ME/CFS as indicated by these metabolite studies also occurs in starvation. So I don't see why the mitochondrial pathways would prevent refeeding syndrome. But I find it quite interesting that you didn't get refeeding syndrome, these are the variations that might be important in defining ME/CFS. What were you fed through the PEG?
Thankyou so mich @Kati for putting these up.
Huge thanks to @ChrisArmstrong for this research and availability to be on here answering questions! I am stoked for this research and can't quite believe the direct input we have had from researchers the last few months. So valuable.
I am glad the research is pointing to the probability we are all on the same page.
The starvation link is particularly interesting to myself due to repeated phases of low calorie ketosis (for bodybuilding) the year before I became ill. I even remember the day a couple of months before I got ill that my body metabolism felt like it de-regulated (not in the sense of how ketosis feels-this was different). And it snowballed from there with gut and a viral episode.
The anecdotal mutterings are probably worthless, but I have always wondered.
B
Chris, before all else, let me thank for your presence on these forums and responding to our questions. It means the world!I guess we have to prove the hypothesis before we start recommending anything at this stage. Rituximab destroys B cells, if this hyptohesis is correct then it should remove the drain on energy metabolism and should help ME/CFS in that regard as well as limiting the ROS. As Naviaux stated it may not be as simple as supplementing the cofactors that are lost, studies need to focus on studying how to bring people out of hypometabolism.
This is great stuff, thank you so much.
Some have argued that these recent metabolomics studies showing hypometabolism in ME/CFS are meaningless and simply reflect inactivity. How plausible is this 'explanation' given that Naviaux notes in his paper that inactive people with the metabolic syndrome (abdominal obesity, hypertension, dyslipidemia etc) are in a hypermetabolic state with elevated purines, sphingolipids etc.; in other words the exact opposite of ME/CFS?