A Metabolic Trap for ME/CFS?

[Wishful]

One observation that might be useful in understanding the feedback loop is the temporary remissions in the early stages of the disease. The feedback might be limited at first, or the tripping point just slightly above/below normal, allowing random fluctuations to occasionally kick us out of the abnormal state. Then gradually it becomes worse, requiring a much stronger correcting signal to break it out of the abnormal state.

 

[perrier]

One observation that might be useful in understanding the feedback loop is the temporary remissions in the early stages of the disease. The feedback might be limited at first, or the tripping point just slightly above/below normal, allowing random fluctuations to occasionally kick us out of the abnormal state. Then gradually it becomes worse, requiring a much stronger correcting signal to break it out of the abnormal state.

Yes, Wishful, this is the pattern I am seeing; initially, remissions (though not 100%), and with time less of these and more of flatlining.

I hope they figure this out fast.

 

[alex3619]

I

I'm slightly reluctant to speculate but possibly your comments may also apply to people who have problems with their blood-brain barrier [see Baraniuk's 2017 paper & Cort Johnson's article on same]. Great to see OMF testing the metabolic trap theory and we should have results later this year.

I think the encephalitis subset and the EDS subsets are high on the list of candidates for blood brain barrier issues. However I suspect this is more to do with the trigger than the ongoing problem, but it could not help to have a vulnerable brain in any case.

 

[Wishful]

In situations like this, where there might be difficulty in deciding which of many options to research, a gambling pool can be quite good at 'choosing a winner'. We of course can't actually place monetary bets here, but the results might be interesting. I'm going to bet that peroxynitrite deficiency (in the affected brain cells) is part of the positive feedback loop.

 

[Wishful]

@perrier, in addition to what seemed to be spontaneous temporary remissions, there were a few drugs and supplements that also triggered similar temporary remissions. They worked a couple of times, then never worked after that, even at higher dosages. Too bad I can't 'try them for the first time' again to see if they would be as effective now, or if they were only that effective at that point in the development of my ME/CFS.

 

[kurt]

The PEM I experience has a specific pattern, just like clockwork. It's hits me at 48 hours after I over do it physically and never lasts more than 24 hours. So the flares are something very different and are alleviated by the coq10.

It just seems like the coq10 is doing something in the mitochondria that affects my immune system somehow and has stopped these devastating flu like flares, that would usually put me in bed for 4-5 days.

That's interesting Jim... I've been studying autoimmunity the past few days, since the Scheibenbogen study, and that clockwork PEM pattern, what you describe, matches the timing of a type IV hypersensitivity, a consistently delayed immune system response. So in theory, this makes me wonder if PEM is a strange autoimmune response, rather than delayed recovery from ATP depletion as we have been told for years. Maybe a bit of both, but still, interesting that you said 48 hour delay. And after coq10, it improves, and coq10 works on the immune system. That all fits. But makes me wonder how the coq10 helped. Since coq10 boosts immune function, maybe it boosted the T-cells and they got rid of the autoantibodies? They do have that function naturally. But I can't find any studies on T-cells and coq10, so that is just a wild theory....

I get that two day PEM delay sometimes too, but often forget about the exertion due to memory and brain fog issues.

@perrier, in addition to what seemed to be spontaneous temporary remissions, there were a few drugs and supplements that also triggered similar temporary remissions. They worked a couple of times, then never worked after that, even at higher dosages. Too bad I can't 'try them for the first time' again to see if they would be as effective now, or if they were only that effective at that point in the development of my ME/CFS.

This happened to me also, twice. I thought I was recovered, each time the improvement lasted for about one year. But it was only remission, and the ME/CFS returned worse than
before each time, and I tried both treatments again and neither worked.

 

[perrier]

@perrier, in addition to what seemed to be spontaneous temporary remissions, there were a few drugs and supplements that also triggered similar temporary remissions. They worked a couple of times, then never worked after that, even at higher dosages. Too bad I can't 'try them for the first time' again to see if they would be as effective now, or if they were only that effective at that point in the development of my ME/CFS.

Identical pattern on this end

 

[alex3619]

The most extreme improvement I ever had was only once, on a high dose of the grape version of pycnogenol, the original product made in France to the original formula. My body fizzed, starting in my stomach, its like someone had installed a soda fountain there. Then it moved out to my limbs, like someone was mainlining softdrink/soda into my veins. It was most unpleasant. When it finished, about half an hour to an hour after ingesting, I felt very very good for the first time in forever. This is of course a very powerful antioxidant. Most of the substances people have found to help have been antioxidants or B vitamins.

 

[Mel9]

That's interesting Jim... I've been studying autoimmunity the past few days, since the Scheibenbogen study, and that clockwork PEM pattern, what you describe, matches the timing of a type IV hypersensitivity, a consistently delayed immune system response. So in theory, this makes me wonder if PEM is a strange autoimmune response, rather than delayed recovery from ATP depletion as we have been told for years. Maybe a bit of both, but still, interesting that you said 48 hour delay. And after coq10, it improves, and coq10 works on the immune system. That all fits. But makes me wonder how the coq10 helped. Since coq10 boosts immune function, maybe it boosted the T-cells and they got rid of the autoantibodies? They do have that function naturally. But I can't find any studies on T-cells and coq10, so that is just a wild theory....

I get that two day PEM delay sometimes too, but often forget about the exertion due to memory and brain fog issues.


This happened to me also, twice. I thought I was recovered, each time the improvement lasted for about one year. But it was only remission, and the ME/CFS returned worse than
before each time, and I tried both treatments again and neither worked.

That is really interesting. I get Type 4 hypersensitivity reactions to bandades and to PEG and other glycols. The delay is usually 24 hours. And my PEM delay period is about the same. A connection I have never madeuntil your post.

 

[Ben H]

Hi guys,

I have just spoke to Robert Phair (what a wonderful guy), and he now has enough 23andme data and does not require anymore-thank you to everyone who sent some in.

However if anyone has WES (whole exome sequencing) or WGS (whole genome sequencing) he is still interested in having that data.

Thanks,


B

 

[Murph]

Hi guys,

I have just spoke to Robert Phair (what a wonderful guy), and he now has enough 23andme data and does not require anymore-thank you to everyone who sent some in.

However if anyone has WES (whole exome sequencing) or WGS (whole genome sequencing) he is still interested in having that data.

Thanks,


B

You were a weightlifter Ben, is that right? I bet you are interested in his hypothesis! Were you on any aminos or similar before you got sick?

 

[Ben H]

You were a weightlifter Ben, is that right? I bet you are interested in his hypothesis! Were you on any aminos or similar before you got sick?

That’s right @Murph . Absolutely live and breathed it (the ‘lifestyle’) was my ‘job’ and had plans to naturally compete..then became ill.

Yes I was on a few supplements. I was a natural bodybuilder, so no steroids etc, but supplements such as Whey protein, L carnitine, ZMA, possibly the occasional pre workout NOS drink. The usual stuff really. I wasn’t on BCAA’s separately bar those in the whey. Some people took them aswell as whey.

I would have had a very high (200g at least) protein intake for obvious reasons, and I also dieted heavily ketogenically (mainly) to get to around 6-7% bodyfat.

I am very, very interested in the hypothesis. Robert Phair is a really clever guy, also really lovely too.


B

 

[bertiedog]

Yes, Wishful, this is the pattern I am seeing; initially, remissions (though not 100%), and with time less of these and more of flatlining.

This was my experience too. That phase went on for about 2 years with me until it went into full blown ME/CFS.

Pam

 

[wigglethemouse]

I would have had a very high (200g at least) protein intake for obvious reasons, and I also dieted heavily ketogenically (mainly) to get to around 6-7% bodyfat.

@Ben H From your chat do you know if Robert is interested in supplements body builders take or the reduced body fat %.

 

[ljimbo423]

that clockwork PEM pattern, what you describe, matches the timing of a type IV hypersensitivity, a consistently delayed immune system response. So in theory, this makes me wonder if PEM is a strange autoimmune response, rather than delayed recovery from ATP depletion as we have been told for years.

Since coq10 boosts immune function, maybe it boosted the T-cells and they got rid of the autoantibodies?

Hi Kurt- It looks like type 4 hypersensitivity is not an antibody response but rather a cell mediated immune response. So auto-anti-bodies don't cause type 4 hypersensitivity.

Type 4 hypersensitivity is often called delayed type hypersensitivity as the reaction takes several days to develop. Unlike the other types, it is not antibody-mediated but rather is a type of cell-mediated response.

https://en.wikipedia.org/wiki/Type_IV_hypersensitivity

I get that two day PEM delay sometimes too, but often forget about the exertion due to memory and brain fog issues.

Me too! Two days is a looong time to remember something with brain fog and fatigue.

My own personal view of what causes PEM is explained extremely well in this study.

One current model of disease suggests that a trigger event (e.g. infection) results in a chronic inflammatory state characterized by increased proinflammatory cytokine production, increased reactive oxygen and nitrogen species, altered intracellular signaling, increased intestinal permeability and systemic activation of innate immune receptors, altered glutaminergic and dopaminergic neurotransmission, mitochondrial dysfunction, and aberrant autoimmune responses

I don't think it's just coincidence that there was increased levels of bacterial DNA- (lipopolysacharides etc.) maintained at 72 hours post exercise in the CFS group versus the control group.

I believe it's the lipopolysacharides from bacteria in the gut, getting into the bloodstream, causing an immune system reaction, impairing mitochondria and causing PEM.

Many people with CFS experience their worst PEM symptoms anywhere from 24 to 72 hours after exercise, which matches the increase of bacterial DNA found in the blood.......

There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.

In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance.

Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation.

To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined.

Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005).

There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.

These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls.

In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise.

These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684203/#sec011title

 

[ljimbo423]

Here is another quote that explains what could be described as part of a metabolic trap....

Moreover, mitochondrial dysfunction induces inflammation, while the converse, inflammation results in mitochondrial dysfunction, is also true [11, 13–15].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480219/

Mitochondrial dysfunction in CFS, I think is becoming clearer and clearer. Mitochondrial dysfunction, as this review states, creates inflammation and inflammation, causes mitochondrial dysfunction.

Causing to some degree, a locked system of ongoing, chronic, low grade inflammation and mitochondrial dysfunction. I think this is probably a part of what makes CFS a chronic condition.

However, I don't think mitochondrial dysfunction is the core cause of CFS. For me, I believe it's increased intestinal permeability that is causing low grade inflammation and mitochondrial dysfunction.

The mitochondrial dysfunction is causing more inflammation and in turn, causing more mitochondrial dysfunction and fatigue.

Jim

 

[Ben H]

@Ben H From your chat do you know if Robert is interested in supplements body builders take or the reduced body fat %.

Hey @wigglethemouse

The supplements I believe. I just added about my bodyfat and ketogenesis in my post as I believe the latter may have been implicated for me (a ton of things happen while in and transitioning to keto). But thats just me going on about it, not Rob.


B

 

[Rossy191276]

Hi all...

I think this hypothesis is the one that matches my experience the best and gives me great hope.

I am 41, I was a professional tennis player then always super fit post career running a marathon in 2013, working out and still on the tennis court a lot for work.

In late 2015 I had a friend tell me about the kero diet and I went on what I would say was a strict paleo diet... about 2 weeks in I started having effects like weakness, dizziness for about a weak until collapsing after about a week.

Interesting things were that I thought I had what was a complete recovery after about 2 months... during this time I developed an incredible appetite the size of which is hard to describe. I still have a list of one day that I kept because I couldn’t believe how much I had to eat even though at this point I was housebound. It was something like 2-3 times the amount I was eating when healthy and exercising a lot.

As I said I became symptom free after about 2 months and over another 6 weeks I started building up exercise to point where I believed I had fully recovered. At this point one weekend I ran 6miles, played tennis, and swam 45 mins. On the Monday morning I was doing a tennis session with a client and within 2 mins I felt the ‘metabolic switch’ happen again and I got symptoms back at about 20% of original collapse. A week later I went for a surf and suffered full crash again.

Since then with each crash I have achieved partial remissions that have been smaller and smaller and a year ago I became completely bed bound, and have spent most of the last year too weak to speak.

The idea of this being some sort of metabolic trap that clenches harder with each crash certainly makes a lot of a sense for me. I know some people seem to have different experiences and symptoms but I have always felt that my illness was some sort of catastrophic failure of energy production that was somehow initially triggered by going on that diet while exercising a lot.

 

[Murph]

That’s right @Murph . Absolutely live and breathed it (the ‘lifestyle’) was my ‘job’ and had plans to naturally compete..then became ill.

Yes I was on a few supplements. I was a natural bodybuilder, so no steroids etc, but supplements such as Whey protein, L carnitine, ZMA, possibly the occasional pre workout NOS drink. The usual stuff really. I wasn’t on BCAA’s separately bar those in the whey. Some people took them aswell as whey.

I would have had a very high (200g at least) protein intake for obvious reasons, and I also dieted heavily ketogenically (mainly) to get to around 6-7% bodyfat.

I am very, very interested in the hypothesis. Robert Phair is a really clever guy, also really lovely too.


B

Interesting. I also got sick while I was doing more exercise than ever before. (running 10km several times a week, on top of playing hockey (games and training)). But my diet was probably very low in protein. I was a vegetarian, and pretty lax at nutrition. I mostly just ate carbs.

 

[TreePerson]

It’s all very interesting and very puzzling. Some people feel that the ketogenic diet might have triggered their ME while others are using it specifically because they believe it aids recovery. By bypassing a blocked energy pathway? And then there is Dr Naviaux who saw a metabolic similarities with ME and starvation.

I wasn’t dieting but I was very physically active and experiencing acute sustained stress for several years previously. And then I caught a virus. And followed the same pattern of deterioration described by others. Falling further down the well. It took about 18 months to find myself right at the bottom.