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What is your personal theory or understanding of ME/CFS?

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
This study sums up my understanding of CFS very well-

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 verses the control group.

I believe it's the lipopolysacharides from the bacteria causing an immune system reaction and PEM.

Many people with CFS experience their worst PEM symptoms anywhere from 24 to 72 hours after exercise. My worst PEM always hits after 48 hours!

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/

Jim
 
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percyval577

nucleus caudatus et al
Messages
1,302
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Ik waak up
It´s caused by to much nitric oxide released by microglia i.e. the immunesystem in the brain (counting a quarter). This nitric oxide affects the other three quarter of the brain (the nerves), which are using it semselfs constantly for conditioning purpose (remembering, learning).

There is a special mechanism that gets out of normalitiy because of to much Manganese averaged over time and strength of infection, including all day bacteria etc:
Microglia adapt their nitric oxide production to the consumption of arginine in the liver, because their production of nitric oxide consumes arginine as well. And they do it via manganese because both - manganese and arginine - are used there in the liver by a life-important enzyme.

This adaption has become necessary for the purpose to support the nerves with the same amount of random nitric oxide.
But with to much nitric oxide steadily coming from the microglia the nerves now are doing to much much.

And because the nerves of the whole brain are out of normality therefore our symptoms can be widespread and somehow typical enough at the same time.
Nerves control many things in the body. Nerves percept everything in the body.
And the immunesystem of course is complicate and will not be understood in details for still long time to come.
 
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Stretched

Senior Member
Messages
705
Location
U.S. Atlanta
My understanding of what M.E is.

Myalgic Encephalomyelitis is not merely a symptom, or a syndrome, but is instead a distinct disease. It has been recognised by the World Health Organisation (WHO) since 1969 as a distinct organic neurological disease with the code G93.3.

The onset of M.E. is always acute and M.E. can be diagnosed within just a few weeks. M.E. is an easily recognisable distinct organic neurological disease which can be verified by objective testing. If all tests are normal, then a diagnosis of M.E. cannot be correct..

I would agree with most of your post. However, onset always being acute is questionable, at least IMO. My situation is kind of screwy: I'm a 'victim' of Lake Tahoe in 1985, onset starting shortly thereafter, ~90 days into 1986.

The key question in my mind is that I was working, growing my own company for years before Tahoe and after; but I got hit with the flu, an event as you suggested, while jogging. It cycled over the next few year while I continued pushing - rising and falling in health.

So, my question remains, did the systemic stress (to the immune system) set up the onset and continuation of the syndrome or was it solely caused by exposure in Tahoe? I think the former, and IMO others knowingly or not have experienced a similar assault on the immune system.[/QUOTE]
 

duncan

Senior Member
Messages
2,240
@ljimbo423, yes, that is a good theory. One difficulty I have is explaining cognitively-induced PEM. I know many of us can relate to this, but it appears to be, at least on the surface, different from exercise-induced PEM. So, I'm not talking about emotional PEM - that readily can fit because of heart beat etc. But simply concentrating to long or too much - like reading an entire study in one sitting, or attempting to solve a complex math problem.

It gets interesting real fast.

I have the same issue trying to explain away persistent subclinical infections as causative for ME/CFS. I vacillate between those and immune dysfunction/autoimmune response - or even a combo of the two, which it would seem more and more are subscribing to.
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
@ljimbo423, yes, that is a good theory. One difficulty I have is explaining cognitively-induced PEM. I know many of us can relate to this, but it appears to be, at least on the surface, different from exercise-induced PEM. So, I'm not talking about emotional PEM - that readily can fit because of heart beat etc. But simply concentrating to long or too much - like reading an entire study in one sitting, or attempting to solve a complex math problem.

I think the lipopolysaccharides from the gut cause some level of neuro-inflammation from both immune system activation and mitochondrial dysfunction in the brain.

The dysfunctional mito. in the brain would supply brain cells with less energy and possibly causing cognitively-induced PEM. Sometimes, from using just small amounts of cognitive energy, because there is so little available.

I don't know if that's what's happening but that's my first guess off the top of my head.:)
 

Wishful

Senior Member
Messages
5,679
Location
Alberta
I'm disinclined to accept the theory that gut bacteria are directly involved in PEM. My exercise-induced PEM has a quite consistent delay (24 hrs) and an abrupt transition to that state, and also a fairly consistent level of response to a particular trigger. I expect that if gut bacteria were involved, those responses would vary far more, and would vary with diet, time of day, and other such factors that would affect the gut ecosystem. Antibiotics should also have a major effect on those responses, but I never noticed any such changes when taking antibiotics.

Also, for me, 72 hrs is way past my PEM period, so bacterial LPS is pretty definitely not causing my PEM. Maybe my gut ecosystem is altered 48 hrs (or whatever) after PEM starts. It could even be a delayed response to PEM's termination. PEM involves plenty of physiological and psychological changes which could explain later changes in gut function. Just feeling grumpy about the elevated symptoms might be enough to alter gut function.

My preferred hypothesis about the exercise/PEM delay is elevated cytokines. Activities that damage muscle cells trigger immune activation, resulting in elevated cytokines. IFN-g is elevated 24 hrs following exercise, which increases kynurenine production through indole oxidase. My responses to tryptophan makes me believe that this may be the major cause of many of my symptoms.

The study shows that gut bacteria are affected by PEM, but doesn't seem to provide any evidence that those changes are responsible for any ME/CFS symptoms. They could be, but I don't see any reason at this point to claim that they are.

My ME started with type IV food sensitivity. That abnormal t-cell response stopped after food poisoning 2.5 years later, so that might have been a case of dysbiosis causing additional symptoms. The ME remains.
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
The study shows that gut bacteria are affected by PEM, but doesn't seem to provide any evidence that those changes are responsible for any ME/CFS symptoms.

My apologies, I put up the wrong link to the wrong study, which I have now corrected.

The study shows a clear link in elevated blood levels of lipopolysaccharies and other bacterial by products from the gut, to PEM.

The elevated levels were not sustained in the control group but were in the cfs/me group for at least 72 hours post exercise.

Lipopolysaccharides have been used in animal models to induce immune responses (ie, increased cytokines etc.) and neuro-inflammation, for decades. Even slightly elevated blood levels of lipopolysaccharides can cause a significant immune response.

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.

This is the right link!:):redface:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684203/

Jim
 

Stretched

Senior Member
Messages
705
Location
U.S. Atlanta
<<Also, for me, 72 hrs is way past my PEM period, so bacterial LPS is pretty definitely not causing my PEM. Maybe my gut ecosystem is altered 48 hrs (or whatever) after PEM starts. It could even be a delayed response to PEM's termination. PEM involves plenty of physiological and psychological changes which couldexplain later changes in gut function. Just feeling grumpy about the elevated symptoms might be enough to alter gut function.>>

Maybe cortisol release fits your onset time frame?
 

Wishful

Senior Member
Messages
5,679
Location
Alberta
If cortisol were a major factor in PEM symptoms, my PEM should vary with time of day, which it doesn't, as far as I can tell. The delay would probably be more variable too. My non-PEM baseline symptoms do tend to elevate around 2 PM, regardless of other factors, so I'd say that cortisol does have an effect that way.

While I had the type IV food sensitivity, I asked the doctor if there were any other body mechanisms that would provide such a precise and consistent 48 hr (+/- less than 15 minutes) delay from a trigger. She said no, the immune system was the only one she knew of.
 

gregh286

Senior Member
Messages
976
Location
Londonderry, Northern Ireland.
Whilst I tend to agree that LPS are the trigger, the mechansim behind fatigue is related to PDH enzyme.
I can retrieve myself from a crash very quickly by hammering into tonnes of amino and fats to body.
also, when in crash, total avoidance of carbs and sugar is a must, body seems to shunt into damaging body, I get brutal neuropathy etc at that time.
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
Whilst I tend to agree that LPS are the trigger, the mechansim behind fatigue is related to PDH enzyme.

I agree completely. I believe the immune system activation and the oxidative stress caused by it, from LPS getting into the bloodstream, cause the PDH enzyme to become dysfunctional and a switch to glycolosis from oxidative phosphorylation.

This causes a low production of ATP in the mitochondria and fatigue. It seems clear to me that LPS can cause a switch to glycolosis in the mitochondria.....

Activation of macrophages or DCs with a range of stimuli, including LPS10, the TLR3 ligand poly(I:C)11, and type I interferon (IFN)11, induces a metabolic switch from OXPHOS to glycolysis, in a phenomenon similar to the Warburg effect10

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493277/#__sec3title
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
also, when in crash, total avoidance of carbs and sugar is a must, body seems to shunt into damaging body, I get brutal neuropathy etc at that time.

This quote might explain why avoiding carbs and sugar (glucose) helps you so much. LPS are a toll like receptor (TLR) agonists.

TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources.

We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423780/#__sec11title

If I understand this right, it says that restricting carbs and sugar (glucose) leads to premature death of the dendritic cells (immune system cells) and that leads to reduced oxidative stress and inflammation. LPS activate TLR and dendritic cells.

One cause of Neuropathy is inflammation. So the reduction in oxidative stress and inflammation from reducing carbs and sugar (glucose) could be why it helps you so much in a crash.
 

gregh286

Senior Member
Messages
976
Location
Londonderry, Northern Ireland.
This quote might explain why avoiding carbs and sugar (glucose) helps you so much. LPS are a toll like receptor (TLR) agonists.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423780/#__sec11title

If I understand this right, it says that restricting carbs and sugar (glucose) leads to premature death of the dendritic cells (immune system cells) and that leads to reduced oxidative stress and inflammation. LPS activate TLR and dendritic cells.

One cause of Neuropathy is inflammation. So the reduction in oxidative stress and inflammation from reducing carbs and sugar (glucose) could be why it helps you so much in a crash.

Yea, thats what i thought mostly, also, I get good reaction to Oxymatrine. Its seems to be a TLR immodulator.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467070/

I figured out after this with 6 years that when I drink alcohol body seems chemical threat, and has ability to shutdown oxphos pathway to protect cell from ethanol damage.........
Thanks Ljimbo
 

Wishful

Senior Member
Messages
5,679
Location
Alberta
Carbs also increase tryptophan transport into the brain, increasing kynurenines (at least if your immune system is activated), which causes many of the symptoms of illness. My symptoms increase 20-30 minutes after a high-carb meal, but that increase is blocked (or maybe just delayed and spread out a lot) if I take BCAA's along with the meal, which blocks TRP transport into the brain.

There are lots of theories about what eating carbs does, but the way BCAA's block the effect on me seems like pretty strong evidence that TRP transport is involved.
 

neweimear

Senior Member
Messages
215
I believe the primary cause in most, is a leaky gut and most cases of leaky gut are caused by dysbiosis. Although there are many things that cause or contribute to a leaky gut.

This is the basic path I believe CFS takes-

  • Dysbiosis=
  • leaky gut=
  • immune system up-regulation from lipopolysaccharides (LPS) entering the bloodstream, causing auto-immunity in some and significant oxidative stress=
  • Mitochondrial dysfunction (CDR) from up-regulated immunity and oxidative stress
  • Activated microglia, from LPS's effect on the brain, causing neuro-inflammation and flu-like symptoms in many
How this unfolds on a biochemical level in each person with CFS is highly dependent on there genetics and epigeneics. That's why there are so many subgroups and why it's so difficult for researchers to find a consistent bio-marker.

EDIT- Lipopolysaccharides (LPS) are toxins that make up some of the outer membrane of gram negative bacteria, many of which live in the gut. LPS cause a big immune response even at very low levels, once they enter the bloodstream.

Jim
So on that basis, can healing a leaky gut help improve level of ME?
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
So on that basis, can healing a leaky gut help improve level of ME?

It has mine and I haven't fully healed my leaky gut yet.:) 11 months ago I started aggressively treating dysbiosis and leaky gut.

I was able then, to do about 2 hours of physical activity a day without suffering PEM. Now, 11 months later and still treating dysbiosis and leaky gut, I'm able to do between 4-6 hours a day of physical activity without PEM and I continue to improve.

I recently have also been treating mitochondrial dysfunction more aggressively. I believe the mitochondrial dysfunction is being caused by immune system activation and oxidative stress from a leaky gut.

It seems to me the mito. dysfunction is the cause of my fatigue and PEM but the dysbiosis and leaky gut are the cause of the mito. dysfunction.

Jim
 

gregh286

Senior Member
Messages
976
Location
Londonderry, Northern Ireland.
It has mine and I haven't fully healed my leaky gut yet.:) 11 months ago I started aggressively treating dysbiosis and leaky gut.

I was able then, to do about 2 hours of physical activity a day without suffering PEM. Now, 11 months later and still treating dysbiosis and leaky gut, I'm able to do between 4-6 hours a day of physical activity without PEM and I continue to improve.

I recently have also been treating mitochondrial dysfunction more aggressively. I believe the mitochondrial dysfunction is being caused by immune system activation and oxidative stress from a leaky gut.

It seems to me the mito. dysfunction is the cause of my fatigue and PEM but the dysbiosis and leaky gut are the cause of the mito. dysfunction.

Jim

Hi jim.
How are you treating leaky gut.
Btw i was.in top 2% of population in leakiness in a gut test.