Naviaux et. al.: Metabolic features of chronic fatigue syndrome

[serg1942]

Hi everybody,

Ok, I have already read your posts, and I have to tell that I have enjoyed it and also laughed with some of your comments!

Thank you @alex3619 for your always interesting posts. You definitely have a privileged way of thinking that I admire and enjoy.

Hi @JaimeS , I have read your article. Congratulations for it! I’d like to comment on this conclusion of yours:

“The presence or absence of a systemic pathogen may in fact be a source of patient subsets, with a group of patients still experiencing active or latent infection, and another stuck in an autoimmune-type symptom picture in which the initial-insult pathogen is no longer active, but the system is unable to come unstuck from protective-hibernation mode.”

My current view of ME/CFS , is based on the following facts (scientifically demonstrated) and suppositions :

FACTS: ME/CFS symptoms are the direct consequence of 1. Chronic inflammation, either directly (caused by pro-inflammatory cytokines) or indirectly (polyclonal B and T cells proliferation), 2. Autoimmune processes (cross reaction, over-reactive T and B cells…), 3. Immune suppression of the innate (NKs) and the specific response (low Th1, low inflammatory branch of the Th17, low Igs), and 4.Low grade chronic immune activation (high complement—innate--, high auto/over reactive T and B cells, low non-pathogen specific T-regs, elevated inflammatory branch of the Th2…).

SUPOSSITIONS: What is the cause of this chronic immune profile proven to exist in ME/CFS and to be the cause of the symtoms? Well, another fact is that the immune profile found in ME/CFS is that that we would expect to find in chronic inflammatory conditions caused by intracellular chronic infections.

Alright, I am personally a ME/CFS book patient and also a clear chronic Lyme disease patient. So I did my work and found the literature on Lyme disease showing the same immune profile that I have described above. Even more, the symptoms of Lyme disease are not caused by the bacteria itself (borrelia b.), but rather by an improperly set immune system—the same found in ME/CFS.

There are many ways the borrelia can enter cells. I think lipid rafts might be one of them. Just from a quick search (note that Sphingolipids =Galactosylceramide and Sulfatide):

“Infectivity and arthritis induction of Borrelia japonica on SCID mice and immune competent mice: possible role of galactosylceramide binding activity on initiation of infection.”

http://www.ncbi.nlm.nih.gov/pubmed/9570282

I should check if this is also true in humans though.

According to my personal situation I am treating my ME/CFS/-Lyme with LDI (Low dose immunotherapy), which is based on the assumption that a chronically improperly active immune system causes a disease, and by giving low doses of the antigen that has promoted that state, you train your immune system, making it not to over-react to this pathogen.

Alright. I won’t go into more details about this therapy for ME/CFS here. Thing is that there are many papers showing astonishing results using different types of the same therapy for other chronic inflammatory diseases (Crohn’s, ulcerative colitis), autoimmune conditions (multiple sclerosis, RA, anquilosant spondilitis, and many others), and chronic intracellular infections (such as hepatitis B).

Interestingly, the same therapy (using much higher doses of antigens) constitutes a standar treatment that cures (at least while you get the shots) all sorts of allergy.

So, in conclusion, what I’m trying to do here is to give a possible answer to the question of what could trigger this hypometabolic state? It has to be epigenetic in nature (appears at 35-45 average), so, over-simplifying: either toxins or pathogens or an improperly set immune response (pretty much what happens also with strep and rheumatic fever (even if you kill the bacteria, the immune system attacks perpetually the heart).

You can remove toxins, and some fellows improve, but it is not a cure for most (for sure they are a trigger). It could be an unknown pathogen, or it could be a pathogen that we know exist and causes the same abnormalities shown in ME/CFS (I’m talking here about some primary and intracelular infections in general (brorrelia, bartonella, babesia, chlamydias...) and also the opportunistic ones that for sure contribute when the immunity goes down (herpes viruses, even yeasts..).

It is funny that this study, aside from corroborating some already known metabolic abnormalities, and finding new ones, also describes the immunological scenario I have described as possible:

(…)ultimately may represent a fundamental response to oppose the spread of persistent viral and intracellular bacterial infections. (…)This pattern is also opposite of what is found during acute inflammation and infection (…) Plasma FAD was decreased in both males and females with CFS (...)FAD is mobilized from tissues, increased in the plasma, and renal secretion is increased under conditions of stress or infection (…) Hydroxyproline was increased(...)Another metabolic fate of hydroxyproline is glyoxylate, which can be transaminated in mitochondria to produce glycine and metabolized in peroxisomes to oxalate and peroxide for cell defense and innate and antiviral immunity (…) Arg levels were also increased in chronic fatigue(...)Increased Arg is associated with a decreased risk of infection after operative stress and is used to synthesize the antimicrobial molecule agmatine under conditions of active infection (…) HICA was decreased in both males and females with CFS.(..)HICA has antibacterial and antifungal activity.(…)

Finally: YES, I wish Rich was with us to live these wonderful times of discoveries and new therapies and theories…he was sooo close… We just couldn’t restore the methylation cycle without first “treating the terrain” as he used to say…

Best!
Sergio

 

[serg1942]

Please could someone explain this apparent contradiction to me, I'm finding it hard to understand:

In the Open Medicine Foundation article it states:

http://tinyurl.com/z6sgbbh

"This result supports the controversial idea that while infection is often the initiating event for ME/CFS, it does not contribute to the ongoing illness."

However, the Naviux paper itself states (at the bottom of page 3):

“The low sphingolipid profile in CFS appears to be an adaptive response...and ultimately may represent a fundamental response to oppose the spread of persistent viral and intracellular bacterial infections”.

Not sure how to reconcile those two statements?

Hi @Daisymay, : "This result supports the controversial idea that while infection is often the initiating event for ME/CFS, it does not contribute to the ongoing illness."

This might mean that a perpetual immune state promotes the symptoms, without the need of an actual infection being in the body... ¿How? A very good example is reumathic fever; the immune system got trained to attack the sreptocuccus. You can eradicate the bacteria from the body, but the immune system is still attacking cells of your heart, specifically proteins of our heart cells that resemble the proteins of the bacteria... This leads to chronic inflammation, redox abnormalities, etc. In other words, this causes stress signals that "tell" the cells to adapt into a "pathological homeostasis", i.e., the hypometabolic state found (already guessed by Dr. Cheney, Dr. Myhill...)..

But while this scenario is possible, I think what really happens is a mixture between this and a actual chronic infection: So the response of the body to the infection is, in part, this hypometabolic and catabolic state...

Best,
Sergio

 

[Daisymay]

Hi @Daisymay, : "This result supports the controversial idea that while infection is often the initiating event for ME/CFS, it does not contribute to the ongoing illness."

This might mean that a perpetual immune state promotes the symptoms, without the need of an actual infection being in the body... ¿How? A very good example is reumathic fever; the immune system got trained to attack the sreptocuccus. You can eradicate the bacteria from the body, but the immune system is still attacking cells of your heart, specifically proteins of our heart cells that resemble the proteins of the bacteria... This leads to chronic inflammation, redox abnormalities, etc. In other words, this causes stress signals that "tell" the cells to adapt into a "pathological homeostasis", i.e., the hypometabolic state found (already guessed by Dr. Cheney, Dr. Myhill...)

Best,
Sergio

Thanks Sergio!

 

[JPV]

paleo diet is seen as starvation by human body. not exactly what is needed in a dauer state.

I'm not an expert on the subject but I wouldn't take the references to "dauer state" too literally.

Though it's not the primary rational behind the Paleo Diet, it does remove a lot of highly inflammatory foods, such as grains and sugars, which would seem to be of benefit here.

 

[wdb]

Are there any statistics experts following this who able to comment how rock solid this evidence is ? The sample sizes are on the low side and number of items measured very high, can we confidently rule out a fishing expedition ?

Glad to read they are planning a replication on additional groups that would presumably go a long way to removing any doubt if those show the same results.

Also does anyone know how likely it is they will share anonymised raw data ?

 

[JaimeS]

Naviaux told you that he tested the patients' cholesterol and they were all low?

Everyone's? No, I meant mine had been tested. What he found was that, overall, the trend in both men and women was lower cholesterol. From the supplemental materials:

Cholesterol Synthesis through the Lathosterol Pathway was Decreased

The final conversion of desmosterol to choleterol is catalyed by the FAD- and NADPH-requiring enzyme, 24-dehydrocholesterol reductase... When [the enzyme] is dysregulated, desmosterol accumulates in cell membranes, but does not change significantly in plasma. Membrane accumulation of desmosterol inhibits endocytosis and pinocytotic import through caveolae, and inhibiting the production of sphingolipid-rich and cholesterol-rich lipd rafts needed for cell signalling...

Then he links this to inhibition of Lyme and Q-fever.

Here is an image from the supplemental materials: things colored in green are low. Women:

Men:

Remember that all of these are averages of many people. If you have high cholesterol, it doesn't mean you don't have ME.

[Edit: as discussed below, this is just one pathway as well. It appears that overall, patients 'leaned on' the other major pathway to cholesterol synthesis to make up for the low values here.]

-J

 

[JaimeS]

The sample sizes are on the low side and number of items measured very high, can we confidently rule out a fishing expedition ?

One of the most important things Naviaux did was to compare how many metabolites were at abnormal levels in healthy controls. Not 'zero' but nowhere near what showed up in CFS patients.

 

[alex3619]

One of the most important things Naviaux did was to compare how many metabolites were at abnormal levels in healthy controls. Not 'zero' but nowhere near what showed up in CFS patients.

From what we have so far been told about Ron Davis' research, we know that many metabolites are not slightly off, they are many orders of magnitude off. Huge signals mean that smaller numbers are necessary to reach statistical reliability. The confound here is the risk of false positives. That is, how many things will show up by random chance? Again, huge signals make this much less likely.

 

[JPV]

Remember that all of these are averages of many people. If you have high cholesterol, it doesn't mean you don't have ME.

I have high LDL and low HDL.

My mother, who also suffers from ME/CFS, has very high LDL. What's so unusual, is that she's abnormally skinny and avoids eating any fats.

I'm wondering if her high LDL might be her body's response to some sort of chronic inflammation, which is what a lot of the current medical literature now seems to indicate.

Any thoughts on this?

 

[JaimeS]

From what we have so far been told about Ron Davis' research, we know that many metabolites are not slightly off, they are many orders of magnitude off. Huge signals mean that smaller numbers are necessary to reach statistical reliable. The confound here is the risk of false positives. That is, how many things will show up by random chance? Again, huge signals make this much less likely.

As I understand it, Naviaux measured the number of metabolites that were in the bottom 5%, top 5%, or yet more abnormal, in either direction. Controls had 16 (?) off this much (they measured a lot!) CFSers had 40-something at least that off. I didn't see an analysis of 'how off', but I wasn't looking for one.

-J

 

[JaimeS]

My mother, who also suffers from ME/CFS, has very high LDL. What's so unusual, is that she's abnormally skinny and and avoids eating any fats.

I'm wondering if her high LDL might be her body's response to some sort of chronic inflammation, which is what a lot of the current medical literature now seems to indicate.

Any thoughts on this?

Yes, and ditto -- my mama with ME avoids fats because she had EBV and went into liver failure early in the disease. As you do.

Her cholesterol is sky-high.

Her body has likely found a way 'around' the low production of cholesterol by amplifying another signal. Without dietary fats she's probably got to make a bit more cholesterol (?). Wild mass guessing at this point, but. Compensatory mechanism on top of compensatory mechanism.

[Edit: and YES ty for pointing out that cholesterol is anti-inflammatory, so many ppl confused on this.]

-J

 

[alex3619]

Hmmmm, names. How about Persistent Hypometabolic Disease? PHD?

 

[Bob]

Are there any statistics experts following this who able to comment how rock solid this evidence is ? The sample sizes are on the low side and number of items measured very high, can we confidently rule out a fishing expedition ?

It may have been a fishing expedition (i haven't read it in detail yet), but Ron Davis wouldn't rely on this single study alone; i think he's said that they are getting similar results in different studies which is giving him cause for optimism. I assume the follow-up study will be robust enough to give us some meaningful insights if the results are similar.

Also does anyone know how likely it is they will share anonymised raw data ?

My understanding is that all OMF-funded data will be made available online for other researchers to access. I don't know if that applies to this particular study.

 

[Gingergrrl]

Wow, I just read through this thread and my brain is about to explode!!! I have not read the other thread or Jaime's article or the email from OMF yet.

My initial thoughts/questions are:

- I have always had high cholesterol and it remains very high to this day since getting sick so if this is a marker for ME/CFS, I don't have it. I also have a normal SED rate of six, and some prior threads say that PWC's have SED rates of 1-2, so I do not match on that either. Would cholesterol levels and SED rates be linked together or are these totally unrelated factors?

- I still feel that there are subsets or groups (at least two) b/c some people constantly feel sick/fluish, get fevers and colds, sore throats, swollen lymph glands, and fatigue vs. the opposite who are autoimmune, crazy allergic responses, never sick, no fevers or colds in years, and don't really feel fatigue.

- Am still curious how the autoantibodies and RTX fit in with this new theory? (I haven't read Jaime's article yet that explains this so I may understand this later).

 

[Forbin]

Please could someone explain this apparent contradiction to me,
"This result supports the controversial idea that while infection is often the initiating event for ME/CFS, it does not contribute to the ongoing illness."

However, the Naviux paper itself states (at the bottom of page 3):

“The low sphingolipid profile in CFS appears to be an adaptive response...and ultimately may represent a fundamental response to oppose the spread of persistent viral and intracellular bacterial infections”.

Not sure how to reconcile those two statements?

Yes, this confuses me, too. I was thinking that maybe the reduced cellular metabolic state might simply be another facet of what the elevated cytokines apparently do in the brain during a flu, i.e. they enforce immobility so that you rest and recover rather than continue as normal and wind up with pneumonia or something. Perhaps this reduced cellular metabolic state is the opposite of what happens during the acute phase because this "extreme measure" is only rolled out if the infection becomes chronic after previous measures at resolution have failed.

Of course, all this could be way off base and it's really all about protecting the cell, but it also seems to be a pretty efficient way of immobilizing you... as we all know too well.

 

[alex3619]

The core of the disorder, based on this data, is from only about a quarter of the metabolites. Three quarters of the metabolites seem to be personal. So the core disease is the same, the bells and whistles vary, if this research is right and I am interpreting it correctly. We should expect huge variations in symptoms, its the core chemistry that is the same or very similar.

 

[Kati]

Wow, I just read through this thread and my brain is about to explode!!! I have not read the other thread or Jaime's article or the email from OMF yet.

My initial thoughts/questions are:

- I have always had high cholesterol and it remains very high to this day since getting sick so if this is a marker for ME/CFS, I don't have it. I also have a normal SED rate of six, and some prior threads say that PWC's have SED rates of 1-2, so I do not match on that either. Would cholesterol levels and SED rates be linked together or are these totally unrelated factors?

- I still feel that there are subsets or groups (at least two) b/c some people constantly feel sick/fluish, get fevers and colds, sore throats, swollen lymph glands, and fatigue vs. the opposite who are autoimmune, crazy allergic responses, never sick, no fevers or colds in years, and don't really feel fatigue.

- Am still curious how the autoantibodies and RTX fit in with this new theory? (I haven't read Jaime's article yet that explains this so I may understand this later).

We are still very early in the game, if this is a game. Personal results will vary. There needs to be more and more patients tested. There needs to be further understanding.

 

[wastwater]

I have high cholesterol but does that mean low good cholesterol
systemic shutdown rather than hibernation

 

[Advocate]

They thought of everything!

 

[rosie26]

I agree; hibernation sounds far too benevolent, comfortable almost. All the wrong connotations.

Yes, more accurately it's a hibernation in hell, ravaged by unrelenting insomnia and all manner of extreme physical symptoms. Not the sweet and peaceful kind of hibernation.