Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Tunguska]

The sphingosine-1-phosphate (S1P) hypothesis can also explain the "It's in the blood" finding. From the Fluge & Mella study:

So the problem would be perhaps not something in the blood that shouldn't be there, but instead too little of something (S1P) that should be there.

S1P is initially made inside the cell but then, remarkably, is transported outside the cell to bind to its receptor on the cell surface. (Reference)

This "inside-out signaling" by S1P can also explain Julia Newton's study results of impaired AMPK in cultured ME/CFS muscle cells where she thought she had effectively removed the possibility of any blood borne factors.

They use Niacinamide in skin care because it helps with ceramides... https://www.ncbi.nlm.nih.gov/pubmed/10971324 (Niacinamide is heavily glucose-oxidation promoting, and fairly strong, and I've wondered if modulates mTor in any way; also lingering interest from Kimsie's posts, which recommended glutamine)

Massively supraphysiologic doses of thiamine, particularly transdermally applied allithiamine (which is fat-soluble and penetrates the cells much more effectively) and sublingual thiamine pyrophosphate to a lesser extent, were effective for me in combination with low dose lipoic acid and sublingual FMN around the clock.

I think transdermal was the only form I didn't try. But like you now, I focus more on brain health, out of necessity, with some indescribable but quite "physical" symptoms. The leucine+glutamine is worth a try for that, since crosses BBB, but I have my doubts it will match or work without something else (like ketamine/sarcosine/etc. mentioned earlier, or NMDA/AMPA in general) since I've already done high protein in general to death.

 

[eljefe19]

since crosses BBB, but I have my doubts it will match or work without something else (likeketamine/sarcosine/etc. mentioned earlier, or NMDA/AMPA in general) since I'vealready done high protein in general to death.

Thanks for bringing this up. I am going to add Sarcosine and/or DXM for mTor on top of Leucine, glutamine, creatine, PA, and Ursolic Acid. Will report back.

 

[nandixon]

S1P doesn't appear to be in the list of raw data from the PNAS study.
http://www.metabolomicsworkbench.or...SEARCH_TYPE=KNOWN&STUDY_TYPE=MS&RESULT_TYPE=1

Nor is it explicitly in the published list in the recent Hanson study.

Thanks, I had also downloaded the raw data but have to do everything on a smartphone so wasn't sure if I'd missed it.

S1PR1 is on my list of potential autoantibody targets, given it's role in lymphocytes, endothelial function. (and potential role in eye diseases...)

One of my hypotheses is that it is dysfunction (perhaps autoantibodies) of a receptor like this, rather than say, low levels of S1P (which itself requires a cause).

Yes, I had noted that possibility in an earlier post:

So if S1P is low due to low ceramides (or if there is actually plenty of S1P being made but there are antibodies against either S1P or to its receptors) then mTOR will not be sufficiently activated.

Too little of something doesn't really explain the results - there has to be something in the serum that actively stimulates or blocks something (and is not cleared out)

Everything fits for me. From my analysis, either low S1P or autoantibodies to one or more of its receptors seem nearly equally possible. The low S1P would be the block (i.e., impaired signaling), and low ceramides would be the immediate cause of the low S1P (or autoantibodies to S1P itself).

(FWIW, non-autoimmune, low S1P has the additional advantage of explaining Julia Newton's cultured muscle cell results - because of S1P's "inside-out" manner of signaling to activate AMPK, this means no autoantibodies are required to explain her results. Also, Montoya supposedly found a "100%" mRNA gene expression match for ME/CFS with systemic inflammatory response syndrome/SIRS, and S1P is low in sepsis.)

I think we need to know what the level of S1P is, and also of the precursor intermediate, sphingosine.

If S1P is low, then presumably it's either because of the low ceramides or because it has autoantibodies directed against it. As to why ceramides might be low in this case, I'll make another post.

If S1P is normal or high, then presumably it's because there are autoantibodies directed against one or more S1P receptors (e.g., S1P1 aka S1PR1), causing S1P production from ceramides to be upregulated to try to overcome this (and making ceramides low in the process).

It makes me a bit mad to think that sphingosine-1-phosphate levels may have never been tested in our disease. It just shows how pitiful the funding has been for ME/CFS. It only requires a little extra sample preparation to run this analysis on LC-MS/MS, for example.

Interestingly, S1P has fairly slow kinetics when expressed following muscle injury (matching PEM timeframes)
https://www.researchgate.net/public...uscles_through_a_S1PR2STAT3_Signaling_Pathway

Thanks, that's very good to know.

 

[Hip]

I take these together EVERY day! The benfotiamine is really helpful for me in particular. I've noted very similar supplements to the one I'm taking don't have the same degree of helpfulness if they don't have the benfotiamine.

When my virus induced chronic recurrent body-wide paresthesias (pins and needles), that lasted for around 9 years (typically getting worse after exercise, and possibly a sign of some neuropathy), benfotiamine was one of the few treatments that had a (temporary) impact on this symptom.

Since 2012, though, when I started taking high dose selenium and N-acetyl-glucosamine every day (and have taken these daily ever since), I have not had any recurrence of my viral paresthesias.

 

[nandixon]

@nandixon https://en.m.wikipedia.org/wiki/Fingolimod

What do you think about this S1P receptor agonist? Says it prevents lymphocytes from contributing to an autoimmune reaction.

Not sure. If it turns out there is impaired S1P signaling, and it has an autoimmune basis, then I guess there might be a chance of it being helpful. [Edit: Although fingolimod initially acts as an agonist to the S1P receptor it ultimately behaves as a functional antagonist, so definitely not what we want.]

But if there's not an autoimmune basis, we'd want an agonist with a purer mode of action and fewer side effects, I think.

S1P itself has an extremely short half-life in the blood. (Reference) So any agonist analogue has to improve upon that (like desmopressin for vasopressin or fludrocortisone for aldosterone).

Alternatively, we might find something to inhibit one or more of the various enzymes that degrade S1P, especially S1P lyase (S1PL), which irreversibly degrades S1P.

And of course there's rituximab (which may or may not be working by an autoimmune mechanism), but that's a different concept than a daily medication.

 

[eljefe19]

of course there's rituximab (which may or may not be working by an autoimmune mechanism), but that's a different concept than a daily medication.

I am considering Rituximab treatment actually.

 

[alicec]

supplement sulbutiamine, which is a fat-soluble derivative of vitamin B1

Sulbutiamine, as you note, effectively crosses the BBB which allithiamine does not, at least not in my experience. Allithiamine got rid of my physical limitations but helped only marginally with my main problem which is severe loss of cognitive function, especially executive function.

Allithiamine is a natural form derived from garlic. Sulbutiamine is a synthetic analogue based on allithiamine structure. They act in the same way.

They are described as fat soluble (even though allithiamine at least is very water soluble - presumably sulbutiamine is also) because their structure allows them to readily cross cell membranes, including the BBB. Lipophilic would be a better description.

@Sidereal, perhaps the lack of effect of allithimine on the cognitive function is simply because the cause is not related to thiamine. Allithiamine certainly crosses the BBB.

This capacity to readily cross the cell membrane means they are not limited by the slow uptake mediated by a specific transporter that applies to thiamine. High levels can be built up in cells.

Note that benfotiamine is often claimed to be one of the allithiamine family. It is not. It has a different structure, does not have the same capacity to cross membranes and does not cross the BBB. It is not lipophilic.

 

[junkcrap50]

The sphingosine-1-phosphate (S1P) hypothesis can also explain the "It's in the blood" finding. From the Fluge & Mella study:

Exposing cultured muscle cells to serum from ME/CFS patients indicated the presence of blood-borne substances affecting energy metabolism.​

So the problem would be perhaps not something in the blood that shouldn't be there, but instead too little of something (S1P) that should be there.

S1P is initially made inside the cell but then, remarkably, is transported outside the cell to bind to its receptor on the cell surface. (Reference)

This "inside-out signaling" by S1P can also explain Julia Newton's study results of impaired AMPK in cultured ME/CFS muscle cells where she thought she had effectively removed the possibility of any blood borne factors.

Not sure. If it turns out there is impaired S1P signaling, and it has an autoimmune basis, then I guess there might be a chance of it being helpful.

But if there's not an autoimmune basis, we'd want an agonist with a purer mode of action and fewer side effects, I think.
[....]
Alternatively, we might find something to inhibit one or more of the various enzymes that degrade S1P, especially S1P lyase (S1PL), which irreversibly degrades S1P.

If your theory is correct and it is impaired S1P signalling, wouldn't it be fairly easy to measure and test? First, measure S1P levels sine neither Naviaux and Fluge seem to have done so. Second, add some (in increasing concentration/dose) S1P to cultured CFS/ME cells and see how they behave and if they act like they do when exposed to non CFS blood. Third, test for antibodies to S1P.

Have you thought about writing a paper of your theory and sending it to Naviaux and Fluge & Mella or their contacts/representatives that are on Phoenix Rising? You seem to have a good grasp of the science and maybe they haven't thought of it yet.

 

[J.G]

In his post here, @J.G points out that in acute liver failure, there is actually an anti-mitochondrial autoantibody that specifically targets the pyruvate dehydrogenase E2 subunit (as detailed in this study, and in this Wikipedia article).

I actually test positive for anti-mitochondrial autoantibodies, albeit at a borderline titre (1:40).

One possible interpretation is that, if one sees ME/CFS as a purposeful, adaptive response to a uncleared/unclearable pathogen (as Naviaux et al 2016 speculate), AMA could serve as a secondary mechanism to inhibit the Krebs cycle. I think of them as a non-essential annexe to whatever primary autoab and/or pathway up/downregulation suppresses PDH.

If they'd been present in significant quantities in patient groups' serum we would have heard about that from the German-Norwegian nexus by now, I feel.

 

[Hip]

if one sees ME/CFS as a purposeful, adaptive response to a uncleared/unclearable pathogen (as Naviaux et al 2016 speculate), AMA serve as a secondary mechanism to inhibit the Krebs cycle.

My own hunch is that it may be more the other way around: that ME/CFS is a purposeful state that is carefully organized and orchestrated by the pathogens that infect us, in order to prevent the body and immune system from destroying these pathogens, and clearing the infection.

If you look at the numerous cunning techniques that infectious pathogens use to thwart the immune response (collectively called immune evasion), it becomes apparent that pathogens are masterful "hackers" of the human body and immune system; pathogens have evolved ways to control the bodies of the hosts they infect, in order to ensure they are not destroyed and cleared from the body.

In this earlier post, I mention how the viral VP capsid protein from coxsackievirus B (a virus found active in the muscles of most ME/CFS patients) has a molecular similarity to the mitochondrial adenine nucleotide translocator (ANT) protein, and thus this virus appears to trigger an autoimmune attack on the mitochondria. This autoimmune attack has been observed in coxsackievirus B myocarditis, which is a disease involving viral infection and a low energy state of the heart muscle. This autoimmune attack on the mitochondria found in myocarditis may be the basis for the low energy state of ME/CFS as well.

From the viruses' perspective, creating this low energy state via autoimmune attack may simply be an immune evasion survival strategy, that prevents the immune system from effectively clearing the virus.

That's just speculation, but what I am saying is in general is that the state of ME/CFS may be more the result of viral immune evasion, rather than an adaptive response of the body to an unclearable pathogen. Although it might be a bit of both.

 

[nandixon]

Have you thought about writing a paper of your theory and sending it to Naviaux and Fluge & Mella or their contacts/representatives that are on Phoenix Rising?

I tagged @Ben Howell in a previous post a couple pages ago here, and this is @deleder2k's thread, who I believe is actually in the current Phase 3 rituximab trial in Norway, so hopefully he'll ask Fluge/Mella about testing for S1P levels and looking for autoantibodies to the S1P receptors and to S1P itself.

 

[Learner1]

I'd posted this on another thread, but a couple of wise people suggested I also post it here...

Investigating why I'm always so short of P5P, and what it's used for, I stumbled upon this:

This describes PLP (P5P or B6) and it's importance in sphingolipids and immune function.

http://www.folk.uib.no/mfapu/Pages/papers pdf/2013/paul_2013_nr_71-239.pdf

I extracted this from the PDF:

PLP-dependent metabolism of sphingolipids

Reduced availability of PLP is associated with reduction
in several components of the immune response, includ-
ing significant decreases in lymphocyte numbers, espe-
cially T-helper cells and IL-2 production in humans.6
Lymphocytes isolated from vitamin B6-deficient subjects
also show reduction of lymphoproliferative responses to
mitogens that activate both T and B cells when grown in
a culture medium containing adequate concentration of
PLP.6 This has been attributed to the lower numbers of
T-helper cells in the lymphocyte population from vitamin
B6-deficient subjects. Maturation and egress of lympho-
cytes, especially T-cells, from thymus and lymph nodes
relies on the gradient of sphingosine-1-phosphate (S1P).
PLP-dependent enzymes play a major role in the synthe-
sis and breakdown of S1P, which is a potent metabolite
that regulates inflammation and immune response pro-
cesses such as cell growth, survival, differentiation, lym-
phocyte trafficking, vascular integrity, and cytokine
and chemokine production.58,59 PLP is required for the
activity of serine palmitoyl transferase that catalyzes the
condensation of serine and palmitoyl CoA into 3-keto-
dihydrosphingosine, which is then converted to S1P
in a series of reactions.58–60 PLP is also a cofactor for
sphingosine-1-phosphate lyase, which irreversibly cleaves
S1P to regulate its concentration.58,59,61 A gradient of S1P
is required for lymphocyte egress from thymus and
peripheral lymphoid organs, which is maintained by S1P
lyase.62 Administration of vitamin B6 antagonist 4’ deoxy-
pyridoxine interferes with the S1P gradient, results in
accumulation of mature lymphocytes in the thymus, and
depletes B- and T-lymphocytes from lymph causing lym-
phopenia.62 These conditions can be reversed by provid-
ing excess vitamin B6 in the diet.62 During inflammation,
S1P concentration increases in the inflamed peripheral
tissues,63 which functions as a chemoattractant for the
inflammatory cells.
One of the intermediate products during the synthe-
sis of S1P from 3-keto-dihydrosphingosine is ceramide,
which plays an important role in inflammatory processes.
Ceramide functions as a second messenger mediating the
effects of tumor necrosis factor-a and interferon-g on
programmed cell death and regulating senescence.64,65 An
increase in cellular ceramide concentration is observed in
cystic fibrosis, experimental autoimmune encephalomy-
elitis, and diet-induced insulin resistance, all of which are
marked by chronic inflammation.66–68 The importance of
ceramide in these diseases is demonstrated by the fact
that manipulation of ceramide concentration via inhibi-
tion of serine palmitoyl transferase or mutation of sph-
ingomyelinase, reverses the pathology of the disease.66–68
Ceramide-1-phosphate, which is derived from ceramide,
activates mast cells that mediate inflammation.69
Thus, it is possible that is a higher demand exists for
PLP during inflammation due to the role of PLP in the
synthesis of S1P and ceramide, and maintenance of S1P
gradient.

 

[lansbergen]

Old veterinary knowledge: when you suspect a virusinfetion give them Vit B6. Better the whole B complex or B6-B12-B1-B2 together.

 

[Ben H]

I tagged @Ben Howell in a previous post a couple pages ago here, and this is @deleder2k's thread, who I believe is actually in the current Phase 3 rituximab trial in Norway, so hopefully he'll ask Fluge/Mella about testing for S1P levels and looking for autoantibodies to the S1P receptors and to S1P itself.

Hey @nandixon

This is an interesting discussion. I will certainly put this across. As for Naviaux I do not know.

Thanks,

B

 

[Ben H]

I actually test positive for anti-mitochondrial autoantibodies, albeit at a borderline titre (1:40).

One possible interpretation is that, if one sees ME/CFS as a purposeful, adaptive response to a uncleared/unclearable pathogen (as Naviaux et al 2016 speculate), AMA could serve as a secondary mechanism to inhibit the Krebs cycle. I think of them as a non-essential annexe to whatever primary autoab and/or pathway up/downregulation suppresses PDH.

If they'd been present in significant quantities in patient groups' serum we would have heard about that from the German-Norwegian nexus by now, I feel.

Hey @J.G

One thing to point out is that with Naviaux, the belief is not that a pathogen is uncleared, but rather a response to a 'trigger' that has not 'reset' itself properly. The initial trigger may be long gone, but the maladaptive systemic response is the issue.


B

 

[Sidereal]

Allithiamine is a natural form derived from garlic. Sulbutiamine is a synthetic analogue based on allithiamine structure. They act in the same way.

Perhaps so but in my experience at least their effects in vivo are vastly different. Sulbutiamine does seem to improve cognition, it's just that its side effects are intolerable.

I tend to think that all the symptoms of this illness are fundamentally caused by the same problem: lack of energy. Allithiamine didn't just improve the "fatigue"/exertional intolerance (while it lasted), it also cleared up other wacky problems frequently found in ME/CFS: alcohol intolerance, inability to catch normal infections like colds/flus, hypersensitivities to sound/light/movement/crowds/etc., hypokalemic reactions to methylation supplements etc.

 

[Snow Leopard]

This is an interesting discussion. I will certainly put this across. As for Naviaux I do not know.

If there are autoantibodies involved in this disease, it is most likely subset(s) of GPCR that are targeted (some GPCR have already been studied by Carmen Scheibenbogen et al) - these receptors that tend to internalise after antibody binding and thus are less likely to lead to inflammitory immune complexes. The second aspect is targeting specific GPCR is a plausible explanation for the symptoms and symptom kinetics (PEM), as discussed in this thread.

 

[Learner1]

Old veterinary knowledge: when you suspect a virusinfetion give them Vit B6. Better the whole B complex or B6-B12-B1-B2 together.

Why B6?

 

[J.G]

One thing to point out is that with Naviaux, the belief is not that a pathogen is uncleared, but rather a response to a 'trigger' that has not 'reset' itself properly. The initial trigger may be long gone, but the maladaptive systemic response is the issue.

Ben, thanks for pointing that out. Hit-and-run indeed seems the prevailing paradigm at the moment, but to my (limited!) understanding, the Naviaux paper doesn't make the argument either way (hit-and-run or latent/chronic pathogen). Maybe they've later clarified their position elsewhere, but in the paper, they simply say:

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

That could go either way, adaptive or maladaptive. There's some anecdotal evidence suggestive of a persistent pathogen floating around these boards (success with antivirals/antibacterials; or maybe I'm just misunderstanding how/why they might help).

I fully agree that hit-and-run is a cleaner, elegant, and scientifically more helpful hypothesis than chronic pathogen, since it is helping to direct our attention towards energy metabolism, gene expression, etc. rather than orchestrating pathogen hunts that are doomed to fail due to heterogeneity and the maladaptive (sub)group. But I think it's too early to discount the persistent infection hypothesis entirely. Agree to disagree, of course!

 

[lansbergen]

Why B6?

No idea. Its more than 30 years ago. i am pretty sure it was based on clinical observation. .