Biarritz13
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Naviaux et. al.: Metabolic features of chronic fatigue syndrome
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JaimeS
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Recently saw a survey with "I frequently think about my poor health"
.....this sounds like a trick question.
JaimeS
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10% met! I will be writing this...
Kati
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Very loaded. Assessing obsessiveness traits.
A.B.
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What I'm reading between the lines here, and getting from other people's comments, is that yes intracellular pathogens are present in ME/CFS but they have adapted to their host and are now part of the microbiome rather than part of a life threatening infection, and the problem is more the host response to this situation. And Rituximab seems to tell us that B cells are involved in the host response.
My mother worked in a virology lab and on tick borne diseases. She developed severe ME/CFS, but eventually got better. Both her sons got ME/CFS for "no reason" in the second half of puberty (metabolic changes!).
And Naviaux and Davis don't want to say this openly because it could lead to even more people taking dangerous antimicrobials. Note the language "antimicrobials may do more harm than good". They could only do good if microbes were part of the problem to begin with.
This all seems to make sense in some way.
It could also explain a lot in regards to why some people are very healthy and achieve a lot in life whereas other don't achieve much. My understanding is that genetics has given us few answers here.
PS: or maybe the host response (ie. the dauer like hypometabolism) is appropriate in cases where the microbiome could be potentially deadly if it ever got out of control.
My mother worked in a virology lab and on tick borne diseases. She developed severe ME/CFS, but eventually got better. Both her sons got ME/CFS for "no reason" in the second half of puberty (metabolic changes!).
And Naviaux and Davis don't want to say this openly because it could lead to even more people taking dangerous antimicrobials. Note the language "antimicrobials may do more harm than good". They could only do good if microbes were part of the problem to begin with.
This all seems to make sense in some way.
It could also explain a lot in regards to why some people are very healthy and achieve a lot in life whereas other don't achieve much. My understanding is that genetics has given us few answers here.
PS: or maybe the host response (ie. the dauer like hypometabolism) is appropriate in cases where the microbiome could be potentially deadly if it ever got out of control.
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JaimeS
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Welllll
Intial pathogen exposure (or other stressor) leads to active immune response which involves the aggregation of lipid rafts for purposes of defense.
This makes patient more susceptible to certain intracellular pathogens.
Rituximab doesn't necessarily say anything about B-cells, since it targets lipid rafts, and not in B-cells only. It may be hindering pathogens from entering new cells.
That last 'may be' is a BIG 'may'. It's speculation on my part.
Rest I absolutely agree.
A.B.
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I understood that Rituximab targets CD20, which is almost only present on B cells. Wikipedia describes CD20 as probable calcium channel, so again according to my understanding it would be found on lipid rafts where these kind of things aggregate. Where did you get the information that Rituximab targets lipid rafts in other cells as well?
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JaimeS
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*nodnod*
But ppl have discovered them now in other places, such as T-cells. They may end up being part of other cell types as well.
Dear god, I come up for air after a week of manuscript and dissertation writing to find 37 pages of comments on the Naviaux article between this thread and other one.
After a couple hours of digesting all this, here's where I'm at regarding the article results:
1) Hooray for a PNAS article using cutting edge methods to do new basic research on ME/CFS patient samples! Congratulations to all of the researchers working hard on this. Also thanks to those involved outreach and keeping everyone in the loop regarding additional info on these forums, such as @Ben Howell @JaimeS and @Rose49.
2) 40 metabolites of the 600+ tested are outside of normal values (did I read 2-sigma outside, or am I making stuff up?) for the ME/CFS cohort, as compared to an average of 16 for controls. These abnormal metabolite levels are predominantly lower than average, indicating a hypometabolic phenotype. Note that this patient population is textbook definition chronic, with average duration of illness around 20 years.
3) Pathway analysis shows 5 independent irregularities for male, six for female, and nine shared. The pathways involved are primarily forms of lipid metabolism (sphingolipid, glycosphingolipid, phospholipid and cholesterol metabolic pathways). Other key results involve low levels of FAD (M + F), purines (M + F), and vitamin B12 (Female only).
4) Interestingly, while these pathways are involved in metabolic syndrome and acute cell danger response, the metabolites are regulated in the opposite direction in the ME/CFS cohort. A similar profile is seen in the dauer metabolic state in model organism C. elegans, where larvae trade off cell replication and sexual maturation in favor of increased hardiness in response to environmental stress.
5) The hypometabolic pathways in ME/CFS are affected by redox state and NADPH availability in the cell, and are thus indicative of low cell energy reserves.
6) This altered homeostasis reflecting a hypometabolic state is consistent regardless of initial onset, and greater deviation from the norm (more metabolites outside of norm/values further from the mean for individual metabolites) correlates with increased symptom severity.
7) Independent replication of these results using the Metabolon system are being hotly pursued as both a baseline for future hypothesis driven research, and as a diagnostic for the disease.
Here are a few of my questions and musings for what they're worth:
1) A lot of the subsequent discussion has revolved around what this research might suggest in terms of treatment and supplementation. If, as this research suggests, an altered homeostasis exists, then supplementation may have transient value as cells try to return to their new homeostatic norm, as @alex3619 has pointed out. It may, however, help suggest why people have had some limited symptom improvement with vitamin B injections (low B12 in females). It will be interesting to see if the OMF B12 trial sees a greater symptom improvement in women vs. men.
2) Great point about the ME/CFS cohort supplementing with DHA/Omega-3's, since it's part of the only consistently increased phospholipid - PC(18:1/22:6). I wonder if that info could be captured for a post-hoc analysis with a questionnaire to the participants.
3) I don't have a good handle at all on how dependent synthesis of these lipid metabolites is on their intake. Their synthesis dependency on NADPH and FAD is discussed in the paper, but it's possible that increasing dietary supply of their precursors would have some value as a novel target (though see caveat of musing #1). For example, digestive enzyme supplementation with amylase or lipase to improve dietary uptake of lipids could improve some of these values. Let's let that get tested in the lab first though, yeah?
4) I'm a little unclear regarding the plasma preparation phase for analysis, which is described in another paper. It looks like there's a single extraction step for all of the metabolites tested, with 4 volumes of acetonitrile:methanol (50:50) per volume of plasma containing controls and standards. Is that correct? I'm hoping that's the case, rather than requiring additional drying and enrichment steps for the lipids, since that helps with designing a diagnostic screen.
5) Is there a murine (mouse) model in literature which demonstrates dauer-like metabolic characteristics? If so, this metabolic pattern might be something to look for as researchers attempt to develop and validate an animal model of ME/CFS.
6) This one is way out there folks. Just to drag this back to self-management of disease, assume we see independent replication and confirmation of these results, with correlation of disease severity to a subset of around 10 metabolites. We're starting to see initiatives like Cor starting to pop up, where regular home blood monitoring can be linked by apps and aggregated in the cloud using advanced data analytics. The idea is that you start a regimen (supplement, exercise, etc), combine it with important daily subjective outputs (pain, energy level, was I able to clean the house?) see how it affects your day to day blood values, and come up with something that works for you. Right now these systems are being developed to monitor basic values like blood glucose, cholesterol, LDL, HDL and fibrinogen. It wouldn't be surprising to see variants for specific diseases following on in the next 5 - 10 years though. Then we could really make progress on some of these treatment questions we've been asking
Apologies for the massive post. Common side effects of dissertation writing include verbal diarrhea and wild hypotheses on future research directions.
After a couple hours of digesting all this, here's where I'm at regarding the article results:
1) Hooray for a PNAS article using cutting edge methods to do new basic research on ME/CFS patient samples! Congratulations to all of the researchers working hard on this. Also thanks to those involved outreach and keeping everyone in the loop regarding additional info on these forums, such as @Ben Howell @JaimeS and @Rose49.
2) 40 metabolites of the 600+ tested are outside of normal values (did I read 2-sigma outside, or am I making stuff up?) for the ME/CFS cohort, as compared to an average of 16 for controls. These abnormal metabolite levels are predominantly lower than average, indicating a hypometabolic phenotype. Note that this patient population is textbook definition chronic, with average duration of illness around 20 years.
3) Pathway analysis shows 5 independent irregularities for male, six for female, and nine shared. The pathways involved are primarily forms of lipid metabolism (sphingolipid, glycosphingolipid, phospholipid and cholesterol metabolic pathways). Other key results involve low levels of FAD (M + F), purines (M + F), and vitamin B12 (Female only).
4) Interestingly, while these pathways are involved in metabolic syndrome and acute cell danger response, the metabolites are regulated in the opposite direction in the ME/CFS cohort. A similar profile is seen in the dauer metabolic state in model organism C. elegans, where larvae trade off cell replication and sexual maturation in favor of increased hardiness in response to environmental stress.
5) The hypometabolic pathways in ME/CFS are affected by redox state and NADPH availability in the cell, and are thus indicative of low cell energy reserves.
6) This altered homeostasis reflecting a hypometabolic state is consistent regardless of initial onset, and greater deviation from the norm (more metabolites outside of norm/values further from the mean for individual metabolites) correlates with increased symptom severity.
7) Independent replication of these results using the Metabolon system are being hotly pursued as both a baseline for future hypothesis driven research, and as a diagnostic for the disease.
Here are a few of my questions and musings for what they're worth:
1) A lot of the subsequent discussion has revolved around what this research might suggest in terms of treatment and supplementation. If, as this research suggests, an altered homeostasis exists, then supplementation may have transient value as cells try to return to their new homeostatic norm, as @alex3619 has pointed out. It may, however, help suggest why people have had some limited symptom improvement with vitamin B injections (low B12 in females). It will be interesting to see if the OMF B12 trial sees a greater symptom improvement in women vs. men.
2) Great point about the ME/CFS cohort supplementing with DHA/Omega-3's, since it's part of the only consistently increased phospholipid - PC(18:1/22:6). I wonder if that info could be captured for a post-hoc analysis with a questionnaire to the participants.
3) I don't have a good handle at all on how dependent synthesis of these lipid metabolites is on their intake. Their synthesis dependency on NADPH and FAD is discussed in the paper, but it's possible that increasing dietary supply of their precursors would have some value as a novel target (though see caveat of musing #1). For example, digestive enzyme supplementation with amylase or lipase to improve dietary uptake of lipids could improve some of these values. Let's let that get tested in the lab first though, yeah?
4) I'm a little unclear regarding the plasma preparation phase for analysis, which is described in another paper. It looks like there's a single extraction step for all of the metabolites tested, with 4 volumes of acetonitrile:methanol (50:50) per volume of plasma containing controls and standards. Is that correct? I'm hoping that's the case, rather than requiring additional drying and enrichment steps for the lipids, since that helps with designing a diagnostic screen.
5) Is there a murine (mouse) model in literature which demonstrates dauer-like metabolic characteristics? If so, this metabolic pattern might be something to look for as researchers attempt to develop and validate an animal model of ME/CFS.
6) This one is way out there folks. Just to drag this back to self-management of disease, assume we see independent replication and confirmation of these results, with correlation of disease severity to a subset of around 10 metabolites. We're starting to see initiatives like Cor starting to pop up, where regular home blood monitoring can be linked by apps and aggregated in the cloud using advanced data analytics. The idea is that you start a regimen (supplement, exercise, etc), combine it with important daily subjective outputs (pain, energy level, was I able to clean the house?) see how it affects your day to day blood values, and come up with something that works for you. Right now these systems are being developed to monitor basic values like blood glucose, cholesterol, LDL, HDL and fibrinogen. It wouldn't be surprising to see variants for specific diseases following on in the next 5 - 10 years though. Then we could really make progress on some of these treatment questions we've been asking
Apologies for the massive post. Common side effects of dissertation writing include verbal diarrhea and wild hypotheses on future research directions.
JaimeS
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Wellllll
It's 2 sigma but, like, that still means bottom or top 5% (or rarer). So it's in the top or bottom 5% without any suggestions as to whether this is 'technically' in or out of range. Most of this stuff doesn't have a standardized range on the books, so it's just a matter of how common or uncommon it is to have that many metabolites that low. Imp't bit is the comparative stuff, 40 vs 16.
-J
I dont want to destroy this thread but I am often thinking how to get more donations for Davis/Naviaux and Lipkin´s team. What do you think about that we could maybe put to our facebook pictures some appel or picture or something creative to attract the attention of other patients that they think about the possibility to donate
Sea
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I don't think the concept of diet improving or even curing autoimmune disease is unpopular or contested. What is fought against is when people think their theory should apply to all, when in the real world it obviosly does not. There are many who have followed Paleo and have had responses that vary from getting worse, no change, improvement to cured.
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Thank you for this observation. The reality for some ME/CFS patients like my daughter is that a consequence of het autonomic dysfunction is drastically dysfunctional GI motility, both gastric emptying and large intestine motility are too slow. Food sits her stomach for too long and rarely digests as thoroughly as it should. She also has evidence of autoimmune disease in her GI tissues. She, as some of Naviaux's evidence for a hypometabolic state seems to indicate, falls into the category of struggling to keep weight on.
Hardcore dietary and supplement interventions aren't an option for her. She doesn't metabolize them properly. A paleo or vegan diet would have the potential to make her very ill. Her GI has advised against fiber supplements and has recommended she try to eat easily digestible foods in a balanced way.
For some patients with what is being hypothesized to be a hypometabolic state, diet changes may not be a starting point. They are simply too sick and their bodies may need more conventional medical interventions and therapies. I firmly believe that once recovery is underway--and possibly to maintain remission--diet and supplements will be a vital component.
Forbin
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This may be a blindingly obvious observation, but ~
The Lipkin/Hornig study showed that, on average, patients have elevated cytokines in the first three years of illness, which then subsequently become depressed. The elevated cytokines in the brain seem to explain why you feel like you have the flu - and perhaps feel like you don't have any energy, but they didn't seem to account for an actual lack of energy, such as might explain a poor performance on a 2-day exercise test.
This new hypometabolic response found by Dr. Naviaux, on the other hand, seems to explain why patients actually have no energy - or rather, perhaps, only limited energy that is restored at an abnormally slow rate.
All this suggests that there's a real distinction between feeling crappy with the "flu" and not having any real energy (which might be another sort of crappy feeling in itself). It also might explain why people don't seem to feel much better after the three year mark, when the cytokines cease to be elevated.
[I suppose it's also possible that low cytokines might also make you feel crappy, but I've never seen anything on how low cytokines make you feel.]
The Lipkin/Hornig study showed that, on average, patients have elevated cytokines in the first three years of illness, which then subsequently become depressed. The elevated cytokines in the brain seem to explain why you feel like you have the flu - and perhaps feel like you don't have any energy, but they didn't seem to account for an actual lack of energy, such as might explain a poor performance on a 2-day exercise test.
This new hypometabolic response found by Dr. Naviaux, on the other hand, seems to explain why patients actually have no energy - or rather, perhaps, only limited energy that is restored at an abnormally slow rate.
All this suggests that there's a real distinction between feeling crappy with the "flu" and not having any real energy (which might be another sort of crappy feeling in itself). It also might explain why people don't seem to feel much better after the three year mark, when the cytokines cease to be elevated.
[I suppose it's also possible that low cytokines might also make you feel crappy, but I've never seen anything on how low cytokines make you feel.]
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alex3619
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http://www.healthrising.org/forums/threads/solve-me-cfs-webinar-with-maureen-hanson-sept-1.4788/
It appears that the Hanson/Younger study is also showing a hypometabolic state!
It appears that the Hanson/Younger study is also showing a hypometabolic state!
JaimeS
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Hanson has a webinar coming soon...
I should say 'apart from that one'.
I should say 'apart from that one'.
JaimeS
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Hey, we met two goals today!
1) #MEAction has raised enough for a PR firm -- hallelujah!
2) I have met 10% of my fundraising goal!
Therefore, I will be doing that write-up for those who donated! Now I have to come up with ideas for when I reach 25%....
-J
1) #MEAction has raised enough for a PR firm -- hallelujah!
2) I have met 10% of my fundraising goal!
Therefore, I will be doing that write-up for those who donated! Now I have to come up with ideas for when I reach 25%....
-J
Research 1st
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You're correct, Cytokines make you feel crappy and in pain (Including causing psychiatric symptoms) but we need something better, in terms of unique to us to change the game.
E.g other illnesses have high Cytokines too, including infection, but they don't have the unique 'features' of ME CFS.
So we need this for sure, and good point indeed, hence I wanted to reply.
One problem though I must pick you up on (not to be rude, but informative), is that PWCFS can equally have High Cytokines as Low. One published CFS paper (maybe more?) has also shown a Severe Vs Moderate correlation with elevated Cytokine levels for the more severely affected (Australian I think, I can't remember off hand) and Dr Montoya's was going to show this too, - his study is 2 years, 3 months overdue though.
Dr Lipkin's study design (as do many others I should add) unfortunately has a entry criteria that removes patents with disease that causes fatigue, this means the more sick PWCFS, PWME are excluded! So that's how they came to the incorrect conclusion that all PWCFS have Low Cytokines, it's actually just their samples that they tested. Conversely, other researchers find no difference, or higher levels.
So all in all, this is why you're correct to say, inflammation, although interesting (mine are repeatedly high after 30 years sick), isn't good enough to be a game changer, but a unique 'to us' test, will do just that.
That's what we've always missed. I mean Lupus has inflammation but sausage fingers gets you understood, why need the same, when we go to to a Hospital on stretcher, get a blood draw and someone says, OMG, have you seen his/her level of 'X', how are they still alive?
Then we get respect, and understanding from the medical profession and that's something long overdue.