Chris Armstrong's presentation for Solve ME/CFS October 20 2016 (metabolomics)

[ChrisArmstrong]

I suppose in that case an obvious research design presents itself. Take a group of ME/CFS patients and match them according to activity levels (number of daily steps) and body mass index to controls and see whether they differ.

I like it. Simple and effective.

Hello @ChrisArmstrong,

So grateful you are here.

Reading about the starvation. I was adopted from Sri Lanka. And there was definitely starvation happening my first year until I moved to Europe.
ME might be h genetic but this could have started my problems at a young age. In hindsight I always had issues with metabolism.
Lactose, sugars, always gut problems, being overactive as a kid and as an athlete.
And although my onset was viral with Cytomegalie. The issues always started with the gut.

And how does this all relate to Post Exertional Malaise?

Regards,

Grigor

Well the starvation is a model for the metabolite pathways we see, it may be starvation at a cellular level but it may be something else that presents similarly. Certainly gut problems seem to be a common thread, there has been some interesting work from our group on this but also Maureen Hanson's group and Hornig's group is studying this area too.

PEM is something I will be studying more, we have some thoughts on it but they are a little more complex and personally I don't like to get behind something until it's line of reasoning is relatively simple (Occam's razor). However the thoughts are in the realm of pH, purine signalling, oxidative stress and glycolysis.

@ChrisArmstrong

In the as yet unpublished paper on the gut microbiome and metabolites in feces do you look into propionate production. I know that reading the Venket Rao et al paper on a the impact of probiotic (yakult) on anxiety in CFS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664325/ they suggested that one possible reason for the impact they saw may come from the L Casei Shirota crowding out propionate producing bacteria.



(I have not really delved into the propionate research, just glanced at some papers, but it seems like it may have a U shaped response, reducing inflammation in the gut in small doses and increasing inflammation in the brain in large doses.)

I was interested in this study because A I have issues with anxiety (like Hip and quite a few others here) and B the measure they used was the Beck Anxiety Inventory and it has a has a lot of symptoms (dizzy, lightheaded, hands shaking, heart pounding etc) that seem very CFS/ME very POTS http://www.brandeis.edu/roybal/docs/BAI_website_PDF.pdf

Which makes sense to me I have issues with POTS and a large chunk of my anxiety seems to be POTS related. Indeed when my POTS has been really bad panic is the best term.

P.S.
Oh and I should add that since reading the paper a week or so ago I have been wondering if all the fibre I pride myself in eating is actually being turned into injurious byproducts. If this is another intervention as daft as GET. Another case of applying what works for normal people to a body that is clearly no longer aquainted with normal.

Ah yes I too have anxiety issues so I know what you are talking about there. I think fibre is great and definitely stick with it. i actually helped myself a lot with fibre during bad periods of anxiety. The negative byproducts is a theory and it only happens from the breakdown of proteins into SCFA (not fibre).

Another anecdote here too. On a good day I can shift a ton of firewood as long as I take it steadily but if I tried to saw one of the logs and started to get breathless then everything collapses in a heap.

Incidentally I know we're talking primarily about the immune system here but might the Warburg effect also apply more generally to other cell types?

There is some evidence in ME/CFS of a switch to fast twitch Type II (glycolytic) muscle fibres as discussed in threads such as this :

http://forums.phoenixrising.me/inde...res-from-patients-with-cfs.11860/#post-496278

Yes very interesting information and that thread and research is interesting too. I think I've read similar things on here before, it's the quick increase in oxygen-based energy metabolism that effects people negatively. Glycolysis allows you to create energy without oxygen, we think glycolysis is being used in the muscles. This is why like the model of starvation because that too shows an increase in glucose in blood and a decrease in just about everything else, the reason for it is that the body globally uses amino acids and lipids for fuel except for the brain and muscles which rely on glycolysis.

@ChrisArmstrong I produce lactic acid much quicker since ME/CFS; my anaerobic threshold is much lower; is this in conflict with your results of low lactate?

No not at all, we studied people at rest. As in the answer just above the starvation model suggests that muscles are likely to increase a reliance on glycolysis when activated. Our metabolite findings reflect the global body metabolism at rest (mostly organised by the liver).

@ChrisArmstrong If it is true that ME patients are nutritionally depleted by an ongoing low grade sepsis from immune activation. Why do all our regular blood tests not show up this malnutrition (most of the time)? Is this a reflection of how non-useful these tests are in assessing nutritional status?

Because it's at a very low level that can vary though out the day. We can only tease out these significant pathways by looking at large cohorts not relevant to the individual profile. Not yet anyway.

Thanks for your time here, so does this mean an individual metabolite analysis/report might be worthless? Additionally would this suggest metabolites are not useful as potential biomarkers?

It will tell you what is happening in your blood at that one point in time, which would be altered if you ate or if you exercised or if you had an infection or if it was late in the day or if you were sleepy. So on its own I would take it with a grain of salt and personally I think it is useless. However, well organised longitudinal metabolite profiles I think will be very useful for the individual. We are running a project on this and I think Ron Davis is too.

So far I see no potential biomarkers from metabolites but that's because no one has tested whether you can differentiate someone with ME/CFS from other illnesses by using metabolites. Someone has to show me this first.

Excellent job by Chris Armstrong yesterday at the SMCI webinar... these are very sense concepts and the work is very promising and important. Keep pushing forward,Chris, and hello everybody.
Z

Thank you very much for your support Zaher and the brilliant work you do at Solve ME/CFS.

 

[ChrisArmstrong]

@ChrisArmstrong
It is just so brilliant that you are doing longitudinal studies especially in this area, it is something many patients feel is needed. The use of models of sepsis and starvation are also extremely interesting.

So much information is coming at the moment and it is hard to keep up. Regarding Jo Cambridge's talk and metabolomics findings along with many things your talking about. It brings to mind my own patient experience with respect to longitudinal work as well as the plasma cytokine studies by Lipkin and Hornig.

It seems that we need to pin down what is happening but also when within the immune system and omics to figure out initiating factors and what may be perpetuating apart from also helping to figure out the PEM mechanism. At the moment we don't know what is cause or effect so this latest information is exciting. IM beginning to think we are getting somewhere lately with possible connections across research areas.

Lipkin and Hornig's cytokine paper suggests immune exhaustion after the first 3 years or so. Personally I don't know if it is just correlation but in the first few years I was really bad, of course exhausted etc but my body felt like it was going crazy wired/exhausted and at about 2.5 years and I remember it distinctly - something started changing. The underlying wired was still there and still is but it felt like the ability my body had to keep firing at that level wore down and subsequently I started coping better or managing better with the symptoms. However, over time and I mean over years my physical strength and mental stamina still keeps dropping.

The initial trigger or whatever process with the wired still feels like it's there and sometimes I wonder if treating the downstream affects may just reverse me back to the initial major intense stage - rather than deal with initial kicker. I think in some ways that's not the way I should think about it though because really we don't know what is involved yet and what is coming first, or what is even causing that sense of underlying wired or amped up thing. I do wonder about others experiences and if they have kicked themselves back into what I call those nasty early stages even though I know we experience things differently. We would probably learn a lot with trying to get some of these levels back to normal so I'm finding this re feeding syndrome and talk about it interesting as well.

So much can be gained from longitudinal studies!

Yes I know how excited you are regarding the longitudinal monitoring work. I think it will take some time too perfect it but it will probably the most worthwhile studies to the individuals with ME/CFS in developing treatments. Yes the models are good to use for the biochemistry, I just hope people understand the use of a model as opposed too suggesting that ME/CFS is one and the same. Interestingly the treatment for both requires constant monitoring of metabolites and mineral levels. The parallels could run deeper.

Yes it's truly exciting era of research, I think we are turning a corner. So many strong research groups hunting for answers, it all has a lot to do with the introduction of well organised funding groups I believe.

Yes it is interesting to read about starvation and refeeding. Here are two documents that provide a nice summary:

https://www.ncbi.nlm.nih.gov/books/NBK22414/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440847/

 

[acer2000]

Are we sure that oxygen is being delivered effectively from the blood to cells? The strange thing about ME/CFS is that sp02 looks normal, but V02 is not. So it would seem to suggest that oxygen is getting from the Lungs into the blood but not from the blood into the tissues. Or if it is its not being burned at a normal rate.

 

[voner]

@ChrisArmstrong,

it's such a pleasure and what a learning experience to have you participate in this forum.

the Naviaux metabolic study states:

Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84–100%] in males using eight metabolites and 96% (95% CI, 86–100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environ-mental stress known as dauer.

to me, this seems to be contrary to what you are saying. they seem to be indicating that he metabolic analysis of a single blood draw can identify patients with ME/CFS.

Also, do you know of any metabolic studies being planned to be measured while a patient is in postexertional malaise (post exercise)?

 

[Kati]

Just a comment, @ChrisArmstrong as you were speaking yesterday about AST. According to Hillary Johnson's Osler's Web, (journalist with ME, because who has done epidemiological studies on us?) 50% of the Lake Tahoe Cohort had gallbladder issues and needed it removed.

In my case i had liver issues at my disease onset with EBV infection. It can happen. But an ultrasound revealed sludge in the GB no stones. And a month later I had another attack. 2 months later i got admitted to the hospital with a very diseased gallbladder. 5 months after onset. Surgeon said it wasn't related. There is no family history of gallbladder disease in my family.

All that to say, the 50% number may be significant and could possibly be explained by metabolomics. Since that time, I have developed GERD and am moving on up with the GERD meds. It's not normal.

We need good epidemiology. Heck, we need everything.

 

[ChrisArmstrong]

Are we sure that oxygen is being delivered effectively from the blood to cells? The strange thing about ME/CFS is that sp02 looks normal, but V02 is not. So it would seem to suggest that oxygen is getting from the Lungs into the blood but not from the blood into the tissues. Or if it is its not being burned at a normal rate.

Well oxygen diffuses across membranes, nothing can stop it. Only thing that slows it down are protein density in the membrane but that's only a slight slow down. VO2 just suggests it's not being used, that implies that electron transport chain isn't work which is what the metabolites and some proteome research suggests too.

@ChrisArmstrong,

it's such a pleasure and what a learning experience to have you participate in this forum.

the Naviaux metabolic study states:



to me, this seems to be contrary to what you are saying. they seem to be indicating that he metabolic analysis of a single blood draw can identify patients with ME/CFS.

Also, do you know of any metabolic studies being planned to be measured while a patient is in postexertional malaise (post exercise)?

Well we never published it but 100% of ME/CFS could be identified from controls in our blood study using the same analysis. Telling you they are different from healthy is one thing, but for it to be a diagnostic it has to tell you that it's different from any other illness too. That hasn't been tested yet.

Just a comment, @ChrisArmstrong as you were speaking yesterday about AST. According to Hillary Johnson's Osler's Web, (journalist with ME, because who has done epidemiological studies on us?) 50% of the Lake Tahoe Cohort had gallbladder issues and needed it removed.

In my case i had liver issues at my disease onset with EBV infection. It can happen. But an ultrasound revealed sludge in the GB no stones. And a month later I had another attack. 2 months later i got admitted to the hospital with a very diseased gallbladder. 5 months after onset. Surgeon said it wasn't related. There is no family history of gallbladder disease in my family.

All that to say, the 50% number may be significant and could possibly be explained by metabolomics. Since that time, I have developed GERD and am moving on up with the GERD meds. It's not normal.

We need good epidemiology. Heck, we need everything.

Well it possibly could have. AST is measured in blood often as a marker for liver and gall bladder duct disruption; however, that is a different test to the amount of AST measured in the mitochondria of a cell.

 

[nandixon]

@ChrisArmstrong Thank you for your work!

Speaking of sepsis, early last year Dr.Montoya (Stanford) said that:

"We analysed messenger RNA gene expression data from the cohorts of 200 [ME/CFS] patients and 400 controls. We compared the data to other diseases. The closest resemblance was to Systemic Inflammatory Response Syndrome [SIRS]; the correlation was 100%..."

(Sepsis is SIRS caused by an infection.)

I'm not sure if it's been published yet. Are you familiar with that gene expression study?

 

[ChrisArmstrong]

@ChrisArmstrong Thank you for your work!

Speaking of sepsis, early last year Dr.Montoya (Stanford) said that:


(Sepsis is SIRS caused by an infection.)

I'm not sure if it's been published yet. Are you familiar with that gene expression study?

Really? No I am not, which is quite exciting!

 

[nandixon]

@ChrisArmstrong Yes, I can't remember whether it was Montoya's group or another (e.g., Ron Davis) there at Stanford who actually did that study.

Edited to add: If it was Ron Davis, perhaps @Rose49 may know something about that study.

 

[Neunistiva]

It will tell you what is happening in your blood at that one point in time, which would be altered if you ate or if you exercised or if you had an infection or if it was late in the day or if you were sleepy. So on its own I would take it with a grain of salt and personally I think it is useless.

.

Well we never published it but 100% of ME/CFS could be identified from controls in our blood study using the same analysis. Telling you they are different from healthy is one thing, but for it to be a diagnostic it has to tell you that it's different from any other illness too. That hasn't been tested yet.

Does that mean that metabolic test, while yet unable to prove we have ME/CFS, would be able to prove that we have some physical illness?

That would be far from useless for people with ME/CFS as one of the biggest issues we face is convincing our surroundings we are really sick, getting our Universities to offer us extensions, getting social services to assign help, getting doctors to monitor our condition etc.

 

[Kati]

Well it possibly could have. AST is measured in blood often as a marker for liver and gall bladder duct disruption; however, that is a different test to the amount of AST measured in the mitochondria of a cell.

Trying to retrace when and where you mentioned it and can't find it. So frustrating to work with a messed up brain. i want my money back

 

[aimossy]

@nandixon it was definitely Montoya who reported that your right. I was thinking about that too. Not sure who he was working on that with and no publishing on it yet as far as I've seen.

@ChrisArmstrong thanks so much for the replies! I am very excited about longitudinal studies and so grateful you have grabbed it by the horns so to speak. Plus any focus on PEM is brilliant in my view to catch things. Do you have any idea what the metabolic chamber will be able to analyse for the NIH intramural study. I thought gas exchange but wondered if they will be looking at other things with respect to this too. I'm a bit fascinated with what it might see as well.

I'll be a bit cheeky and tag @znahle in this too.

 

[AndyPR]

transcript

I've obviously created a rod for my own back I'll add it to my to do list, it'll be a couple of days before I can start it.

 

[BurnA]

Well we never published it but 100% of ME/CFS could be identified from controls in our blood study using the same analysis. Telling you they are different from healthy is one thing, but for it to be a diagnostic it has to tell you that it's different from any other illness too. That hasn't been tested yet.

This seems like it is very important, can I ask why you didn't publish it ?

 

[Hutan]

Speaking of sepsis, early last year Dr.Montoya (Stanford) said that:

"We analysed messenger RNA gene expression data from the cohorts of 200 [ME/CFS] patients and 400 controls. We compared the data to other diseases. The closest resemblance was to Systemic Inflammatory Response Syndrome [SIRS]; the correlation was 100%..."

(Sepsis is SIRS caused by an infection.)

Further on sepsis, there was this paper on Shock Index (heart rate divided by systolic blood pressure).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628475/
Shock Index and Early Recognition of Sepsis in the Emergency Department: Pilot Study

A Shock Index of more than 1.0 was the most significant predictor of hyperlactatemia and 28 day mortality of a range of measures applied to a group of 2524 patients presenting at an ER department, screened for severe sepsis and admitted. (14% of the patients died within 28 days).

Experimental and clinical studies have shown that Shock Index is linearly inversely related to physiologic parameters, such as cardiac index, stroke volume, left ventricular stroke work, and mean arterial pressure.

The shock state causes cellular hypoxia, leading to anaerobic metabolism and increased lactate production, as well as decreased clearance, even before vital signs are compromised.

My shock index when standing in the morning is over 1.0 about half of the time and is always more than the 0.5 to 0.7 range reported for healthy people. My orthostatic intolerance, PEM symptoms and shock index are all positively correlated.

FWIW.

Thanks very much Chris for spending time on PR and researching this disease. Feel free to have a day off tomorrow!

 

[Sasha]

Watched part of the video now and impressed that you were presenting live at 3 am Oz time because of the US timezone difference, @ChrisArmstrong! You're a hero!

 

[Forbin]

From what I can tell, it was research led by Mark M. Davis at Stanford, as well as the research of Mady Hornig and Ian Lipkin at the CII, that revealed a similarity to SIRS.

In a CDC outreach conference call on February 23, 2015, Dr. Montoya said:

"Our group at Stanford is also in the process of examining messenger RNA gene expression data from our cohort of 200 patients [and] 400 healthy controls. In one of the analyses, we compared the gene expression data from patients with ME/CFS with other diseases for which data had been published to see what was the disease process that had the closest resemblance to ME/CFS.

"The disease process that most resembles ME/CFS was Systemic Inflammatory Response Syndrome, also known as SIRS. This correlation had a staggering 100% resemblance.

"From the Lipkin/Hornig data, and our data, the picture that clearly emerges is that ME/CFS is indeed an inflammatory disease."

Conference Call recording here: [quote at 37:00]
http://www.rme.nu/sites/rme.nu/files/Updates_from_CDC_2015-02-23.mp3

About three months later, Stanford published a letter which said, in part...

In a separate cytokine-related study carried out in partnership with the Human Immune Monitoring Center, we found that several cytokines, chemokines, and cell factors clearly correlated with the severity of ME/CFS. This data contradicts claims that ME/CFS is not an inflammatory disease. Not only does inflammation exist in these patients, but also our study opened the door for using anti-inflammatory drugs or biologics to treat ME/CFS. Further analysis of mRNA gene expression, in a study led by Dr. Lipkin and Dr. Mady Hornig, showed that the disease with the closest resemblance to ME/CFS is Systemic Inflammatory Response Syndrome (SIRS). These two studies provide objective evidence that ME/CFS is indeed an inflammatory disease.

https://med.stanford.edu/content/dam/sm/chronicfatigue/documents/MECFSNewsletter_Spring_2015.pdf

[I'm not sure if the Lipkin/Hornig data referred to was that which was published in their 2015 plasma and CSF cytokine papers. I'm also not sure if a paper was ever published that made a case for a resemblance between ME/CFS and SIRS.]

 

[FMMM1]

Chris, thank you very much, good to see some objective analytical work.

You used NMR, can it be used as a diagnostic test or is it really a research tool?

Even if NMR cannot be used as a diagnostic test it still appears really useful since it appears to provide an independent way of testing the Mass Spectrometry data (from Naviaux, folks in Japan and Pisa) and vice versa.

 

[ErdemX]

Hello @ChrisArmstrong

It is so wonderful and encouraging to have you here with us. Your efforts mean a lot. I watched your presentation and read your comments here. I have some questions..

1- My illness started in one day, I had a regular flu and just after that in a single day, my body went into an energy crisis. At the end of the day I was experiencing such an incredible fatigue as if all my cells were in an energy crisis which gets worse despite resting. That shows that at least for some of us, the full course of the disease can happen in a very short time, like an attack. If the body doesn't need a long time to go into that state, theoretically, shouldn't it be able to go back to its normal state (with the right intervention) within a similar short time?

2- Based on your findings about the illness, what kind of an (positive or negative) impact would you expect form Hyperbaric Oxygen Therapy to the metabolomic state of a person with CFS?

Thank you..

 

[ChrisArmstrong]

.
Does that mean that metabolic test, while yet unable to prove we have ME/CFS, would be able to prove that we have some physical illness?

That would be far from useless for people with ME/CFS as one of the biggest issues we face is convincing our surroundings we are really sick, getting our Universities to offer us extensions, getting social services to assign help, getting doctors to monitor our condition etc.

This seems like it is very important, can I ask why you didn't publish it ?

Well it's already proven to be a physical illness from research over the past decades, unfortunately people don't always listen to proof, it takes campaigning and marketing I think. I knew it were a physical illness before I started 6 years ago. In our 2015 paper alone we saw 20% of the metabolites to be significantly altered compared to controls. Using unsupervised multivariate analytical techniques the patients were separated from controls. That is, without telling the algorithm the people were different it could tell that they were based on the metabolites alone. This was all published and more telling in our opinion. In the figure below, the top unsupervised plot is in blood and the bottom unsupervised plot is in urine, both showed decent separation, only minor intermingling. We figured our paper did show it was clearly a physical disorder but it didn't seem to get much exposure and I think the marketing of research and big names has really helped recently.

We didn't publish the work because usually to report such findings you want to do what the recent group from Osaka did (http://www.nature.com/articles/srep34990), training and validation sets with larger cohorts. The reason is because if you tell an algorithm to find differences between two cohorts then it will find those differences even though they may only be specific to that cohort. If you take a new cohort (different ME/CFS and different controls) then those markers may not stand because the differences it found may only be due to that cohort. Even though the Osaka group had hundreds in the study, with training and validation sets they still conclude that they need a larger study.

I'm not saying it's useless, it would be very valuable if it was obtained. At this point I wouldn't have felt comfortable releasing that as a metabolite test. I mean I consider you all to have a disorder, I'd hate for some to be told they didn't have a physical illness (when they clearly do) based off a test that wasn't properly researched.

@nandixon it was definitely Montoya who reported that your right. I was thinking about that too. Not sure who he was working on that with and no publishing on it yet as far as I've seen.

@ChrisArmstrong thanks so much for the replies! I am very excited about longitudinal studies and so grateful you have grabbed it by the horns so to speak. Plus any focus on PEM is brilliant in my view to catch things. Do you have any idea what the metabolic chamber will be able to analyse for the NIH intramural study. I thought gas exchange but wondered if they will be looking at other things with respect to this too. I'm a bit fascinated with what it might see as well.

I'll be a bit cheeky and tag @znahle in this too.

Haven't seen it before but just looked and it would be for measuring O2 and CO2. CO2 is made from the front half of TCA cycle in mitochondria, I suspect they will be looking at exercise/diet/sleep to see how these levels are altered in ME/CFS patients. Great tool for assessing aerobic respiration. I also hope they test accumulative exercise stress tsts, some suggestion that the dynamics of a stress spike followed by a second stress spike during recovery can be detrimental.

My shock index when standing in the morning is over 1.0 about half of the time and is always more than the 0.5 to 0.7 range reported for healthy people. My orthostatic intolerance, PEM symptoms and shock index are all positively correlated.

Thanks very much Chris for spending time on PR and researching this disease. Feel free to have a day off tomorrow!

Yes these symptoms all seem to be somewhat related.
Haha yes I had a couple days off.

From what I can tell, it was research led by Mark M. Davis at Stanford, as well as the research of Mady Hornig and Ian Lipkin at the CII, that revealed a similarity to SIRS.

In a CDC outreach conference call on February 23, 2015, Dr. Montoya said:

About three months later, Stanford published a letter which said, in part...

[I'm not sure if the Lipkin/Hornig data referred to was that which was published in their 2015 plasma and CSF cytokine papers. I'm also not sure if a paper was ever published that made a case for a resemblance between ME/CFS and SIRS.]

Thank you for the information.

Chris, thank you very much, good to see some objective analytical work.

You used NMR, can it be used as a diagnostic test or is it really a research tool?

Even if NMR cannot be used as a diagnostic test it still appears really useful since it appears to provide an independent way of testing the Mass Spectrometry data (from Naviaux, folks in Japan and Pisa) and vice versa.

Yes it can be. It's actually the gold standard instrument for metabolite quantitation. Extremely reliable so very useful as a metabolite test. I imagine they would use it to develop a specific test or at least validate it.