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

A.B.

Senior Member
Messages
3,780
Hmmm interesting question. I haven't seen any studies that link inactivity to hypometabolism. I can imagine muscle mass would deplete with inactivity but I can't imagine how a inactivity would cause hypometabolism. The plausibility of the explanation will be weighted based on the evidence, I can't comment because I'm not aware of the evidence for inactivity and hypometabolism.

Interesting response. Deconditioning is a crucial component of behavioural explanations for this illness. If deconditioning were shown to not result in these metabolic changes then it should clear away a lot of skepticism. Globally, tens of millions of US dollars are spent every year on research and interventions that assume CFS is a behavioural disorder, where symptoms are mostly due to deconditioning.
 
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2,087
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.
It's so obvious you'd have thought it would be the first study anyone proposing the deconditioning model would have done.

But then they might not have a model anymore and they'd have to find something else to study.
 

Grigor

Senior Member
Messages
462
Location
Amsterdam
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
 
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Sidereal

Senior Member
Messages
4,856
It's so obvious you'd have thought it would be the first study anyone proposing the deconditioning model would have done.

But then they might not have a model anymore and they'd have to find something else to study.

To be fair, this sort of mass spectrometry work did not exist / was not possible when the deconditioning model of ME/CFS was proposed decades ago. The reason we're seeing a flurry of this work now is because the technology is making it financially viable to measure all these metabolites simultaneously.
 

Richard7

Senior Member
Messages
772
Location
Australia
@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.

Propionic acid is a short chain fatty acid produced primarily by Clostridium and Bacteroides spp.; emerging research suggests that this acid may be involved in anxiety. Elevated production of propionic acid in the gut has been shown to increase behaviors associated with anxiety and aggression in animals [23]. It has also been shown recently that when propionic acid gains access to the brain it can impair the social behavior of animals. Changes to the animal behavior include decreased playful behavior, increasing social isolation, and an increase in repetitive behaviors that may indicate anxiety [24]. While human data is lacking, a study in animals did show that the LcS as used in our study can lower cecal propionate levels [25].

(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.
 
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Ben H

OMF Volunteer Correspondent
Messages
1,131
Location
U.K.
No problem Ben. I think it's good to discuss thoughts on here and I think the questions that are asked and anecdotal experiences are really helpful, especially for hypotheses.

Yeah the metabolite studies in the blood seem to be pointing to the same issues.

Your experiences are interesting. Do you still do weight lifting? I only ask because I think it's interesting that some people I have heard from say they can take anaerobic exercise (like small sets of heavy weights) but nothing aerobic without feeling awful after.

I wish more researchers had that approach @ChrisArmstrong.

Unfortunately I am 98% bedbound now so nope, no weightlifting. In the begging of illness I tried strictly anaerobic, but I had no stamina or strength. I also tried aerobic,simply walking but that also was exhausting.

The very first clue that something was very wrong was after the dieting and gastro issues I talked about where one day I went to the gym as per usual, did one set of repetitions and had to stop because I had no strength whatsoever. Took a month off (massive for me as I trained 6 days a week) and just did walking but that was very difficult. And it went progressively downhill from there.

The preceding events to this was a gastro issue of some sort (sterreorhea etc) which partially resolved itself, and the fact that I had been in and out of ketosis for a year (to get my bodyfat down to 6-7%), though I felt fine in ketosis once adaptation period had occurred, and also felt fine with the gastro issue, though it was unusual.

Then like I say-2 months later this episode at the gym happened and I never got better. I also got 'proper' flu 2 months after that, but something was VERY wrong from that gym session. I have had gastro issues ever since (low hcl, bile it would seem, IBS-D to a degree). Never any issues before.

Hence why I am interested in the starvation ties as that is what I had been doing (below my basal metabolic rate/caloric restriction with periodic refeeds) for a whole year.

Any more details feel free to PM me.

And again, thankyou so much for being on this board and doing this research!


B
 
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Sasha

Fine, thank you
Messages
17,863
Location
UK
Your experiences are interesting. Do you still do weight lifting? I only ask because I think it's interesting that some people I have heard from say they can take anaerobic exercise (like small sets of heavy weights) but nothing aerobic without feeling awful after.

I've also seen a lot of anecdotes like that and recently amazed my physio by being able to build up to lifting my bodyweight on my arms with just two or three reps a day, when I can't build up higher reps on lower weights.
 

aimossy

Senior Member
Messages
1,106
@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!
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
I only ask because I think it's interesting that some people I have heard from say they can take anaerobic exercise (like small sets of heavy weights) but nothing aerobic without feeling awful after.

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
 
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67
@ChrisArmstrong

Sarah Myhill has argued that a problem with pwcfs/me is that they are taking ATP to ADP and then onto AMP which can then be lost in urine, and she has suggested using ribose supplementation to increase ATP production.

From what you were saying about hypoxanthine and the creation of ROS would both the conversion of ADP to AMP and the conversion of ribose to AMP increase the concentration of AMP and therefore the amount of traffic down hypoxanthine that pathway and the total concentration of ROS in the cell.

Is Ribose likely to give some energy in the short term but make things worse overall?

Also, early on you mentioned that your research was on women not men because the chemistry is so different, is it so different that these patterns may only apply to women?

What you describe is certainly possible. Usually though AMP is salvaged back to ATP and adenine back to AMP by a molecule called PRPP. PRPP is made from ribose in the pentose phosphate pathway. This is the molecule you require to salvage energy and stop nucleotides forming ROS.

In our study the indication was that the increased oxygen in the ME/CFS system had converted hypoxanthine to allantoin at a faster rate. It didn't suggest that more hypoxanthine was produced to begin with.

The same underlying pattern of metabolism is the same between men and women. We separate them so that we can highlight the underlying pattern effectively.

This is an important point that needs to be understood, individual metabolite profiles aren't going to match what these metabolite studies are showing. You need a large population to tease out this information in comparison to a control. The reason for this is that the individual metabolite profile will vary from person to person such that it might even show the opposite to what has been shown in these studies. By looking at a whole group you are looking at the average across it, and the average across the group is what has changed in ME/CFS. If it was defined such that everyone could observe it in their individual metabolite profile then we'd already have a clinical marker, it just doesn't work like that unfortunately.
 

Kati

Patient in training
Messages
5,497
This is an important point that needs to be understood, individual metabolite profiles aren't going to match what these metabolite studies are showing. You need a large population to tease out this information in comparison to a control. The reason for this is that the individual metabolite profile will vary from person to person such that it might even show the opposite to what has been shown in these studies. By looking at a whole group you are looking at the average across it, and the average across the group is what has changed in ME/CFS. If it was defined such that everyone could observe it in their individual metabolite profile then we'd already have a clinical marker, it just doesn't work like that unfortunately.

Very important point indeed. As patients, the best we can do is support research, request our governments to fund research and participate, hopefully, in sound research, when opportunity arises.
 
Messages
2,087
This is an important point that needs to be understood, individual metabolite profiles aren't going to match what these metabolite studies are showing. You need a large population to tease out this information in comparison to a control. The reason for this is that the individual metabolite profile will vary from person to person such that it might even show the opposite to what has been shown in these studies.

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?
 
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67
Yay! I've learned to use multi-quote.

This was quite useful because I've read a lot on this forum about high lactate, when very low lactate in urine is my son's experience. Looking at his OATS test, his pyruvate was also low, and this goes some way towards explaining why.

Yes well he sounds like he fits with the group we studied. We took metabolites at rest in our study.

We look at blood and urine and generally found decrease of lactate and pyruvate. There are studies that show increased lactate and they have been in the cerebrospinal fluid and muscle. This is the reason we found the starvation model so attractive because glucose is suggested to be increased in the blood for the purpose of fueling muscle and brain, which would suggest that they would perhaps have increased lactate.

Thank you for being here and answering questions, @ChrisArmstrong - it's very kind of you!

What I've always found interesting about the "stuckness" of ME/CFS and considerations about what it might take to get patients out of it is that people do have substantial spontaneous remissions (I went from being bedbound for years to - over the course of a couple of years - being able to work full-time for years, and now have been relapsed and housebound for years, for example - and I don't know what, if anything, I did to make my remission happen).

Do you think that there's some underlying button to push that can just make everything come right, without the need for careful refeeding programmes, etc.? Any idea what that button would look like (tons of extra rest, maybe?)?

Yeah I don't expect there to be a button but it all depends what is occurring in the individual. We will be engaging in genetic profiling during the long-term monitoring to determine if individuals have a genetic issue that is hindering their recovery. We all have genetic variations that can affect metabolism, it's the extent to which we have them that's important. This is the idea of predisposing factors, people with ME/CFS may have a reduced ability to increase their metabolism, which was never a problem before it was reduced.

So the trick might be like an expansion of Myhill's mineral mix
http://drmyhill.co.uk/wiki/Nutritio..._taking_all_the_time_even_if_nothing_is_wrong

which is a mixture of minerals and b12 dissolved in a litre of water and sipped over the day.

just expanded to all minerals and vitamins and cofactors

I can't say there is a trick. Metabolites, cofactors, minerals and vitamins are complicated because of the way they are transported in the body. The ratios to each other are important for entry into the blood and cells. They also have to get through the bacterial mass in your gut. I'm assuming it will take long-term monitoring to bring the metabolism up together. That being said, I think eating as healthy as possible and taking mineral and vitamin mixes is a good idea, it certainly could help. I assume people here probably know their body quite well and experiment from time to time with vitamins, minerals and diets?


Chris, before all else, let me thank for your presence on these forums and responding to our questions. It means the world!

You're quite right - I ran fast of established facts in my previous post. Basically I'm asking myself whether metabolite availability of some kind is arbitrating the difference between responders and non-responders to Ritux.

The underlying assumption is I guess twofold. First that Rituximab removes the presumed 'something in the blood' - autoantibodies, maybe - that somehow induce altered metabolic patterns in ME/CFS. And second - a big one! - that once the lid is off, the body is capable of coming out of this 'altered state' by itself in at least a proportion of patients treated with Rituximab, which coincides with improved symptoms.

Following on from these assumptions, I wonder whether we could effectively increase the Ritux response rate by simultaneously correcting the metabolic deficiencies associated with a hypometabolic state through targeted supplementation. This might aid the snap out of hypometabolism - presuming that's what's happening in Ritux responders, of course. I would love to see a metabolomic study based on the Norwegian cohort...

It's difficult to know but the study of metabolites in conjunction with Rituximab would certainly be very beneficial.
 
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Thank you for hosting these webinar, @znahle :thumbsup:[/QUOTE

U bet!
And I select people with talent who deserve exposure like Chris with a balanced portfolio (young, established, agencies, clinical and basic science)

And thank you guys here for promoting it too. Not sure if my buddy AndyPR is doing a transcript this time too, the great AndyPR who does it for no return or benefit just to spread knowledge and disseminate information...
Z
 
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67
Hi @ChrisArmstrong thanks so much for a great webinar and for being so helpful with questions.

I will just highlight something @Mark noted about a talk Jo Cambridge gave at the RME Sweden conference just a day or so ago on the other thread. Jo's talk was really good and included some new information regarding B cell behaviour. I don't know if you may have time to check out her talk.

Geraldine (Jo) Cambridge's lecture Rituximab for ME/CFS: Revealing immunological cues to underlying disease mechanisms starts at 02.53 https://play.vll.se/category/5/video/214/rme-konferens-19-october-2016-2

Mark said:

"Swedish conference thread, Jo Cambridge reports they are now finding elevated glycolysis in naive B cells of ME patients, working this up now:
http://forums.phoenixrising.me/inde...ilable-for-streaming.47449/page-3#post-776570
Could this hook up with the finding of non-mitochondrial excess ATP?"

She also noted other things about B cells that were interesting I can't pull out of my memory. Ill try and find them in her talk but someone may recall them better than me right now.

@ChrisArmstrong EDIT I just took another look at Jo's talk she said (in summary):

Changes in B cells in both naïve and memory B cell subsets compared to healthy controls.

Mitochondrial function.
  • energy production/supply of key metabolites
  • ? mitochondria not able to 'recover' from stress in ME/CFS?
Found differences in the way naïve B cells use energy compared to memory B cells and differences in resting B cells. They are writing all this up right now.

Somehow I missed the bit that Mark noted which is also really interesting. I wonder if you have thoughts about how all this might fit together.

I hve yet to watch it, I will have a look and get back to you. Yes it would fit with the other group that found increased glycolysis in the cell. The blood metabolites in the blood indicate an inhibited glycolysis but that doesn't necessarily mean that's what is happening, we mention this in our newest paper but what appears like inhibited glycolysis could actually equally be increased gluconeogenesis. I haven't gone into it and merely presented our findings from the 2015 paper, but it will be explained in the gut paper because the anomalies we found are known to enhance gluconeogenesis and it changed the perspective for us (on the increase glucose, decreased lactate/pyruvate phenomena).

I am watching these cell metabolism finding with keen interest. One thing that also must be considered is the technique that was used to monitor them.

The ME/CFS blood average tends to show increased glucose, decreased lactate, decreased TCA cycle metabolites, decreased lipids, decreased amino acids. It also is likely to have a myriad of decreased cofactors and vitamins. The immune cells are functioning in that environment in ME/CFS. If these experiments (and I think they do) require the researchers to remove the cells and put them into a metabolite pool then it is changing the environment they exist in and may not be representing how that cell actually functions in ME/CFS patients. Taking that into consideration will give important insight from their findings though. For instance, the cell may have upregulated proteins to conduct glycolysis because it was inhibited in the ME/CFS blood condition, once it's in a standard metabolite mix for growing cells it may have all the nutrients it needs but with its already increased enzymes and proteins it could cause a much larger flux through glycolyis than would be exhibited in a control immune cell.