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

Kati

Patient in training
Messages
5,497
Earlier today Solve MECFS aired a pre-recording of @ChrisArmstrong 's presentation on his work with metabolomics. The video presentation will be available on You Tube soon, but I am posting the slides here, screen shots, with Chris's permission.

There are 23 slides, I will post them by batches of 5 in a different message. Here is 1-5




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GreyOwl

Dx: strong belief system, avoidance, hypervigilant
Messages
266
Hi @ChrisArmstrong thank you so much for making yourself available to us after such an early start this morning.

I have two questions for you:

I was interested in the slide you presented (below):
upload_2016-10-21_13-1-1.png


and if I remember correctly you explained that you thought there might be an enzyme which triggered an alternate metabolic path in the TCA cycle which resulted in increased AST. I was wondering if you could write a little about that please.

Also, I am interested in your thoughts on an auto-immune process which triggers this alternate cycle. I wonder whether you think an immune response to a metabolite or an enzyme itself could trigger this?
 
Messages
67
@GreyOwl

Yes, so aspartate transanimase is an enzyme found in the cytosol and the mitochondria of a cell. It taks the amino group from glutamate and gives it to oxaloacetate, this produces a-ketoglutarate and aspartate. This effectively maintains the TCA cycle by using amino acids without the use of acetyl-coA (which comes from glycolysis and lipolysis). In doing so you make half the amount of NADH and one third of the amount of CO2.

The lack of CO2 may explain patients with ME/CFS that feel much worse after eating, because the cells in your stomach that produce acid actually do so by combining the CO2 made from their mitochondria with H2O to produce H+ (the acid) and HCO3 (bicarbonate - alkaline). They pump the acid into your stomach and release the bicarbonate in your blood. Now if they only produce one-third of CO2 from each TCA cycle then it may be exhaustive.

The reason this enzyme may be upregulated is for the very fact that it reduces NADH production. The electron transport chain (ETC) is the source of reactive oxygen species (ROS) or oxidative stress and as this rises the ETC itself is down regulated in response. If the ETC proteins are down regulated then the mitochondria can't make ATP from H+ fast enough and there may be an inbuilt mechanism to purposefully stall the overproduction of NADH and H+ in mitochondria so that it doesn't acidify itself. More research needs to be done in this area though.

Sepsis and starvation both lead to this metabolic pathway through different avenues but the suggestion is that the chronic immune activation (whatever the cause) is exhausting the body of the body of cofactors, vitamins and minerals to serve immune cell proliferation. The immune system uses ROS to fight infection and the increased ROS may be the trigger.
 

Kati

Patient in training
Messages
5,497
Hi Chris, I have so many questions, here are a few:

There are seemingly 2 kinds of ME patients, those who gain a lot of weight from onset and those who have much trouble maintaining their weight. Does it have to do with metabolic impairment discussed here, glycolysis and the TCA cycle?

Second question is would there be different metabolic pathway problems under the umbrella of ME in which the metabolic profile shows variation?

Thirdly: do you see metabolomics as biomarkers that would be used in the mainstream medicine, and would it be accepted. Would mito clinicians make sense of this?

Lastly: are these results in the realm of nutrition or is it more complicated than popping glutamine supplements?
 

GreyOwl

Dx: strong belief system, avoidance, hypervigilant
Messages
266
The reason this enzyme may be upregulated is for the very fact that it reduces NADH production. The electron transport chain (ETC) is the source of reactive oxygen species (ROS) or oxidative stress and as this rises the ETC itself is down regulated in response. If the ETC proteins are down regulated then the mitochondria can't make ATP from H+ fast enough and there may be an inbuilt mechanism to purposefully stall the overproduction of NADH and H+ in mitochondria so that it doesn't acidify itself. More research needs to be done in this area though.

Sepsis and starvation both lead to this metabolic pathway through different avenues but the suggestion is that the chronic immune activation (whatever the cause) is exhausting the body of the body of cofactors, vitamins and minerals to serve immune cell proliferation. The immune system uses ROS to fight infection and the increased ROS may be the trigger.
Love it.
 

Kati

Patient in training
Messages
5,497
Eeek. Is there not a ppt or pdf of the slides available?
There will be the solve MEcfs youtube video available @hixxy. i posted the slides for convenience, and I kind of crashed because I was sitting at the desktop uploading the files and in general it's too much cognitive work for me (horizontal, at the tablet is better)... let me know if I can help you but you need to give me rest time for my body to settle down.
 
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Kati

Patient in training
Messages
5,497
Thanks @Kati. I think it's great to have the slides in the thread - it's really easy to refer the questions back to the context. Thanks for your effort.

I can understand it can be visually challenging for the cognitively impaired, I am sorry o_O
 

*GG*

senior member
Messages
6,391
Location
Concord, NH
@GreyOwl

Sepsis and starvation both lead to this metabolic pathway through different avenues but the suggestion is that the chronic immune activation (whatever the cause) is exhausting the body of the body of cofactors, vitamins and minerals to serve immune cell proliferation. The immune system uses ROS to fight infection and the increased ROS may be the trigger.

Can you clarify the bolded part? Thanks!

GG
 

J.G

Senior Member
Messages
162
Sepsis and starvation both lead to this metabolic pathway through different avenues but the suggestion is that the chronic immune activation (whatever the cause) is exhausting the body of the body of cofactors, vitamins and minerals to serve immune cell proliferation.

Posted this in the Lawson et al thread, but since the discussion is migrating I'll add it here as well.

In this context, might it make sense for Rituximab responders to supplement heavily during treatment with vitamins, minerals and cofactors (such as those that Naviaux et al. 2016 found depleted) to make sure the picket fence stands firmly by the time B-cells come back online?

A supplementation package shouldn't be difficult to put together - a precedent in KPAX002 already exists (no endorsement given) - and might ultimately arbitrate between relapse or long-term remission. It could even be highly tailored to the variability of metabolite depletion in each individual patient (which if I read Naviaux correctly is quite high).
 
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hixxy

Senior Member
Messages
1,229
Location
Australia
@ChrisArmstrong You mention refeeding syndrome on one of your slides. I recently went through having a PEG placed and being refed after a very long period of severe dietary restriction, malabsorption and resulting malnutrition. The doctor was anticipating that I would get refeeding syndrome but it didn't eventuate. Could the mitochondrial problems in CFS prevent refeeding syndrome from happening?

It seems to make sense as unlike a "healthy" person I wouldn't be able to switch back suddenly to making normal levels of ATP, depleting my phosphate stores (and other nutrients) in the process.
 
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