The itaconate shunt hypothesis

https://www.youtube.com/watch?v=RiVDNhg4l48

 

Anyone able to summarise, please?

 

Here's one summary:

https://twitter.com/user/status/1546885304749006849

 

Basic summary —

It's a hypothesis based around dysfunctional immunometabolism: specifically with the innate immune system.

Because viruses need our cellular energy machinery for their own nefarious purposes, the innate system switches off/down-regulates energy production so they can't have it. It should ramp back up after infection, but doesn't, leaving us with reduced cellular energy production. His model estimates 43%. The TCA/Krebb's cycle remains "short-circuited" via the itraconate shunt, leaving us reliant on amino acids, rather than glucose and fat as the inputs.

He gives an example in the brain (in glia, glutamate and GABA neurons) where neurotransmitters have to be diverted to be used for energy production. This might explain "brain fog" and hypersensitivity.

He plans to continue with interview 2 to discuss why it might stay in the pathological state. I'm assuming could be something akin to the metabolic trap, or a feed-forward loop or simply viral persistence that remains unmanaged.

 

For background on itaconite, see thread: The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities.

 

I wonder what the theorized impaired use of glucose and fat at the mitochondrial level, compensated for by increased use of amino acids, would imply on the macro level. What would we expect to see for the effect of diet on patients? What would happen to the excess glucose and lipids? What about a protein deficiency (this one might be pretty hard to distinguish from ME symptoms in general)?

 

Not sure, but I guess fatty liver could be one effect. Presumably it's not all or nothing, ie not all cells would be chronically in this itaconate-shunted state. Some cells would still make use of glucose and lipids in the normal manner. I think the suggestion was made that more cells might be involved in more severe disease. Might be difficult to tease apart macro effects though as severe/very severe patients may be on enteral support.

This idea recalls previous commentary on FGF21. Perhaps the FGF21 signal described in Are Circulating FGF21 and NT-proBNP promising novel biomarkers in ME/CFS? might be a secondary effect. Ie as a response to down-regulate glucose and lipid availability to cells that no longer "want" them. As we've previously noted, FGF21 biology is complex, with multiple targets and effects: see papers posted under its tag.

ETA another thought: could reduced glucose inputs/requirements be an explanation for reduced 18FDG uptake in certain brain regions on PET/CT (in LC)?

 

I suppose with a typical western diet having much more protein than we strictly need, it's unlikely that a lack of amino acids would be an issue unless a person had a lot of cells in this state.

Non-alcoholic fatty liver is so common and presumably under-diagnosed, so unlikely to show up in patients in any kind of useful way.

The potential FGF21 connection is interesting.

 

A question I proposed here, Glycolytic impairment - what are the practical implications?

 

No, nothing more than the context of partial or total parenteral nutrition that itself can lead to eg fatty liver deposition.

 

EDIT - "on brief reflection I may have reiterated my usual response rather than thinking of your question! Surplus this or that may not be a problem - the problem may be that the system isn't working normally/you persist in a "disease" state. Check out the papers I've referenced and bear in mind that potentially GWAS could provide some independent evidence re Phair/Armstrong/Fuge & Mella's observations."

To be fair there seems to be some previous research pointing to this downstream effect. E.g. in 2014/15 Chris Armstrong published a paper(s see*&**) in which he demonstrated excess glucose (potentially indicating decreased use of glucose for energy production) and reduced levels of certain amino acids (potentially indicating increased use for energy production).
Fluge & Mella in effect built on this in 2016***

I can't really articulate why but I'd like to see the outcome of a large GWAS study (Chris Ponting):

• to see if GWAS independently supported this idea; &
• it seems that this is downstream effect (metabolism), understanding the upstream cause (via GWAS) might actually be the way to understand how to reverse this effect.

Grateful to Jonathan for supporting the idea of funding the GWAS study i.e. at the MRC convened expert group. Also, to Simon and all of those who have worked so hard to get it up and running.


*"4. Armstrong CW, McGregor NR, Sheedy JR, Buttfield I, Butt HL, Gooley PR. NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Clin Chim Acta. 2012;413(19-20):1525–1531. doi: 10.1016/j.cca.2012.06.022. [PubMed] [CrossRef] [Google Scholar]"
**"14. Armstrong CW, McGregor NR, Lewis DP, Butt HL, Gooley PR. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics. 2015;11(6):1626–1639. doi: 10.1007/s11306-015-0816-5. [CrossRef] [Google Scholar]"

***https://pubmed.ncbi.nlm.nih.gov/28018972/

 

LarsSG is asking what additional problems would be seen from the surplus, as I understand it, not whether the surplus is influential in ME, so I think you have missed the point completely.

 

Not sure it is e.g. I think Jonathan* has pointed out that the role of complement in Lupus became obvious from GWAS - following the same logic, a GWAS study should/may find indicators pointing to people with ME/CFS being stuck in a "lower energy mode" associated with post infection.

*"I see it as a bit like C1q deficiency, which accounts for a tiny proportion of cases of lupus but provides a hugely powerful piece of evidence for the importance of complement in the genesis of lupus.

It turns out that there are a number of other ways to get C1q to malfunction in lupus, probably mostly not genetic. There might be lots of other ways to get tubulin assemblage to malfunction - which again may not be genetic. But if thee is a genetic weighting to a variant in TPPP that ought to be telling us something very important."
https://www.s4me.info/threads/genet...022-hajdarevic-et-al.25070/page-2#post-411468

 

Yip I certainly haven't directly answered his question but if he checks out the paper(s) I've referred him to the I think he'll find what becomes of the various things being utilised /not utilised. Think Chris Armstrong looked at blood plasma and urine etc, using NMR, finding high glucose in blood and potentially it being excreted in urine. Amino acids have to be modified (get rid of the amino group) before being excreted and there are clues in the urine [something normally associated with catabolism/starvation &/or eating too much chicken]. I think the issue is more is this really happening and if it's stable rather than the normally (post infection) transient then why?