The itaconate shunt hypothesis

Where is the evidence that we are reliant on amino acids for energy? I wasn't aware that was a solid finding.

Again, we have no good evidence (yet) of any genetic differences in ME/CFS. I'm worried about pursuing hypotheses based on shaky foundations.

Let's get the core science right first: what do we actually know and can replicate?

 

I haven't noticed much benefit from high protein diets and I haven't heard of many others benefiting. It is still an interesting theory though, maybe all those additional amino acids you get from a high protein diet can't get to the brain where they are needed?

 

thanks for the clarification on the genetic stuff.

But my concern is more fundamental than that. Such hypothesis work is inevitably speculative. By building on sand, the whole process looks like a waste of time to me. The hypothesis is based on the idea that we burn more amino acids for energy than is normal. I don't think there is good evidence for this — so why pursue the hypothesis instead of trying to nail down whether or not there is an amino acid issue?

The problem is that biological systems are unbelievably complex. Everything connects to everything else. Many biomolecules have many different functions in different cells. It's so easy to explain symptoms by, frankly, a million different stories. It's what you see in the discussion section of every ME biomedical paper. A new finding, a new explanation. It's not getting us anywhere.

 

No it is shipped

My poor phrasing: I simply meant that the original claim that we rely more on amino acids is not robust and hasn't been independently replicated (and there have been many metabolomics studies).

 

This is exactly what I'm thinking. The evidence for decreased use of glucose and increased use of glutamate is pretty weak:

• Armstrong found less serum glucose in one study and slightly more in the other, altogether a tiny difference relative to what you'd see in normal variability over time in the same person or in the difference between someone who had even very mild diabetes versus a control. The evidence for a difference in serum glucose is pretty much non-existent.
• Armstrong found lower glutamate in patients in one study, but not significantly different glutamine — and still a pretty small difference. In another study, they found quite a bit lower glutamine, but not significantly different glutamate — that one only had 11 patients.
• Fluge and Mella also showed only a small but significant difference for the sum of glutamine and glutamate, though they found some other differences for other amino acids.

So it does seem like the itaconate shunt hypothesis doesn't have much grounding in real results. I also wonder why there is so much theorizing and so little trying to see if there actually is a significant difference in patients. This seems similar to the IDO hypothesis which is based on pretty weak genetic results from, IIRC, about 20 severely ill patients.

That's why I was asking: if this theory is true, what would we expect to be true about the population of ME patients broadly? But perhaps we wouldn't expect to see anything definitive. I'm pretty sure we'd know if ME patients generally had high blood glucose, because that's something that people get tested for quite a bit (except perhaps if A1c doesn't correlate with glucose as usual in ME patients for some reason).

 

Re the discussion of glutamine metabolism, glucose, fats (etc) in prior work: indeed, nothing is proven yet. Good news is that people are doing follow-up studies to validate these theories (including with different methods or with limitations of prior studies in mind). Some of these projects have been specifically mentioned by posters already, one is that I am also working with Chris to look at these metabolic questions in cells.

 

You might want to check out Chris Armstrong's 2016 (SOLVE) webinar*. From memory he discusses potential downstream effect of the switch in metabolism - bistability (ME/CFS disease state being stable).
I wonder if GWAS (Chris Ponting's genetic study) will turn up clues. E.g. if it's the downstream consequences of the shift in metabolism are key then perhaps GWAS will pick that up - enzyme X, which clears protein, is a risk factor; then potentially its the downstream consequences, of the change in metabolism, that are causal.

*

https://www.youtube.com/watch?v=mlhz7GRAqsg

 

@DMissa are you interested in hearing some ideas on how to investigate PEM and ME/CFS?

 

In the video presentation Phair mentioned that according to the hypothesis the brain uses it's own neurotransmitters for energy (since some of them are amino acids). I think that this could explain PEM from mental activities quite well. Namely, when you engage in those activities you use up the available neurotransmitters and there is nothing left for energy production and then you get PEM. My personal case of CFS seems to fit this theory quite well too.

I wonder also if the positive Abilify reports have something to do with this. Even though from what I read dopamine is not an amino acid, maybe it can somehow be used for energy too.

 

I can't get my head around this yet. But one thing bothers me. When we meet viruses and other infections almost always our metabolism goes UP - so we get feverish - isn't that the way it is?

 

I don't know whether it might be universal or selective metabolism up/down. ETA: ie virally-infected cells could down-regulate, uninfected but active cells such as immune cells could up-regulate their metabolism in the expected fashion.

But I like the concept. Viruses have to hijack our cells' energy production. The innate system develops this mechanism to limit resource availability early to the invader - starve it out. Resource-constrained viruses are then subject to clearance via adaptive cytotoxicity, autophagy etc.

Perhaps this could link in to the autophagy / ATG13 finding, where the virus evolves to stop intracellular clearance by breaking the autophagy cycle. A stalemate ensues, with cells stuck in a degraded TCA cycle in some people.

 

On stalemate, I found Neurons versus herpes simplex virus: the innate immune interactions that contribute to a host–pathogen standoff (2015, Rosato and Lieb, Future Virol).

I wonder if there could be a threshold phenomenon (not a new idea). Dr Phair suggested that the model might involve a dose-response relationship: more cells may be in this shunted state in those more severely affected.

What if this happens more commonly than we realise? EBV (which is very common) often causes postviral fatigue for some months, but it might leave, for argument, 3% of relevant cells in this state, in predisposed people. This is subclinical - the teenager recovers and develops into a fit and healthy adult, but perhaps doesn't quite achieve their maximal performance. This goes unnoticed in the vast majority who never push to athletic extremes or their performance is more than adequate.

Most cells will be turned over, some quickly, some slower, some never. Eg endothelial cells live for around 3 years, neurons indefinitely. Perhaps over time the % remaining drops to 1% or less.

Along come other viruses over following years, more cells get stuck, but again there's turnover and the numbers dwindle. There are peaks and troughs but the %age never gets too high. But with the right subsequent virus/immune response, or simply sufficient numbers of relevant infections, eventually the % gets over, say, 4 or 5% and now the patient demonstrates clear clinical symptoms. That might explain moving into symptomatic, but something else needs to explain failure to recover, including from natural cell turnover. Maybe it involves permanent cells like neurons. Maybe if there was never another infection / immune challenge all patients would recover (over a sufficient timescale). Maybe something about PEM and crashing augments the situation (resetting the disease as postulated by Prof Davis).

(Re neurons, I don't think SARS-CoV-2 has been shown to infect neurons themselves, though EBV/herpesviruses do.)

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Anecdata. The LC groups and their non-scientific polling suggest a high proportion of previous significant EBV illness in earlier life. Obviously difficult to demonstrate a difference when there's such a high prevalence in the population. Support groups are also highlighting LC developing in those who previously breezed through their first two or 3 Covid infections.

Always tempting to think about your own situation for reference. I had EBV at 11 years and was fatigued and off school for 3 months or so, with one brief relapse. Fit and healthy as an adult. Over the last 5-8 years I did develop the habit of not tying my shoelaces for about 20 minutes after showering, following my 10 km morning bike ride to work. While resting heart rate came down promptly after the bike, a hot shower now seemed to leave me with a higher HR for 10-15 minutes and standing up too fast after tying my laces would make me dizzy (so I took the lazy approach). BP and all other cardiovascular parameters were fine. I presumed just aging, but was this the first sign of a POTS phenotype that would later become dramatically more?

 

I think to explain PEM and lowered capacity in a PEM state, maybe it makes more sense to imagine cells that are flipped from the normal TCA cycle state to the itaconate shunt state by some aspect of exertion and then take a few days to flip back. There may be a baseline percentage of cells that never flip back (and perhaps this can be increased by repeated PEM cycles, causing long term symptom exacerbation), but it seems like you'd want to have cells flipping in and out of this state fairly rapidly for this to explain PEM.

Alternatively, perhaps PEM is caused by some kind of by-product or signalling from cells that are in the itaconate shunt state when they need to produce significant amounts of energy (or even a lack of something consumed by the cells in that state). But then you'd need some kind of theory as to how these cells aren't causing significant problems until some overall exertion limit has been passed.

No idea if this is biologically plausible though.

 

From memory proteomics research ( Hanson,? ) showed a difference between metabolism of male and females re TCA deficiencies.

Females were more likely to sub protein ( amino acids) for glucose as fuel. Males more likely to sub fats.
Female immune systems may also have different responses ( eg the pregnancy thing and high levels of autoimmune conditions)

I have not watched the video yet , but it may be something that needs factored in when bottoming things out.