ME/CFS – the GABA shunt hypothesis

I received an interesting website from a LongCovid patient that offers us an explanation and solution for the disease for some patients with ME/CFS or LongCovid.

I am excited about a deeper understanding of the Cell Danger Response according to Naviaux, which may be explained by this theory. This Cell Danger Response is the stuck in a “weakness after infection” – with a decoupling of the mitochondria that permanently produce oxidative stress.

Autoantibody ME/CFS patients

I am still skeptical about GPRAAK carriers for the time being, as the basis of the disease is an autoantibody-triggered dysregulation of the vegetative system and the blood circulation and optimizing mitochondrial function probably has only limited or little effect here.

In any case, this thesis – developed by biochemists – gives us further insights into potential disorders of ME/CFS or LongCovid patients – which I perceive as a heterogeneous group of patients, as we see different pathophysiological mechanisms in practice – with different treatment reactions.

Summary of the Itaconate Shunt Hypothesis and its Relevance to ME/CFS

The Itaconate Shunt Hypothesis, developed by Robert Phair, attempts to explain central problems of ME/CFS, including lack of energy production, postexertional malaise (PEM), brain fog, and immunodeficiency. It is based on the following findings:

1. Energy metabolism in ME/CFS:
   • Affected cells use amino acids instead of glucose or fatty acids as an energy source, resulting in nitrogen byproducts such as ammonia.
   • An immune enzyme called CAD can disrupt the normal citric acid cycle (TCA cycle) during infections and replace it with an “itaconate shunt” that not only inhibits energy production but also withdraws energy.
2. Physiological background:
   • The itaconate shunt is activated during infections to prevent pathogens from replicating by withdrawing energy.
   • In ME/CFS, this mechanism may remain chronically activated, permanently limiting energy production is.
3. Compensation mechanism (GABA shunt):
   • When the TCA cycle is blocked, cells use the inefficient GABA shunt, which only provides 40% of the usual energy and produces nitrogen byproducts such as ammonia.
4. Consequences:
   • Chronic energy deficiency of the cells.
   • Accumulation of toxic byproducts such as ammonia, which exacerbate brain fog, fatigue and other symptoms.
5. Research and significance:
   • The hypothesis is being tested by international teams (e.g. B. Open Medicine Foundation, Amar Foundation).
   • The aim is to understand whether the shunt remains permanently active in ME/CFS and how it could possibly be deactivated.

The hypothesis provides a plausible connection between the immune system, energy metabolism and typical ME/CFS symptoms and could open up new therapeutic approaches in the long term.

This finally explains BENZO effectiveness

This GABA shunt finally explains why benzodiazepines are surprisingly effective in a subset of long-term covid patients. I know feedback from patients who tell me: when I take a lorazepam or oxazepam preparation, I am almost free of symptoms!

The GABA shunt hypothesis could explain the response to benzodiazepines in some long-COVID patients

This hypothesis states that dysregulations in energy metabolism and neuroinflammatory processes can lead to an increased diversion of glutamate into the GABA shunt, which leads to an imbalance between excitatory and inhibitory neurotransmitters.

Benzodiazepines work by enhancing GABA-A receptor activity and could thus:

1. Reduce hyperexcitability: An imbalance with excessive glutamatergic activity could be balanced by increased GABAergic inhibition.
2. Modulate neuroinflammation: GABA-A receptors are also present on immune cellsn expressed and could dampen inflammatory processes.
3. Stabilize autonomic dysregulation: Long COVID is often associated with dysautonomia, and calming via GABA-A mechanisms could have a relieving effect here.

These effects could lead to impressive clinical improvement in a specific subgroup of long COVID patients in whom these dysregulations are particularly pronounced.

Inhibition of interleukin-6 production as a potential therapeutic aid

We know from the many measurements (by our colleagues) that IL-6 levels are extremely elevated in long Covid cases. There is a drug called Jyseleca (r) which slows down the production of IL-6 and could be helpful here.

Here is a corresponding study with ulcerative colitis patients. Some of the patients responded well to the drug:

Filgotinib led to an early and sustained reduction in IL-6 in endoscopic responders, starting from week 2.

However, specific values ​​for the strength of the reduction in IL-6 (e.g. percentage decrease or absolute concentration changes) were not given in the text, but only the general effect of the reduction in responders was highlighted

here again is the article about Prof. Naviaux’s work that I praised so highly

oxidativ shielding – 50 Jahre fehlinterpretierte Forschung – Mitochondriopathien sind als Cell-Danger-Response physiologisch

Source of this article here

Website:  https://www.healthrising.org/blog/2023/12/23/itaconate-shunt-hypothesis-chronic-fatigue-syndrome-fatigue/

here is the original text translated 1:1

The itaconate shunt hypothesis – could it explain the energy problems and PEM in ME/CFS?

THE ESSENTIAL

• Janet Dafoe interviewed Robert Phair twice about his itaconate shunt hypothesis for the Open Medicine Foundation, late last year and early this year. This blog is from the first interview.
• The itaconate shunt hypothesis is compelling because it potentially links infectious disease, impairment of the energy production system, brain fog, post-exertional malaise and immune deficiency. Work to test the hypothesis was initially funded by the Open Medicine Foundation and is now funded by the Amar Foundation, founded by Vinod and Neeru Khosla.
• The roots of the hypothesis lie in discussions between Robert Phair and Chris Armstrong, head of the Melbourne Collaboration of the Open Medicine Foundation in Australia. Armstrong and others had found that people with ME/CFS preferred to use amino acids instead of better fuels like glucose and fatty acids to fuel their cells.
• The increased use of amino acids should have led to high levels of nitrogenous byproducts in their blood. The fact that they weren’t there suggested that the safe breakdown of amino acids wasn’t happening and toxic byproducts like ammonia were being produced instead.
  Phair has uncovered a possible reason for this during the coronavirus pandemic. He found that an immune enzyme called CAD, produced during infection, can create what’s called an “itaconate shunt,” causing a short-circuit of the energy production cycle in the mitochondria.
• In fact, it’s worse. Not only is the energy production cycle (the TCA/cancer/citric acid cycle) disrupted, but the itaconate shunt also turns it into an energy sink. Instead of producing energy, it actually takes energy away from the cell.
• It seems bizarre to shut down or inhibit energy production during an infection, but it serves a purpose. Since the pathogens that infect cells use the cell’s energy to produce more pathogens, the itaconate shunt is thought to temporarily shut down the cell to limit pathogen replication long enough for the next phase of the immune system -the adaptive immune system – can prepare to wipe out the pathogens.
• Phair suggests that in ME/CFS, the itaconate shunt is switched on permanently, not just for a few days.
• However, our cells have produced a backup energy system called the GABA shunt – which may explain why the cells of ME/CFS patients preferentially use amino acids. Unlike the other parts of the Krebs/citric acid/TCA cycle, the GABA shunt uses amino acids for energy and is not affected by the itaconate shunt.
• However, the GABA shunt only produces about 40% of the normal energy our cells produce – and it comes with a problem – it leaves behind nitrogen byproducts that need to be broken down. As mentioned, studies suggest that our amino acids are not being broken down safely – potentially leading to high levels of ammonia – a toxic byproduct that can, among other things, impair energy production.
• The hypothesis is being tested by Chris Armstrong at the Open Medicine Foundation’s Melbourne Centre and by at least one other group of researchers.
• In Part II, Health Rising will explain why the itaconate shunt can become chronic in ME/CFS and what the hypothesis currently looks like.

Janet Dafoe has made an informative video series about the work of the Open Medicine Foundation. Her patient-centered approach – she often interrupts a researcher speaking “researcher-speak” to explain in plain English what is going on – is refreshing.

In late 2022 and early 2023, their two-part series with Robert Phair – the creator of the IDO metabolic trap hypothesis for ME/CFS – focused on his latest approach – the itaconate trap hypothesis.

The itaconate shunt hypothesis – with its potential ability to explain so much in ME/CFS (energy production issues, strange metabolomic results, post-exercise malaise, brain fog, immune issues) – provided a compelling idea.

After the Open Medicine Foundation provided critical support for the development of the hypothesis, Vinod and Neeru Khosla’s Amar Foundation in San Jose, California, stepped in and provided funding to test the hypothesis in Chris Armstrong’s lab at the Open Medicine Foundation’s Melbourne Collaboration at the University of Melbourne in Australia.

Vinod Khosla, co-founder of Sun Microsystems, and his wife Neeru founded the Amar Foundation in 1987. In 2011, they were among the first signatories of the Giving Pledge, created by Warren Buffet, Melinda and Bill Gates, which requires high-net-worth individuals to give away the majority of their wealth during their lifetime or in their will.

The Mind Meld
Dr. Robert Phair is co-founder of Integrative Bioinformatics Inc., a computational biology consulting firm that has taken a systematic approach to modeling biological systems for over 20 years. Phair became interested in ME/CFS when he met a neighbor with the disease at Stanford, and began working with Ron Davis on solutions for ME/CFS in 2016.

In late 2019, Phair and Armstrong were puzzling over the “ammonia problem” in ME/CFS during discussions with Chris Armstrong – the Open Medicine Foundation’s metabolomics expert – and since 2020 the head of the Open Medicine Foundation’s Melbourne Collaboration. Armstrong and others found that the cells of ME/CFS patients preferentially used amino acids instead of the body’s preferred sources – glucose or fatty acids.

Amino acids are not a preferred energy substrate for several reasons. One of them is that they have that pesky nitrogen atom on them that needs to be taken care of. The body normally excretes the nitrogen using a variety of “safe” forms, but ME/CFS studies have not found elevated levels of these safe forms. That suggests that “unsafe” forms of nitrogen, such as ammonia or peroxynitrite, are accumulating. These two highly reactive compounds can, among other things, mess up the energy production systems that power our cells.

Chris Armstrong and the hunt for the metabolic basis of ME/CFS

During the pandemic, when Phair had shifted his work to understanding the innate immune system, he discovered an innate immune enzyme called CAD that he believed could help explain the ammonia mystery. With support from the Open Medicine Foundation and the Amar Foundation, Phair got to work. Using a modeling tool developed by Integrative Bioinformatics Inc., by September 2021 Phair had a possible answer to the amino acid/ammonia problem in ME/CFS—and the itaconate trap hypothesis was born.

The hypothesis is particularly well-known aboutcompelling because it potentially links infection damage, compromised energy production systems, brain fog, post-exertional malaise, and immune deficiency.

The Itaconate Shunt (or Trap) Hypothesis, Part 1 I
Citric Acid Cycle
Important in this diagram are the areas just outside the circle where NADH and FADH2 are produced. They provide the electrons that drive the electron transport chain where ATP is produced. The itaconate shunt blocks their production.

First of all, it is important to know that within the citric acid or Krebs cycle, a variety of transformations occur in the mitochondria that ultimately produce substances such as NADH and FADH2, which provide the electrons that drive the electron transport chain to produce ATP.

However, it all starts outside the mitochondria with energy substrates that the Krebs or TCA cycle uses to produce NADH/FADH2. The cycle’s preferred energy sources are glucose and fatty acids. Note the central role that acetyl-CoA plays in the cycle.

Glycolysis converts glucose to pyruvate, which in turn is converted to acetyl-CoA.
Fatty acids – enter the Krebs cycle by converting to acetyl-CoA.
The Krebs cycle can also use amino acids. However, amino acids enter the Krebs cycle in a completely different way and at a different time.

An infection – energy disruption connection

So far, so good, but then comes the itaconate shunt – initiated by our old “friend,” the innate immune system. The innate immune system is an ancient immune response found in all vertebrates that quickly tries to keep an infection at bay long enough for the adaptive immune response to launch a hopefully devastating pathogen-specific attack a few days later. The innate immune system can also be activated by stress, injury, or environmental toxins.

One of the many factors the innate immune system produces is called cis-aconitate decarboxylase, or CAD. In the second step of the Krebs cycle, CAD interrupts it—and sends it down a different path—one that effectively shuts down its ability to produce large amounts of energy.

First, CAD converts cis-aconitate to itaconate, which is then catalyzed by an enzyme in the Krebs cycle called STK (succinate thiokinase) into something called itaconyl-CoA.

Remember acetyl-CoA? The Krebs cycle normally breaks it down so the cycle can continue. However, in the itaconate shunt, STK loads CoA onto itaconate, making the Krebs cycle an energy sink rather than an energy producer. Instead of the Krebs cycle producing ATP, ATP is actually lost. So the itaconate shunt effectively bypasses the energy-producing steps of the Krebs cycle.

That doesn’t necessarily mean that energy production is completely stopped—some cis-aconitase is probably still getting through—but it’s probably severely inhibited.

Our cells have, however, evolved a backup energy system called a GABA shunt.

A defense strategy
The big question that arises is: why? Why would we build into our cells a way for the innate immune system to shut down energy production during an infection? The shunt has to serve a purpose, and it does. It’s a defense strategy. While the itaconate shunt impairs our cells’ energy production, it also negatively impacts the pathogens that have infected our cells. After all, they need energy to reproduce—energy that they get from our cells. When the cell’s energy centers are shut down, the pathogens have trouble reproducing—giving our adaptive immune system a chance to step up and attack them with pathogen-specific immune hunters.

Although Phair doesn’t mention it in his talk, this energy shutdown during infection seems reminiscent of Robert Naviaux’s Dauer hypothesis. It also seems consistent with the idea of ​​”sickness behavior,” where symptoms like fatigue, brain fog, and other flu-like symptoms paralyze a person and prevent them from spreading an infection.

The idea is that in ME/CFS, the shunt doesn’t stay on for a few hours or a few days at most, but is turned on permanently.

The workaround – the GABA shunt
But what about the preferential use of amino acids for energy production that we see in ME/CFS? We don’t have an answer for that. It turns out, however, that the itaconate shunt hypothesis offers a practical answer to that – if not a pretty one.

As we’ve seen, both glucose and fatty acid metabolism in the Krebs cycle are linked to each other.lus of CoA—the substance that the itaconate shunt essentially takes out of the picture.

Of course, our cells have a workaround—a sort of failsafe to ensure that at least some energy is still being produced. There is an alternative to the normal functioning of the Krebs cycle—the so-called GABA shunt.

The GABA shunt uses four enzymes already present in the Krebs cycle to complete the cycle in the absence of CoA and ultimately produce ATP. It is only about 40% as efficient as the CoA-fueled Krebs cycle, but you do eventually get some ATP out of it.

With the GABA shunt, we have a possible answer to the strange pattern of preferential amino acid usage that occurs in ME/CFS. If the itaconate shunt hypothesis is correct, our cells are primarily resorting to the only remaining substrate—an intermediate amino acid called glutamate—to power their engines.

The effects don’t stop at energy production, though. Using high amounts of glutamate to fuel our mitochondria has its consequences – including failing the brain on its essential energy substrate – glutamate – potentially leading to brain fog, memory and learning issues, etc.

Ammonium

With the GABA shunt, we come to what started the whole thing – ammonia! Both the itaconate trap hypothesis and ME/CFS metabolomics studies suggest that our cells are likely chock full of glutamate. If the hypothesis is correct, amino acids are the only truly usable energy substrate we have left.

But that puts us in a tricky situation. When we exert ourselves and use up our ATP, we’re left with something called ADP. (Instead of adenosine triphosphate (ATP), we’re left with adenosine diphosphate (ADP).) ADP is the normal byproduct of energy production.

However, ADP triggers the breakdown of glutamate, which (partially) leads to the production of ammonia—a highly toxic substance. This isn’t usually a problem because: a) the cancer usually runs mostly on glucose and fatty acids and doesn’t produce much ammonia, and b) healthy people can break it down safely anyway. Because ME/CFS cells may be overloaded with ammonia and people with ME/CFS may have difficulty breaking it down, Phair and Armstrong believe high levels of ammonia may be present.

This is “one of the many ways” Phair believes ME/CFS might get going. Chris Armstrong is developing carbon-13 tracers to determine if the itaconate shunt has become chronic in ME/CFS.

Note that the itaconate shunt is not a hypothesis—we know it occurs in the early stages of infection. However, the itaconate shunt or trap hypothesis posits that it has become chronic in ME/CFS. The next part of Janet Dafoe’s interview with Robert Phair in Part 2 will cover why he believes the shunt may have become chronic in ME/CFS.

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Eventually, something will explain ME/CFS and similar post-infectious illnesses. Whether it will be the itaconate shunt hypothesis or something else, no one knows, but we love highlighting the creative ways researchers are finding to explain these illnesses.