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THE GIST
- What’s going on in orthostatic intolerance (symptoms triggered by standing or sitting up) has been well described – from the outside. What’s happening at the molecular level to cause it is another story – no one really has a clue. That’s what the Simmaron Foundation research team took a look at.
- Their recent study revolves around a compound called tetrahydrobiopterin (BH4) that plays a crucial role in several major processes and at high levels has been associated with mitochondrial dysfunction, cognitive problems, immune dysregulation, inflammatory and autoimmune diseases, and chronic pain.
- The researchers dug into a metabolic pathway called the pentose-phosphate pathway to understand what was happening. Multiple tests suggested that low oxygen levels in the cells of ME/CFS patients were triggering one phase of the pathway to become overactivated and the other phase of the pathway to become underactivated.
- It’s always about balance. The downregulated oxidative phase of the pathway likely resulted in increased oxidative stress (check!), impaired lipid synthesis (check!), tissue repair (after exercise???), and pathogen killing (check!).
- Meanwhile, high levels of a breakdown product of BH4 called BH2 were found in ME/CFS. increased BH2 levels – in the presence of low oxygen levels – do a Jekyll/Hyde-like switch on nitric oxide enzyme. Instead of opening blood vessels and reducing inflammation, the enzyme narrows them down, producing inflammation, clotting, oxidative stress, and mitochondrial dysfunction.
- One of the nice things about this study – done at the cellular level – is how well its findings fit with what we know about ME/CFS. High levels of oxidative stress, low cellular oxygen levels, low glutathione levels, inflammation, neuroinflammation, and problems with blood vessel flows and lipids – all these seem to be part and parcel of ME/CFS.
- The authors propose that high-resolution metabolomics study using a large sample size that was informed by machine learning-based network analyses will confirm or deny the role that PPP-induced BH4 plays in ME/CFS. They have the samples but not yet the funding.
- Check out the Treatment Takeaways section for information on those.
What’s happening on the inside – at the molecular level – is more of a mystery. Yes, we know about norepinephrine levels, but what is causing them? Studies suggest that a messed-up renin-angiotensin-aldosterone (RAA) pathway contributes to the low blood volume found in ME/CFS and POTS but no one, to my understanding, has figured out, molecularly, how that has happened.
A new metabolic problem! Yah! 🙂
In”Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway“, the Simmaron Research Foundation’s small but creative research team led by Avik Roy and Gunnar Gottschalk is trying to get at the molecular roots at them – and in ME/CFS to boot.
The Study
It revolves around a compound called tetrahydrobiopterin (BH4) that plays a crucial role in several major processes. At the right levels, BH4 allows for the production of the feel-good brain chemicals dopamine and serotonin, assists with mitochondrial functioning, and helps the blood vessels to vasodilate or open.
High levels of BH4 have been associated with all sorts of negative results including mitochondrial dysfunction, cognitive problems, immune dysregulation, inflammatory and autoimmune diseases, and chronic pain.
When we last heard from the Simmaron research team, they’d found high BH4 levels in ME/CFS patients with orthostatic intolerance – an outcome that had never been found before.
Another Balky Metabolic Pathway?
Two phases of the pentose phosphate pathway exist. Low oxygen levels appear to be dysregulating them in ME/CFS. (Image by GdenBesten, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons).
Enter the pentose phosphate pathway (PPP). The PPP is a metabolic pathway that runs parallel to glycolysis and is activated during high levels of oxidative stress – which we know is present in ME/CFS. The pathway produces something called NADPH to regenerate the key antioxidant in our body – glutathione – when glutathione levels dip low. Several studies have made it clear that glutathione levels in the brain are low in ME/CFS.
The pathway can also kick in when glycolysis is not functioning. The status of glycolytic functioning in ME/CFS is unclear, as some studies suggest it’s functioning just fine while others suggest it is not.
The PPP contains two phases: an oxidative (antioxidant enhancing) phase, and a non-oxidative phase that synthesizes sugars and produces something called ribose-5-phosphate – which plays a critical role in the production of BH4.
Finding high BH4 levels in ME/CFS, the Simmaron researchers dug into the pentose phosphate pathway to see what was going on. Multiple tests (gene expression study, real-time PCR, and quantitative ELISA analyses) indicated that the non-oxidative side of the PPP pathway – the side that produces BH4 – had been highly upregulated in ME/CFS.
Low Cellular Oxygen Levels Tagged
And what an interesting upregulation it was. The increased expression of genes involved in lactate production and the non-oxidative side of the pathway suggested that low oxygen levels in the cells of ME/CFS patients were triggering the non-oxidative side of the PPP to gear up.
As that was happening, the downregulated oxidative side of the PPP likely resulted in increased oxidative stress (check!), impaired lipid synthesis (check!), tissue repair (after exercise???), and pathogen killing (check!).
The possibility that low oxygen levels, or hypoxia, figure in ME/CFS has been around for quite a while. They tested the hypothesis that low oxygen levels were causing the pentose phosphate pathway to produce increased BH4 levels by creating a hypoxic state and exposing cells to it. The results suggested it was.
Turning a Good Enzyme Bad
Inducible nitric oxide (iNOS) – it’s pretty, but it induces inflammation and may be upregulated in ME/CFS.
In the presence of oxidative stress – which we know is plentiful in ME/CFS – BH4 does something particularly nasty: it turns a “good” enzyme – eNOS – into a “bad” enzyme (iNOS). In its “good” form, eNOS helps to open the blood vessels and keep them healthy.
In its “bad” form, iNOS is associated with the production of reactive nitrogen species (RNS) such as peroxynitrite, activation of the microglial cells in the central nervous system (neuroinflammation), excitotoxicity in the central nervous system, and mitochondrial dysfunction. (Ouch!)
Neuroinflammation Too?
Indeed, when the Simmaron team investigated the impact of BH4 upregulation on the microglial cells and inflammation, they found that under hypoxic conditions, BH4 triggered the production of nitrite – a reactive nitrogen species (a free radical) but only in the ME/CFS patients’ cells. That suggested the elevated BH4 levels in ME/CFS patients’ cells may be triggering neuroinflammation.
Bad Breakdown Product
Further analyses indicated that two byproducts of BH4 breakdown – BH2 and DHPR – were strongly upregulated in the ME/CFS patients as well – and here we come back to the possible molecular origins of orthostatic intolerance.
It turns out that high BH2 levels can produce reduced levels of eNOS – the form of the enzyme that opens the blood vessels. High BH2 levels could also increase platelet activation, cause damage to the endothelial cells lining the blood vessels, and increase the risk of atherosclerosis and blood clotting.
Nasty Oxidative Stress Mix
In fact, it’s worse than that. In the presence of high BH2 levels, instead of producing endothelial nitric oxide, eNOS produces a free radical called superoxide. Instead of opening the blood vessels as it normally does, eNOS does a Jekyll/Hyde about-face and actually ends up clamping down on them.
When superoxide pairs with nitric oxide, it produces peroxynitrite – a dangerous free radical that loves to poke holes in cellular membranes, cause mitochondrial dysfunction, damage our DNA, etc. Peroxynitrite is difficult to measure in the blood, but ample evidence of oxidative stress has been found in ME/CFS. Martin Pall’s 2001 ME/CFS hypothesis proposed that chronically high levels of peroxynitrite were driving the disease, and Bindu Paul and Marian Lemle more recently suggested that oxidative stress plays a key role in it and long COVID.
The high BH2 levels the Simmaron group found in ME/CFS, then, are potentially a big deal.
Treatment Takeaways
The authors did not mention treatment possibilities but AIChatGpt had some ideas about treating some of the potential problems this study found.
Improve eNOS activity
- Eat more dietary nitrates found in beetroot and green leafy vegetables
- Supplement with omega-3 fatty acids, L-Arginine (eNOS substrate – but rapidly metabolized), L-Citrulline (precursor to L-arginine – possibly more effective that L-arginine), antioxidants (Vit. C, E and NAC), nicotinamide riboside, CoQ10, tetrahydrobiopterin (BH₄) (questionable given high BH4 findings?)
- Try statins, metformin, phosphodiesterase-5 (PDE5) Inhibitors (e.g., sildenafil)
Reduce iNOS activity
- Try Resveratrol, quercetin, and curcumin.
- Anti-inflammatories (NSAIDs) and TNF-a inhibitors (etanercept), (anti-TNF therapy) or anakinra (IL-1 receptor antagonist)
- Experimental drugs – L-NIL (N6-(1-Iminoethyl)-L-lysine) and aminoguanidine.
Reduce BH2 levels
- Antioxidants to combat oxidative stress can prevent the oxidation of BH4 to BH2 maintaining the proper BH4/BH2 balance.
- Antiplatelet therapy like aspirin can counteract the pro-clotting environment.
- Supplement with folate to enhance BH4 regeneration from BH2
- Supplement with N-acetylcysteine (NAC) to increase glutathione levels
Potential Therapeutic Interventions
The authors did not mention treatment possibilities, but AI ChatGpt had some ideas about treating the variety of potential problems this study found.
Improve eNOS activity
- Eat more dietary nitrates found in beetroot and green leafy vegetables
- Supplement with omega-3 fatty acids, L-Arginine (eNOS substrate – but rapidly metabolized), L-Citrulline (precursor to L-arginine – possibly more effective that L-arginine), antioxidants (Vit. C, E and NAC), nicotinamide riboside, CoQ10, tetrahydrobiopterin (BH₄) (questionable given high BH4 findings?)
- Try statins, metformin, phosphodiesterase-5 (PDE5) Inhibitors (e.g., sildenafil).
Reduce iNOS activity
- Try Resveratrol, quercetin, and curcumin
- Anti-inflammatories (NSAIDs) and TNF-a inhibitors (etanercept), (anti-TNF therapy) or anakinra (IL-1 receptor antagonist)
- Experimental drugs – L-NIL (N6-(1-Iminoethyl)-L-lysine) and aminoguanidine.
Reduce BH2 levels
- Antioxidants to combat oxidative stress can prevent the oxidation of BH4 to BH2, maintaining the proper BH4/BH2 balance
- Antiplatelet therapy like aspirin can counteract the pro-clotting environment
- Supplement with folate to enhance BH4 regeneration from BH2
- Supplement with N-acetylcysteine (NAC) to increase glutathione levels.
From the study.
Conclusion
One of the nice things about this study – done at the cellular level – is how well its findings fit with what we know about ME/CFS. High levels of oxidative stress, low cellular oxygen levels, low glutathione levels, inflammation, neuroinflammation, and problems with blood vessel flows and lipids – these all seem to be part and parcel of ME/CFS.
A dysregulated pentose phosphate pathway, and the BH4, and BH2 connection provide another explanation for them. Will it turn out? The studies are small and only time will tell if they’re on the right track.
The authors have proposed a way to find out, though. A high-resolution metabolomics study using a large sample size that was informed by machine learning-based network analyses they believe would confirm or deny the role that PPP-induced BH4 plays in ME/CFS.
The small Simmaron research team with their ME/CFS mouse model work, autophagy, rapamycin clinical trial, and now the BH4, pentose pathway, and BH2 findings has been uncommonly productive. They appear to have the samples they need to do the metabolomic project – all they need at this point is the funding. May they get it!
- Coming up – an update on the Simmaron Research Foundation’s ME/CFS Rapamycin clinical trial
Donation Drive Update!
We try and figure it out. If that’s what you want to see, please support us.
Thanks to the over 160 people who have contributed over $14,000 during our end-of-the year donation drive.
This study was a toughie! It’s biochemistry-oriented and took a lot of work to understand – particularly for someone who barely made it through organic chemistry in college (lol) – and for readers to get through. It’s at the molecular level, though, that understanding this disease will probably bring us the greatest breakthroughs. I’m committed to understanding (as best I can) this disease and communicating it.
If that’s what you want to see, please support us!
Thank you for all the great work that you do for those of us with ME/CFS and it’s associated comorbitites. I have donated to you in the past, but unfortunately I am waiting on appeal for my Social security disability claim. If/when I am approved, I will make sure to donate each year to Health Rising. What a valuable service you provide for us.
Thanks! And good luck with disability. I wonder whether you did the 2-day exercise test from Workwell or another exercise physiologist?
Hi Cort,
I used to believe that hypercortisolism was enough to deprive the body of Aldosterone since the Adrenal glands make both of those compounds. Renin, I believe, is made by the kidneys and affects the Adrenals. Since salt retention is what is managed by Aldosterone’s effect on the kidneys, it follows that failure of Aldosterone would fail to retain salt… and we must lose water and salt in the right proportion to each other. That dehydrates and the dehydration results in low blood volume, which results in low blood pressure, but also in low CELL VOLUME. With low cell volume, the nooks and crannies for receptors may become distorted. I *thought* that was the role for Metformin, that it would restore form to the cell …
The only problem was that I read that Aldosterone levels in CFS blood were observed to be normal. At least in the CFS research that payed any attention to Ald. However, if not all CFS patients have POTS, then it might be directly proportional to not all of them having an Aldosterone deficiency. And I’ll go out on a limb and say that then it would seem most likely the most grave examples of CFS would include POTS, while less severe examples may not–then it would be a subset thing where Aldosterone doesn’t show as deficient until the CFS gets *that* grave.
But please keep in mind that even if Aldosterone production were normal, the types of cytokine storms that likely precipitated CFS and long Covid do damage to smooth muscle, especially vessels and organs, and *especially especially to the kidneys. Kidney dysfunction is one of the most likely organ dysfunctions to occur after such illness, even if others do not appear. Even kidney dysfunction could underprocess the Ald. even if the Ald. were sufficient.
In any case, the next stop in blood pressure is nitric oxide and whether or not enough is produced. Too much can also be the result of certain disease states. The smooth muscle of the blood vessels is neither relaxed or constricted in its resting state. It is somewhat constricted and can become even more constricted, but nitric oxide’s job is to relax the constricted vein in response to the systolic pump of the heart. In diastolic, the ambient medium constriction should resume.
To apply that to POTS etc… when one gets up the brain ought to have relaxation of its vessels while the blood is shunted there from vessels that do not need it as much at that moment: like the intestine’s vessels. The blood pressure should be higher down below but lower in the brain. Since it does not happen, dizziness results. A nitric oxide imbalance seems like enough to explain that. But I wonder whether it is a renin dysfunction or an Aldosterone dysfunction that precipitates the problem. Or is it all one big clusterf…oops, typo.
Well…
1. if blood volume is too low from Aldosterone production deficiency, or from kidney inefficiency in responding to it with salt retention
then
2. blood volume will be too low
and
3. blood pressure will be too low even if vessel constriction is business as usual.
…But I do not think that vessel constriction *would be business as usual. Because in Covid we know that ACE2 receptors are blocked by the virus and unable to enzymatically break down the angiotensin, with a cascading message to the nAChR eceptors which should then tell the mitochondria to make more antioxidant (NAD..something). This may be the brain portion of the problem. Not enough dilation.
And please remember that in addition there has been a massive replacement (remodelling) of endothelial SMCs (smooth muscle cells) because *there is no time* during cytokine storm damage to them to replace like with like. Instead, more rigid (collagenic) cells are the ones to remodel the more flexible (elastinic ) cells. So even if the nitric oxide response were normal, the number of flexible endothelial cells remaining to do it are diminished.
You may be wondering: what if I didn’t get long covid, but rather had a pandemic Flu? Well, flus have a cytokine storm because of the blockage of Sialic Acid receptors by the flu viruses. And they are resident in the same smooth muscle locations. This I had to deduce by myself, but I can document it.
But there is one grey area in all of this:
The textbooks say that in a cytokine storm the endothelial flexible cells are not replaced like with like.
However,
we never cease to have EGF– endothelial growth factor for other situations.
So maybe the message is only that the EGF is not used for cytokine storm management, but not that it can never occur, nor never repair in the future.
This opens a new treatment avenue: stimulating EGF.
One of the best — or only — vessel repair compounds is the citrus bioflavonoid. There are 5 or 6 types/names but only 5 fruits in which they seem to occur. Tangerines and tangeritin seem to be the most potent.
I can document an NIH meta-analysis of citrus bioflavonoids both protecting, during, and healing capillaries, after, a massive cytokine storm. But also, Omega-3 helps to also protect, during.
Because you see: we are focussed on ROS. Well, the effect of ROS is upon the endothelial cells. But if we have antioxidants there to bind with them, they can be neutralized and much less damage can occur.
Okay, I’m done. But don’t tell me I never gave ya nuthin:
Polyphenols…antioxidants….bioflavonoids….
are all
antioxidants.
I have documentation that polyphenols in dark fruits like
blueberries and pomegranate can
block:
a) covid injection by ACE2 receptor
b) viral replication by ribosomes
c) viral release by other transporters.
2 Post-Thoughts:
P.T.s
by Chris D.
1. I often describe endothelial damage incorrectly since it is confusing. The inner, or endothelial cell processes the renin/angiotensin. Then it ENCOURAGES the creation of nitric oxide in the smooth muscle cells that are flexible. My apology. This means that massive remodelling that loses these endothelial cells means not enough of them telling their nearby SMCs to produce nitric oxide to relax. The normal dilation reaction is said to be a response to vascular shear pressure, caused by the systolic pumping of increased blood volume.
I guess it must be a baroreceptor
2.
Since Cortisol is the stress-management hormone, it is natural for it to become too high during a crisis like flu or covid…or sepsis…or a serious serious bacterial infection… and then to fluxuate between higher and too high for the rest of CFS, until you alleviate CFS.
But Adaptogens such as Ashwagandha (used for 3000 years in traditional Indian (India) medicine to regulate cortisol levels), Ginseng (used in China and Japan for 2000 years)
https://pmc.ncbi.nlm.nih.gov/articles/PMC7322748/ — ginseng
“Panax ginseng occupies a prominent status in herbal medicine for its various therapeutic effects against inflammation, allergy, diabetes, cardiovascular diseases, and even cancer, with positive, beneficial, and restorative effects. The active components found in most P. ginseng varieties are known to include ginsenosides, polysaccharides, peptides, alkaloids, polyacetylene, and phenolic compounds, which are considered to be the main pharmacologically active constituents in ginseng. P. ginseng is an adaptogen. That is, it supports living organisms to maintain optimal homeostasis by exerting effects that counteract physiological changes caused by physical, chemical, or biological stressors. ”
….adaptogens… can regulate the cortisol response. It may be good to have a sharp response, which dulls the immune system also, not what I might expect.. but yes, if we are already reacting sharply to a disease, we don’t want the system to become even more militaristic and kill us too.
“Mineralocorticoid receptors
The MR is stimulated by both aldosterone and cortisol, but a mechanism protects the body from excess aldosterone receptor stimulation by glucocorticoids (such as cortisol), which happen to be present at much higher concentrations than mineralocorticoids in the healthy individual.”
” The aldosterone mineralocorticoid receptor (MR) complex binds on the DNA to specific hormone response element, which leads to gene specific transcription. Some of the transcribed genes are crucial for transepithelial sodium transport, including the three subunits of the epithelial sodium channel (ENaC), the Na+/K+ pumps and their regulatory proteins serum and glucocorticoid-induced kinase, and channel-inducing factor, respectively.”
“The MR is stimulated by both aldosterone and cortisol, but a mechanism protects the body from excess aldosterone receptor stimulation by glucocorticoids (such as cortisol), which happen to be present at much higher concentrations than mineralocorticoids in the healthy individual. The mechanism consists of an enzyme called 11 β-hydroxysteroid dehydrogenase (11β-HSD). This enzyme co-localizes with intracellular adrenal steroid receptors and converts cortisol into cortisone, a relatively inactive metabolite with little affinity for the MR. Liquorice, which contains glycyrrhetinic acid, can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome.”
Good to know… while sealing your gut with licorice.
After ACE2 triggers cytokines, the immune system may mistakenly attack the lining of blood vessels (endothelial cells), causing damage to collagen and making it difficult for the vessels to repair themselves. Over time, this could result in conditions like APS and lupus. High levels of a clotting protein (vWF) and an increased tendency to form clots further worsen the damage. Ongoing inflammation and scarring (fibrosis) make the vessels stiff and less functional. To restore healthy blood vessels, only cortisone treatments are effective.
That is conjecture. If your source is what you included below, it does not argue those things.
Lupus and APS are way down the road from long covid. What you said us “may” and “could” but the immune system is not making a mistake when covid virus information is found in some tissues 8 or more months after infection.
If you read what I said most recently you will see that there *are other treatments for inflammation, and saying “only cortisone is effective” is a death sentence because you can’t endure ling-term cortisone.
Your arguments do not follow.
“Lupus and APS are often thought to develop much later or as separate conditions from long COVID.”
Unfortunately, that hasn’t been the case for me. After contracting COVID-19, an ELISA test in 2021 confirmed that I have Lupus and APS. I also have a genetic predisposition for von Willebrand disease types II and V.
I think it’s worth revisiting the research on medications and supplements that people with Lupus should avoid, as this could be valuable for others in similar situations.
On top of this, I’ve been taking hydrocortisone for the past 10 years due to adrenal insufficiency.
Your piece from 2 1/2 years ago makes a nice companion piece to this one: https://www.healthrising.org/blog/2022/03/27/novel-approach-mitochondria-chronic-fatigue-syndrome/
Sorry, I forgot to include: “Endothelial inflammation in COVID-19”
https://www.science.org/doi/10.1126/science.add2962
Were unusual levels of BH4 found in the new pre-print study, “Replicated blood-based biomarkers for ME/CFS not explained by inactivity”?
I must be a bit dense, but I can’t find the list of biomarkers in the pre-print document to search!
As I mentioned the importance of “Catecholamines (neurotransmitters and hormones)” in the Phoenix form in February 2024, please keep in mind that there could be an error in the gene GS224 tetrahydrobiopterin.
Hi Cort:
May I have your permission to post this on BlueSky?
Thanks for your answer. SWA
Of course! Please do so! 🙂
Hi, huge thankts Cort, to your interesting and helping work.
What do you think is the best way to reduce oxidative stress in a ME patient.
That;s a good question and I don’t know. I would think NAC would be a natural but I’m really hoping that we’ll get some new and better antioxidants in the not too distant future.
Thanks, Cort, for another interesting article.
If this disease process “turns a ‘good’ enzyme – eNOS – into a ‘bad’ enzyme (iNOS)” though – I do wonder if increasing eNOS levels by taking beet supplements as ChatGPT suggests is really a good thing, or could it be a bad thing?
I would be curious what others who are more gifted in understanding metabolic processes than I, think about that.
If it could selectively promote eNOS and tamp down iNOS I think it would be a good thing. I imagine that given the right environment that the NOS enzyme stays in its healthier form and that things like beets help provide that environment.
Thank you!
Hi Court, thank you for your dedication in reporting on the latest developments in MECFS. I agree that there is a problem with the PPP but am surprised about the findings of increased BH4. Isn’t Ron Davis researching low BH4 in his latest study? I have a G6PD mutation which leads to a low G6PD enzyme and impairment of NADH production and low levels of glutathione as a result. Some of the AI suggestion for treatment also includes BH4 supplementation. How does that sit with the theory of high BH4?
Right – these two findings are at odds. It could be that both are found in ME/CFS; that is some people with deleterious mutations have low BH4 and other people have higher BH4…or one of these studies could simply be off.