Dihydroquercetin and mast cells/histamine issues

Dihydroquercetin (sold as Taxifolin) was suggested in a comment on Fisetin and praised that it worked better for the reader than other items, etc. A friend tried it, as to date, noticed a distinct improvement after just a few days — especially in not having histamine issues after a meal. It’s time to review and summarize what is known about it.

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®….
Modulated NF-κB activation Suppressed the NF-κB activation, protein kinase activation by C-Fos and mitogen, and reduced the expression of osteoclast-specific genes, including Trap, Cathepsin K, Mmp-9, Nfatc1, C-Fos and Rank
Inhibited the osteoclast differentiation induced by RANKL Suppressed the NF-κB signaling pathway and inhibited the osteoclastogenesis

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®….

An insight into the health-promoting effects of taxifolin (dihydroquercetin) [2019]

Now, for histamines we find “low concentrations of H2O2[Hydrogen Peroxide] appeared to augment … histamine release induced by anti-IgE…. Since taxifolin inhibited Hydrogen Peroxide generation but had little inhibitory effect
on histamine release indicates that H202 generation is not a prerequisite for anti-lgE-induced histamine release….By contrast, taxifolin caused a large inhibition of H202 formation but had a much smaller effect on histamine release. ” [1986].

Reading thru several studies [most from the 1980’s], we find that it was inactive against some forms of histamine release. I suspect that it dropped off the radar of people suffering with mast cell and histamine issues because of these studies (using older methodologies)

  • “There was a remarkable correspondence of inhibitory activity for each of these flavonoids against TF’A-, teleocidin-and aplysiatoxin-induced histamine release. Taxifolin was essentially inactive against each tumor promoter,” [1987]

However we also read “Dihydroquercetin in the capacity of antioxidant may be compared or exceeds many synthetic and natural antioxidants and, in particular, known bioflavonoids (quercetin) [1997]”

The status changed in a more recent study specific to mast cells and not generic histamine.

Taxifolin inhibited degranulation, generation of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) through blocking intracellular Ca2+ mobilization, phosphorylation of phospholipase Cγ (PLCγ) and mitogen-activated protein kinases (MAPKs), translocation of cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO), and Akt/IKK/NF-κB pathway, in BMMC cells. 

Inhibitory effect of taxifolin on mast cell activation and mast cell-mediated allergic inflammatory response [2019]

An earlier study also point to too narrow a focus with these “no effect” studies

” Dihydroquercetin (taxifolin), previously considered as inactive, showed an interesting cromoglycate-like behaviour. [1985]”

What is this behavior??

“Cromoglicic acid — also referred to as cromolyn, cromoglycate, or cromoglicate — is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of inflammatory chemicals such as histamine from mast cells….The underlying mechanism of action is not fully understood; ” Wikipedia

Bottom Line


This compound seems to act in a different way than antihistamines. It does not require a prescription. In some ways it acts like cromolyn (which some people take for other conditions “in Crohn’s disease … 60% improved clinically”[1978] ). IMHO, it is likely worth trying one bottle of it. A related suggestion is to take Catelase to reduce hydrogen peroxide (and thus lower histamine release).

Comparing Microbiomes around a CFS/ME flare

I recently got this email (with samples uploaded to Microbiome Prescription). I am going to compare these samples to see if I can gain any insight.

Just this morning received the new Thryve results. ***** was in really bad shape when this sample was taken – full crash. For reference he would have been a “5” for the first sample and a “1” or “2” for this one.

First Impressions

The top one was for “5” and bottom for “1”. There was an apparent drop in ‘rare’ bacteria. With “5”, we have 16.3% in the top 16% (i.e. expected) and with “1” we are down to just 5%. This implies some bacteria have become intolerant or bias against others. In the video below, I am going to walk thru my explorations (i.e. playing hide and seek with the cause). The fact that these two samples were taken close to each other means discovery is a lot easier because microbiome drift is greatly reduced.

Do we have genocide happening?

The above leads us to look at natural antibiotics, we see some very dramatic shifts – especially in bacteriocins (a protein produced by bacteria of one strain and active against other strains). As we saw above, the natural “push and shove” between bacteria has been suppressed with lots of bacteria dropping off the radar.

Hydrogen peroxide is another known bacteria killer, it too had a similar increase of amount

By clicking on the numbers, we can see the bacteria responsible — for example, Hydrogen Peroxide, we see that it’s main producer is Lactobacillus where we went from double the upper normal range to triple the upper normal range .

We can do this for the others (see video for a walk thru). The biggest impact at a genus, was Blautia  (from 64%ile to 93%ile)

We see that Lactobacillus is sitting at the 90th %ile with “1” and was at the 86%ile with the “5”. Almost all of the Lactobacillus is Lactobacillus rogosae. Here was have a catch — it is not a lactic acid producer but one of the greatest hydrogen peroxide (H2O2) producer! it was also high in “5” but much less.

Keeping Focus on the recent change and not the long term condition

There was some shifts that were surprising — for example KEGG computed supplements decreased with the “1” sample. Probiotic suggestions were similarly reduced with less weight.

“5” sample“1” Sample
beta-alanine
D-Ribose
Glycine
iron
L-asparagine
L-Cysteine
L-glutamine
L-Lysine
L-Phenylalanine
L-Proline
Molybdenum
NADH
Phytase (Enzyme)
L-Phenylalanine
Molybdenum

Using the Krona Charts, we see the overall shift well. First the “5” sample

Then the “1” sample, notice that the green area took a major decrease.

With the Krona Charts, we can drill down by just double clicking. Below are the drill downs on Clostridia , again “5” first and then “1”. Drilling down allows us to see how the composition of a group changed.

The main item was an increase of Blautia, especially Blautia wexlerae (91%ile to 98%ile) and Blautia faecis (63%ile to 92%ile). Most of the Blautia species increased — resulting in a lot of bacteriocins being produced.

Suggestions

Because Blautia and Lactobacillus appears to be a major players, we hand picked for them:

The suggestions were no lactobacillus probiotics (obvious)

tea0.361
  glycyrrhizic acid (licorice)0.306
  licorice0.306
  saccharin0.278
  salt (sodium chloride)0.278
  cranberry (flour, polyphenols)0.222

I am not too happy with these, because of the dominant item, Lactobacillus rogosae , having no known modifiers, so the items are generic lactobacillus modifiers — which may or may not apply. I went back and just picked the high blautia.

In the suggestions, we have a slight dilemma, lactobacillus rhamnosus (probiotics) was a to avoid (TOP of the list to avoid) but a mixture was a to take.   lactobacillus rhamnosus gg,lactobacillus,rhamnosus,propionibacterium freudenreichii,bifidobacterium breve (probiotics) . The logical conclusion is that propionibacterium freudenreichii is a to take. I happen to recall having taken this as a probiotic, single species or eat lots of  Emmental cheese! This is the product Nutricology, Securil, Propio-Fidus-Based. For Licorice, my usual favorite source is not tea or supplements, but Spezzatina which Cap’t’ Dave Williams introduced me to back in the 2000’s on CfsFmExperimental (originally on egroup). He too (like myself) went into remission.

Modifier To Add or increaseConfidence
  licorice1
  glycyrrhizic acid (licorice)1
  resveratrol (grape seed/polyphenols/red wine)0.56
  lactobacillus rhamnosus gg,lactobacillus,rhamnosus,propionibacterium freudenreichii,bif (probiotics)0.483
  lactobacillus rhamnosus gg,lactobacillus,rhamnosus,propionibacterium freudenreichii,bifidobacterium breve (probiotics)0.483
  triphala0.439
Modifier To Remove or DecreaseConfidence
 lactobacillus rhamnosus (probiotics)0.841
 cocoa0.747
 resistant starch0.72
 bifidobacterium longum bb536 (probiotics)0.561
 barley0.56
 lactobacillus plantarum (probiotics)0.56
 Slippery Elm0.527
 vitamin a0.483
 iron (Note that Iron disappeared with KEGG from “5” to “1”0.483

Lactobacillus rogosae – What do we know?

There is painfully little data on it, just five studies. In fact, it is “not available in any established culture collection; therefore, they cannot be included in any scientific study.” [2004] [2014]

  • It is reduced by going to space 🙂 [2021]
  • It is reduced by Methicillin-resistant Staphylococcus aureus  [2017]
  • “The species most frequently related to vaginal health were Lactobacillus jensenii and Lactobacillus rogosae.” [1992] This actually hints at why other bacteria appeared to be suppressed — it is a strong hydrogen peroxide producer.

Some interesting nodes:

  • “. The hydrogen peroxide-producing colonic bacteria have been also suggested as causative agents of IBD in young adults (107).” and “hydrogen peroxide … are dangerous to mucosal cells, easily penetrating through membranes and causing, depending on their concentration, their apoptosis and necrosis[death]”
    • IBS is often comorbid with CFS/ME

Blautia wexlerae – What do we know

We have more data, some fourteen.

  • High in prediabetics [2020]
  • Increases with body mass index (BMI) [2021]

KEGG Data

“Resistance to hydrogen peroxide is proportional to pyruvate oxidase expression.” [2003] This is Enzyme 1.2.3.3 in KEGG – which we can look up! The count increase from 12%ile in “5” to 29%ile in “1” indicating an increase of bacteria that tolerates hydrogen peroxide. The following appear in the new sample that have this enzyme: Weissella ceti, Aerococcus urinae and a doubling of Staphylococcus haemolyticus.

Unfortunately, KEGG data applies only to those that are fully sequenced, so data is incomplete and often is only for one strain of a species.

Bottom Line

We can see the probable cause, increase of L.Rogosae which may have saturated the gut with hydrogen peroxide killing off or reducing many other bacteria. Hydrogen Peroxide tolerant bacteria grew. I was unable to find any explicit information on B. Wexlerae being hydrogen peroxide tolerant. However we do find B. Wexlerae, and Blautia in general are “catalase-negative, indole-negative and produced acetate and succinate as end products of metabolism” [2008]. Since catalase breaks down hydrogen peroxide — it implies that they may be tolerant (at least not consuming).

I should note that Staphylococcus aureus is heavily implicated with ME/CFS and is also catalase-negative [2010]. Also see early post: Staphylococcus aureus – the CFS maintainer? and A forgotten treatment for fibromyalgia/chronic fatigue syndrome?

The logical way would be to reduce or eliminate L.Rogosae — but we have no information on what effects it which is acceptable (or affordable!). Contrary to general opinion, Hydrogen Peroxide: the body’s best defence system, too much is not desired.

Strategy to reduce the Hydrogen Peroxide

The basic concept is that the environment and other bacteria are symbiotic (a mutually beneficial relationship). If you alter the environment, then the bacteria will change. We want to shift it away from high Hydrogen Peroxide levels and consuming bacteria. We do not know how to alters those identified — but we do know how to break down the Hydrogen Peroxide.

  • Catelase [Wikipedia] breaks down hydrogen peroxide (H2O2) and is available as a supplement. It appears to be the simplest path forward.
    • There have been NO STUDIES of this supplement with ME/CFS. It is a novel approach.
    • It is being investigated for treating IBD [2021]
  • Additional possibilities include: manganese oxide [Src], yeast (contains catelase)[src],  

As a side note: high hydrogen peroxide (H2O2) is associated with loss of hair color. It was during a ME/CFS relapse that I lost most of my color (older brother and both parents retained their hair colors until they were decades older).

Videos

Video walk thru (more details) of this post

Below is the original analysis

and for the walkthru for this post

Fisetin – MCAS and Histamines Update

The site of this post has disappeared (https://www.syndromea.org/2019/07/23/could-fisetin-be-a-new-treatment-for-me-cfs-autism/ ) and a reader asked me to repost it’s content from a saved copy. I have done an earlier post Fisetin – an off the radar flavonoid. At the bottom I am adding some additional notes.

NOTE: Suggested dosage: for 110lb person – 1000mg/day (see Comments)

In my very first post on this site, I reported that I have a remarkable response to high dose biotin. It reduces my ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) symptoms like severe fatigue and the mental confusion that people with ME/CFS call brain fog. It also reduces my autistic symptoms, relieving anxiety and irritability while improving my ability to read people.

A natural substance called fisetin gives me similar but better results and ▪️▪️▪️fisetin’s effects can last for days and possibly weeks for me. On high dose biotin, I relapse badly if I miss a twice daily dose. I have switched from biotin to fisetin because fisetin seems to improve the function of my brain and body for longer periods of time.Fisetin is found in many fruits in vegetables, but is found in the highest quantities in strawberries.

Fisetin helps pull me out of post-exertional malaise. As a mild ME/CFS patient, I could historically expect to get a few days to a couple of weeks of postexertional malaise after mild exercise like moderate digging in my garden. With fisetin, I am able to dig significantly more without a problem and recover more quickly when I overdo it. Things like going on a bike ride around the block will trigger about 2 days of PEM instead of 5 or 7. Not a panacea, but an improvement.Day to day, in the absence of attempting to exercise, I am so much clearer and sharper mentally. My memory and focus is so much better and I feel less physically weak and forgetful.

Like a lot of autistic people and like many people with my connective tissue disorder, Ehlers-Danlos syndrome, I deal with a lot of anxiety. Three capsules of fisetin reduces my anxiety greatly within 24 hours. It’s like meditation in bottle. Fisetin also helps a great deal with the constant low level depression that I have had most of my life, that many people with autism have.A bottle of fisetin will generally tell you to take 1 capsule. I have never had results with less than three capsules and have taken 5 capsules twice daily with good effects. Fisetin has exceptionally low toxicity. Existing fisetin research might shed light on why it works for me.

✅✅Fisetin Inhibits Mast Cell Activation

Like many people with ME/CFS, Ehlers-Danlos Syndrome and autism, I also have mast cell activation syndrome (MCAS), an inflammatory disorder of a certain type of immune cell called a mast cell. MCAS caused the bouts of flushing and I hives I got when I first became ill with ME/CFS.

This 2007 article found that fisetin downregulated mast cell activation in part by suppressing one of the major inflammatory molecules in the body: NF-kappaB. NF-kappaB

NF-KappaB is considered the master regulator of the inflammatory response in the body. Indeed, fisetin has other effects in the body related to suppression of NF-KappaB activation. In animal study published last year, fisetin inhibited airway inflammation and hyperresponsiveness in an animal model of asthma by interfering with NF-KappaB. In another study, fisetin reduced signs of disease in an experimental animal model of inflammatory bowel disease. In a chronic inflammatory disorder such as ME/CFS, it might make sense to try something that broadly downregulates the inflammatory response. Ischemia-Reperfusion InjuryI actually chose fisetin to try specifically because it seems to protect the body and brain against the effects of a type of damage called ischemia-reperfusion (I/R) injury. I/R injury occurs when cells are temporarily deprived of blood and then blood is re-introduced. Cells don’t do well being deprived of oxygen, but serious damage also occurs when the oxygen supply is re-established.

I have been concerned that some version of mild I/R injury in the brain occurs in ME/CFS because we tend to have low blood pressure as well as syncope or light-headedness when standing.

Low blood pressure makes it hard to pump adequate blood to the brain all the time and syncope is a sign that the brain doesn’t have enough blood. A number of studies have found problems with blood flow to the brain in ME/CFS.I am also concerned that changes in the circulatory system in the body produce conditions of periodic blood impairment to cells. Research from the Open Medicine Foundation has found that red blood cells in ME/CFS fail to deform and flow smoothly through small blood vessels, a situation which would cause cells to be periodically denied oxygen. Fisetin has been found to prevent I/R injury in the heart as well as the brain and protect mitochondria from the damaging effects of I/R injury.Fisetin, Leaky Gut & Microglial Activation.

ME/CFS patient have show elevated antibodies to LPS, a component of bacteria that inhabit the gut. When this component ends up in the blood stream in larger than normal quantities, it can potentially trigger sepsis, an often deadly inflammatory response to bacterial infection.While the quantity of LPS in the blood of ME/CFS patients doesn’t reach that of sepsis patients, one of our researchers has suggested that ME/CFS is like a slow, chronic sepsis.

One part of the body that circulating LPS affects is the brain and many of the symptoms of ME/CFS seem to emanate from the brain, in particular flu-like malaise and brain fog. In animals, LPS exposure causes a depression-like response that may be related to the sensations of fatigue, depression and malaise that people feel when exposed experimentally to LPS. Brain inflammation in general causes feeling of fatigue, malaise, pain and depressed and anxious mood, regardless of the trigger. This response is related to the activation of immune cells in the brain called microglia.

  • Fisetin inhibits the microglial inflammatory response to LPS, and reduces the depression-like response to LPS.
  • Fisetin may be able to broadly suppress brain inflammation caused by microglial activation, even if the cause is something other than LPS exposure.

For more about the involvement of brain inflammation and microglial inflammation in ME/CFS, check out Jarred Younger’s work. He is making really interesting progress with imaging brain inflammation in ME/CFS.Children with autism have also been found to have an ongoing neuroinflammatory process involving microglial activation.Fisetin Affects Pathways Connected to Autism☄️☄️mTOR is a molecule frequently implicated in the pathogenesis of autism. It is involved in the development of the brain and the communication between brain cells. ( Taube added : see Dr Alex Vasquez on NAC inhibiting mTOR ) In animal models, cow’s milk allergic animals show autistic symptoms when exposed to cow’s milk and this effect appears to be caused by ☄️☄️☄️increased mTOR signaling in the brain. My food allergies trigger autistic symptoms in me.

Fisetin inhibits mTOR signaling in the brain.

Fisetin also inhibits a molecule implicated in autism called p38 MAPK. p38 MAPK triggers microglial inflammation as well as ☄️high serotonin levels, which are often seen in autism. Glutathione is one of the most important antioxidants in the body. Oxidative stress is high in autism and in ME/CFS while glutathione is low (here and here) in both conditions. Animal studies suggest that fisetin is able to increase glutathione levels in the presence of oxidative stress.

Fisetin also counteracted a neurotoxin called aluminum chloride. Fisetin blocked aluminum chloride’s effects on inflammation and oxidative stress and protected against the neurobehavioral deficits alumnum chloride can cause, in part by restoring glutathione levels.

Fisetin With Mast Cell Stabilizers When I started taking fisetin, I was already on a very helpful mast cell stabilization regimen that includes ketotifen and Benadryl. I don’t know exactly what difference fisetin would have made for me without additional mast cell stabilization, but added to a mast cell stabilization regimen, fisetin is sort of like a wonder treatment for me.

Comment by Jeff A

Additional Notes

N-acetylcysteine and histamine/allergies

In my last post on vagus nerve and IBS, I noticed some of the discussion mention impacts on acetylcysteine. This caused me to wonder about NAC and histamines/allergies/Mast cell issues. I know someone with severe allergies that was advised to take NAC for liver support by her naturopath.

Since the late 1970s N-acetylcystein has been used as an antidote after paracetamol intoxication. The treatment is traditionally given as three consecutive infusions for 20 hours and 15 minutes. The total dose given is 300 mg/kg. Half of this amount is given as a bolus during the first 15 minutes of treatment. This regime has proven very efficient in avoiding liver injury. However, side effects, caused by histamine release, are common (10-15%). 

Simplified N-acetylcystein treatment after paracetamol overdose – new recommendations from Swedish Poisons Information Centre [2019]

Similar citations:

  • “exposure to antihistamines prior to NAC treatment may protect against these [anaphylactoid] reactions.” [2020]
  • ” Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients” [2019]
  • ” Previous studies suggest the incidence and severity of non-allergic anaphylactic reactions (NAARs) are influenced by the rate of acetylcysteine infusion.” [2015]
  • “N-acetylcysteine (NAC) enhances the release of histamine induced by the fluoride-calcium system” [1991]

Histamine now seems to be an important mediator of the response [to NAC], and there is evidence of variability in patient susceptibility, with females, and those with a history of asthma or atopy are particularly susceptible. … The pattern of reactions differs with oral and intravenous dosing, but reported frequency is at least as high with oral as intravenous. The reactions to the intravenous preparation result in similar clinical features to true anaphylaxis, including rash, pruritus, angioedema, bronchospasm, and rarely hypotension, but are caused by nonimmunological mechanisms.

Adverse reactions associated with acetylcysteine [2009]

Bottom Line

If you are female with histamine issues, asthma or allergies — taking NAC will make some of your worst or more sensitive. If your MD or ND have recommended NAC and you have told them about allergies, asthma etc. you should print this off to inform them. It has been known since at least 1991, just 30 years ago.

Vagus nerve stimulation and ME/CFS/IBS

A reader messaged me:

There reports of people improving using VNS recently; came across this.

https://bioelecmed.biomedcentral.com/articles/10.1186/s42234-018-0004-9
How could this affect the good vs bad bacteria in one’s microbiome?

A reader via facebook

 We have recently reported in a 6 month follow-up pilot study that VNS improves active Crohn’s disease. Preliminary data of another pilot study confirm this interest. Similarly, VNS has recently been reported to improve rheumatoid arthritis, another TNFα mediated disease

Is-there a place for vagus nerve stimulation in inflammatory bowel diseases? [2018]

As a starting point, let us look at how the mind impacts the microbiome due to stress. We see a relatively long list of bacteria associated with stress reported on the national library of medicine. The state of the mind impacts the microbiome; also the microbiome impacts the state of mind (depression, sleeplessness etc). Some readings:

The study above is also cited in

Back to a mechanical/chemical approach to the analysis. What do we know change with vagus nerve stimulation. Remember, a change of circulating chemicals will influence bacteria growth.

The central nervous system recognizes peripheral inflammation via afferent vagus nerve signaling. The brain can attenuate peripheral innate immune responses, including pro-inflammatory cytokine production, leukocyte recruitment, and nuclear factor kappa β activation via α7-nicotinic acetylcholine receptor subunit-dependent, T-lymphocyte-dependent, vagus nerve signaling to spleen.

The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis [2012]

Bottom Line

Vagus nerve stimulation alters the chemicals in the body. Studies in mice with electronic stimulation indicate that it can make inflammation worse or better — depending on the parameters. There are a wide variety of methods to stimulate the vagus nerve — a few common ones[src] are:

  • Cold Exposure. …
  • Deep and Slow Breathing. …
  • Singing, Humming, Chanting and Gargling. …
  • Probiotics. …
  • Meditation. …
  • Omega-3 Fatty Acids.
  • Exercise. …
  • Massage.

The use of electronic means should be done with caution because the setting used can have an adverse effect (according to mice studies). This may also apply to exercise with ME/CFS.

While I could not find studies explicate for CFS/ME, I did find some for items often co-mobid with ME/CFS

I have concern over arbitrary vagus stimulation with ME/CFS, especially electronic means. I know too many people that have adverse reaction to exercise, humming, singing etc. In some of these cases, it is possible that the adverse reaction may be connected to a vagus nerve infection.