Category: health care

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Epigenetic changes may also be involved in Covid19 or LongCovid

Epigenetic changes may be involved in Covid19 and LongCovid, which might be able to be changed back with the addition of plenty of methyl donor vitamins. People with methylation genetic alleles would be more at risk for epigenetic changes to DNA or actin protein filaments. Actin are semi flexible proteins in a double helix shape which support the fluid and organelles inside of cells and around cells and organs of our bodies. Actin also is involved in guiding the work of DNA replication and growth and development of cells or infants.

Methylation is the addition of a methyl group – one carbon atom and three hydrogen atoms, to genes, or actin filaments. A methylated gene is not active for encoding proteins while a demethylated gene is available to be transcribed into a messenger mRNA to be made into a matching protein. Actin filaments are a double helix shape like DNA but do other functions throughout our body. Some have methyl groups also that seem to be essential for proper function of the actin protein whether in muscle contraction or in guiding chemicals within cells to make DNA or do other work. Actin filaments add structure to the jelly like fluid around and in cells and may tether chemicals in place for chemical reactions or guide cellular organization during growth and development.

Actin may be involved with energy fields of our body along with microtubules also, but that is not discussed in greater detail in this post (more information about quantum energy fields and actin is included in Cracking Nature’s Code (2019) (1), and in several posts on another site of mine first in the series, 2nd, 3rd, 4th).

Viral infection and epigenetic changes with a focus on Postural Orthostatic Tachycardia Syndrome and possible dietary and lifestyle changes that may help reverse epigenetic changes is the focus of this post – which got long. It is also available as a section of this document that includes the series on Mast Cells and Histamine. Current standard of treatment for patients with POTS symptoms may leave them unwell for years – a few get better more rapidly. I got better on my own within a few months – twice. More about possible strategies for improvement of epigenetic changes will be included later in the post. More about the epigenetics involved in POTS is included in the Genetics/Epigenetics chapter of my book draft which is available on a platform where you can get an e-copy early (minimum price Free, Leanpub/Tipping The Clock Toward Health) and then be informed of updates with an email subscription.

Viral infection can cause Epigenetic changes.

“Bacterial (Pacis et al., 2015, 2) and viral infection (Lichinchi et al., 2016, 3) directly impact methylation patterns, most likely orchestrated by actin since it is universally hi-jacked in viral infectivity (Cudmore et al. 1997, 4; Ohkawa and Volkman, 1999, 5; Lu et al., 2004, 6; Marek et al., 2011, 7).”

page 34, JB Head, PhD, Cracking Nature’s Code (2019) (1)

I found I have methylation gene alleles in a genetic screening (post: Methylation Cycle Defects – in me – genetic screening “for research purposes only”). Since finding out I stopped taking standard supplements of B12 and folic acid because they are not methylated, not bioactive. I take methyl B12 & methyl folate supplements now. Postural Orthostatic Tachycardia Syndrome (POTS) (9) has been a problem for me in past years a couple times and I got better. Symptoms include a rapid heart rate, tachycardia, and feeling faint or blacking out, especially when getting up quickly from a seated or laying down position to standing. (9) I have heard anecdotal reports of it being a symptom for some LongCovid survivors who had never had the problem before.

To slow the rapid heart rate during an episode I found it helpful to stop and sit or lay down with my feet above my heart if possible and just wait a couple minutes for the rapid heart rate to slow again. Continuing to exercise would make the rapid heart rate worse. Preventing the faintness upon rapidly getting up required trying to remember to slow down and have a support ready to hold if I felt wobbly. I did faint once, odd to find yourself on the floor unexpectedly.

POTS has been found to potentially involve a genetic difference in the norepinephrine transporter gene (SLC6A2) sequence and it can also be an epigenetic problem with links to excess formaldehyde. (9) Formaldehyde can donate methyl groups to DNA that normally would be unmethylated – active. (10) Methylation of DNA is a little like a on/off switch for genes, or the cap on bottle – add the methyl groups and the DNA gene is inactive.

“Formaldehyde as a methyl donor for the methylation of DNA, RNA, and histone acts as an epigenetic factor participating in the reversible and dynamic methylation. DNA demethylation elicits formaldehyde generation in the dividing cells and post-mitotic neurons.” (10) Memory formation involves methylation of DNA and cognitive impairment in older adults is associated with increased internal formaldehyde levels (self-made) and demethylation of DNA. Use of nutrients to remove formaldehyde helped improve memory in an animal based study. (10)

Formaldehyde can be prevalent in secondhand or thirdhand smoke in enclosed rooms, or smog, or we make our own during normal metabolism, and physical or emotional stress conditions may cause an increase, as well as the level potentially increasing in older adults. (11) Elevated levels of formaldehyde within cells causes more breakdown of sugar for energy and increased removal of an antioxidant out of the brain cells, which may increase risk for cognitive damage. “As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde‐induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders.” (11)

Formaldehyde is very reactive and can use the methyl group to form links between protein groups or parts that wouldn’t normally be linked – like bungee cords holding parts together in places that would be separate in normal function. (11) Formaldehyde is used with tissue samples to preserve material for viewing under a microscope. Studies of the effect of formaldehyde on the actin protein of live cells that were low on blood sugar found that modifications to the protein did occur – the authors suggest any prior research on the actin protein in formaldehyde treated samples may be inaccurate. (12) Take home point – formaldehyde is not good for our brain cells and may effect the protein of our brain cytoskeleton structure. (12) Protein tangles in brain cells are associated with dementia and autism.

What is a cytoskeleton? We are mostly water, so how do we walk around? With a balance in tension between string like ligaments and muscles and rod like bones of our skeleton. Within the cellular environment, inside and outside the cell membrane – the tent wall, there are rod like microtubules and string like actin protein that is more flexible, it can change shape but isn’t stretchy as much as structurally able to modify in shape. Actin is a double helix, two spirals like DNA except without the ladder like steps joining the two lengths of protein. When force is applied the double helix can get a little longer or shorter as the coils compress or lengthen slightly – tensile strength – and the protein gets stiffer from a side to side direction – torsion – and is less flexible along the length, less able to bend sideways. (13)

The actin protein may act as torsion sensors – is the environment changing in pressure around that section of the protein length – from increased fluid or gas? How full is the balloon like membrane? (14) Channels in a membrane will open and start to leak rather than letting the membrane burst like an overfull balloon. This may seem like a silly discussion – however it is your brain and organs – leaking is better than bursting. Leaking membranes will release fluid and some types of chemicals while a bursting open, as when viral replication is complete and the virus exit a cell, the membrane bursts and all the remaining chemicals in the cell flood into the surrounding cytoskeleton and can cause inflammatory damage to surrounding cells.

These flexible yet firm cytoskeleton actin filaments also may act like guidelines for directing traffic or tethering organelles in place for activity such as replication of DNA during cell division (one cell doubles its DNA and then divides into two cells). Too much of the proteins within a cell nucleus will prevent DNA replication rather than guiding it. (15) Actin is also involved in muscle fiber motion. The double helix structure can also be methylated with methyl groups doing an unknown but critical function. Loss of methylation of actin in one location is associated with cancer and autism spectrum disorders, (16), loss of it in another location along the protein chain is associated with muscle changes that cause female animals to have delivery problems and fewer babies. (17, 18)

So actin is important stringy protein that effects muscle power, cell division, and the brain – and formaldehyde can cause demethylation of DNA, likely it can cause demethylation of actin also which may lead to autism spectrum disorders, cancer, and muscle problems that can affect a healthy delivery of infants (in an animal study). The visual – we want our jelly like insides to have a strong yet flexible tent membrane, tent poles (microtubules), and tie downs (actin) – without having so many tie downs it starts looking like a haunted house full of cobwebs. The amyloid beta protein associated with Alzheimer’s dementia and autism may be protective against a low level infection (post: Magnesium might help protect against beta amyloid placques) but also may increase changes in actin stress fibers (24) and an excess seems to add to chronic inflammatory damage over time.

How do we achieve this? Healthy actin?

It may help promote appropriate methylation of DNA and actin to have adequate antioxidants and methyl donor nutrients in our diet, to reduce oxidative stress chemicals and provide adequate methylation to DNA and actin. Avoiding excessive physical and emotional stress may also be an important strategy, so we aren’t embalming ourselves with self produced formaldehyde (the mummy in the haunted house being our own brain).

We also want to avoid formaldehyde in our environment, which would include improving air quality, especially during sleep hours when our body is focused on detoxification of the brain. Parkinson’s Disease is another chronic condition that may involve epigenetic changes and reducing formaldehyde exposure may be protective. More information is in this post with a link to a longer post about formaldehyde sources: The Cholinergic System

Increasing methyl donor vitamin rich foods and/or supplements should focus on the methylated form if unsure whether there is a genetic allele problem causing lack of methylation.

“Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline.” … “Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders.” … “Hypomethylation has a wide spectrum of effects that include genetic, epigenetic, and metabolic alterations.” (8)

Gastrointestinal problems have been found to be common among patients with Postural Orthostatic Tachycardia Syndrome (POTS) with malfunction or slowing, dysmotility, of the smooth muscle lining of the intestinal tract. “Case study 1: A 20-year-old woman presented to clinic for further evaluation of a several year history of fullness and epigastric discomfort associated with eating and irregular bowel habits. Her weight was stable. She also described frequent migraine headaches, episodic palpitations and lightheadedness with progressively increasing episodes of syncope. A systems review was notable for profound fatigue, dry eyes and mouth and intermittent flushing and pruritus.” (19) The patient’s symptoms include many in common with Mast Cell Activation Syndrome, however testing for mast cell activation was normal. Patients whose symptoms followed a viral infection tend to get better more often than patients with a family history of POTS. (19)  

“A number of chronic conditions are frequently seen in patients with POTS and contribute to symptom burden and reduced quality of life. Common comorbidities include chronic fatigue syndrome, fibromyalgia, interstitial cystitis, and migraine headaches. Other unique conditions that seem to occur with increased frequency in POTS are autoimmunity, the hypermobile form of Ehlers-Danlos syndrome (HM-EDS), and mast cell activation disorder (MCAD).” (19)  

“Unlike mastocytosis, idiopathic mast cell activation [MCAD] occurs in the absence of mast cell proliferation and with episodic accumulation of mast cell mediators in the plasma or urine, usually present when symptomatic. Patients with MCAD typically present with episodic “attacks” of flushing, urticaria and pruritus accompanied by lightheadedness, dizziness, dyspnea, nausea, headache, diarrhea, and/or syncope; symptoms representative of the hyperadrenergic type of POTS with biochemical evidence of MCAD (20).” (19)

The patient in case study 2 had ongoing nausea, vomiting, abdominal pain, and weight loss continuing for years following a viral infection. She was found to have deficiency in iron, zinc, and vitamin B12 and gastroparesis (slow or little intestinal muscle action). Intravenous iron and B12 were provided and an oral zinc supplement. Nutrient levels improved however the GI symptoms and weight loss continued and the patient was given tube feedings which improved weight, however some intolerance to the tube feedings continued and abdominal pain persisted. (19)  

If demethylation of actin protein in the muscle tissue of the intestinal wall was a problem for the patient in case study 2, then it may have been a factor in the gastroparesis. Genetic screening for methylation defects is not mentioned. Supplements of B12 are often an unmethylated form, cyanocobalamin, and which include cyanide. (21) In a study of 12 patients by Huang et al, (22): “Disturbances in GI motility were found to involve not only the stomach, but also multiple segments of the gut spanning the esophagus to the anus.” (19) The commonly used treatments for GI symptoms associated with POTS (see Table 5) do not include nutrients and do include proton pump inhibitors, (19),  a medication that takes the place of magnesium as a calcium channel blocker, and which may lead to worse magnesium deficiency for some people, a genetic difference may be involved. See post: Original Prilosec Warning, edited.

Small intestinal bacterial overgrowth (SIBO) may occur along with GI problems and lead to fat and carbohydrate digestion and absorption problems and bloating from excessive bacterial growth. Changes in diet due to the discomfort are common in patients with POTS and these more severe GI symptoms and which may lead to deficiencies in fat soluble vitamins A, D, E and K. Megaloblastic anemia may result from deficiencies in iron, folate and vitamin B12. (19) Sulfate deficiency may be an underlying factor (23) and providing Epsom salt soaks of the lower legs and feet, or in a bath one to two times a week might help by providing a topically absorbed form of magnesium and sulfate. See post: To have optimal Magnesium needs Protein and Phospholipids too.

Zinc is also involved in DNA methylation and deficiency of the trace mineral can lead to epigenetic changes and gene transcription problems. Zinc is needed along with actin and other proteins to tell the cell nucleus and cell which genes to make into mRNA to be encoded into a protein. “Accumulating evidence has demonstrated that several key enzymes and zinc finger proteins with zinc atom(s) in the reactive center and binding site play important roles in DNA methylation and histone modifications. Therefore, zinc deficiency may disrupt the functions of these enzymes and proteins and result in epigenetic dysregulation. Furthermore, zinc deficiency may enhance inflammatory response and subsequently alter DNA methylation status of the genes involved in inflammation.” (20) Also see posts: Zinc – big news, CoV and other illness related, and Zinc, cancer, and bitter taste receptors.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. JB Head, PhD, Cracking Nature’s Code: The Potential Answer to Everything. (Balboa Press, Bloomington, IN, 2019) https://www.balboapress.com/en/bookstore/bookdetails/792280-cracking-natures-code
  2. Pacis A, Tailleux L, Morin AM, et al., Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res 2015. 25: 1801-1811 https://doi.org/10.1101/gr.192005.115 https://genome.cshlp.org/content/25/12/1801
  3. Lichinchi G, Zhao BS, Wu Y, et al. Dynamics of Human and Viral RNA Methylation during Zika Virus Infection. Cell Host Microbe. 2016;20(5):666-673. doi:10.1016/j.chom.2016.10.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155635/
  4. Cudmore S, Reckmann I, Way M. (1997). Viral manipulations of the actin cytoskeleton. Trends in microbiology. 5. 142-8. 10.1016/S0966-842X(97)01011-1. https://www.researchgate.net/publication/14077627_Viral_manipulations_of_the_actin_cytoskeleton
  5. Ohkawa T, Volkman LE, Nuclear F-Actin Is Required for AcMNPV Nucleocapsid Morphogenesis, Virology, Vol 264, Issue 1, 1999, Pages 1-4, ISSN 0042-6822, https://doi.org/10.1006/viro.1999.0008. https://www.sciencedirect.com/science/article/pii/S0042682299900089
  6. Lu, S., Ge, G. & Qi, Y. Ha-VP39 binding to actin and the influence of F-actin on assembly of progeny virions. Arch Virol149, 2187–2198 (2004). https://doi.org/10.1007/s00705-004-0361-4 https://link.springer.com/article/10.1007/s00705-004-0361-4
  7. Marek M, Merten OW, Galibert L, Vlak JM, van Oers MM. Baculovirus VP80 protein and the F-actin cytoskeleton interact and connect the viral replication factory with the nuclear periphery. J Virol. 2011;85(11):5350-5362. doi:10.1128/JVI.00035-11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094977/
  8. Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5(9):3481-3495. Published 2013 Sep 9. doi:10.3390/nu5093481 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798916/
  9. Richard Bayles, Harikrishnan KN, Elisabeth Lambert, et al., Epigenetic Modification of the Norepinephrine Transporter Gene in Postural Tachycardia Syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:1910–1916 https://doi.org/10.1161/ATVBAHA.111.244343 https://www.ahajournals.org/doi/full/10.1161/atvbaha.111.244343
  10. Su, Tao & He, Rong-Qiao. (2017). Formaldehyde Playing a Role in (De)methylation for Memory. 10.1007/978-94-024-1177-5_3. https://www.researchgate.net/publication/320523716_Formaldehyde_Playing_a_Role_in_Demethylation_for_Memory
  11. Ketki Tulpule Ralf Dringen, Formaldehyde in brain: an overlooked player in neurodegeneration?, J. Neurochem. (2013) 127, 7– 21 https://onlinelibrary.wiley.com/doi/10.1111/jnc.12356
  12. Vasicova P, Rinnerthaler M, Haskova D, et al. Formaldehyde fixation is detrimental to actin cables in glucose-depleted S. cerevisiae cells. Microb Cell. 2016;3(5):206-214. Published 2016 Apr 12. doi:10.15698/mic2016.05.499 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349148/
  13. Effect of tensile force on the mechanical behavior of actin filaments. J Biomechanics (2011), 44(9): 1776-1781, 2011-06-03 , https://repository.kulib.kyoto-u.ac.jp/dspace/handle/2433/152437 https://core.ac.uk/download/pdf/39280196.pdf
  14. Hayakawa K, Tatsumi H, Sokabe M. Actin filaments function as a tension sensor by tension-dependent binding of cofilin to the filament. J Cell Biol. 2011;195(5):721-727. doi:10.1083/jcb.201102039 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257564/
  15. Hu, X., Liu, Z.Z., Chen, X. et al. MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation. Nat Commun10, 1695 (2019). https://doi.org/10.1038/s41467-019-09636-6 https://www.nature.com/articles/s41467-019-09636-6
  16. Seervai RNH, Jangid RK, Karki M, et al., The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Science Advances, 02 OCT 2020 : EABB7854 SETD2 regulates actin dynamics and cell migration via methylation of actin at Lys68 in a cellular complex containing Huntingtin. https://advances.sciencemag.org/content/6/40/eabb7854? “Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Together, these data identify SETD2 as a previously unknown HTT effector regulating methylation and polymerization of actin filaments and provide new avenues for understanding how defects in SETD2 and HTT drive disease via aberrant cytoskeletal methylation.“… “Loss of SETD2 and the H3K36me3 chromatin mark is embryonic lethal in Drosophila (7) and mice (8), and SETD2 defects have been linked to several diseases, including cancer (9–11) and autism spectrum disorder (12–14).”
  17. Wilkinson, A.W., Diep, J., Dai, S. et al. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 565, 372–376 (2019). https://doi.org/10.1038/s41586-018-0821-8, https://www.nature.com/articles/s41586-018-0821-8 lack of the methylation at histidine 73 seems to interfere with muscles and causes the genetically different animals to have fewer babies due to maternal delivery problems. Graphic from the article shows a CH3 methyl group being added to an actin filament at Histidine 73: https://twitter.com/anandb4/status/1073255833813671937?s=20
  18. Kwiatkowski S, Seliga AK, Veiga-da-Cunha M, et al., SETD3 protein is the actin-specific histidine N-methyltransferase. bioRxiv 266882; doi: https://doi.org/10.1101/266882Now published in eLife doi: 10.7554/elife.37921 https://www.biorxiv.org/content/10.1101/266882v1?platform=hootsuite “Finally, Setd3-deficient HAP1 cells were devoid of methylated H73 in β-actin and exhibited phenotypic changes, including a decrease in F-actin content and an increased glycolytic activity. “
  19. DiBaise JK, Lunsford TN, Harris LA, Nutrition Issues in Gastroenterology, Series #187: The POTS (Postural Tachycardia Syndrome) Epidemic: Hydration and Nutrition Issues. June 2019, Practical Gastro, Vol XLIII, Issue 6 https://practicalgastro.com/2019/10/14/the-pots-postural-tachycardia-syndrome-epidemic-hydration-and-nutrition-issues/
  20. Gu H.F., Zhang X. (2017) Zinc Deficiency and Epigenetics. In: Preedy V., Patel V. (eds) Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Cham. https://doi.org/10.1007/978-3-319-40007-5_80-1 https://link.springer.com/referenceworkentry/10.1007%2F978-3-319-40007-5_80-1
  21. Dody Chiropractic, Why Do Vitamin B12 Supplements Contain Cyanide?, dodychiro.com,  https://www.dodychiro.com/why-do-vitamin-b12-supplements-contain-cyanide/
  22. Huang RJ, Chun CL, Friday K, et al. Manometric abnormalities in the postural orthostatic tachycardia syndrome: a case series. Dig Dis Sci 2013;58:3207-3211 https://pubmed.ncbi.nlm.nih.gov/24068608/
  23. Elliot Overton, Sulfate IV: Chronic SIBO/Gut Dysbiosis As A Protective Adaptation To Supply Sulfate. July 21, 2018, Eonutrition.co.uk, https://www.eonutrition.co.uk/post/sulfate-iv-chronic-sibo-gut-dysbiosis-as-a-protective-adaptation-to-supply-sulfate 
  24. Song C, Perides G, Wang D, Liu YF. beta-Amyloid peptide induces formation of actin stress fibers through p38 mitogen-activated protein kinase. J Neurochem. 2002 Nov;83(4):828-36. doi: 10.1046/j.1471-4159.2002.01182.x. PMID: 12421354. https://pubmed.ncbi.nlm.nih.gov/12421354/
  25. Frederic Dorandeu, Guilhem Calas, Gregory Dal Bo, Raafat Fares, Chapter 36 – Models of Chemically-Induced Acute Seizures and Epilepsy: Toxic Compounds and Drugs of Addiction, Editor(s): Asla Pitkänen, Paul S. Buckmaster, Aristea S. Galanopoulou, Solomon L. Moshé, Models of Seizures and Epilepsy (Second Edition),Academic Press, 2017, Pages 529-551, ISBN 9780128040669, https://doi.org/10.1016/B978-0-12-804066-9.00037-7. https://www.sciencedirect.com/science/article/pii/B9780128040669000377 “Alterations of the neuronal cytoskeleton, and more precisely disruption of actin dynamics, seem then to contribute to changes in brain excitability, but the mechanisms leading to these changes remain still unresolved (Spence and Soderling, 2015).” Excerpt viewable in F-actin, ScienceDirect, https://www.sciencedirect.com/topics/neuroscience/f-actin

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Long Covid survivors – may have antibodies against several coronavirus

Cross-immunity to several human coronaviruses has been found in survivors with “LongCovid”, symptoms lasting months after the initial infectious symptoms. (1)

Mast cells can be activated by viruses. (2) People suffering with over activity of mast cells tend to not have very many colds or flu symptoms, even though they may have many other symptoms associated with the excessive inflammation and elevated histamine levels. Polyphenolic flavonoids are known to reduce mast cell inflammation and some have antiviral benefits such as luteolin. (2) Suppressing a mast cell response while trying to actively fight a viral infection would be limiting the body’s natural defense against a virus.

“A recent report correlated coronaviruses infection with activation of mast cells and subsequent cytokine storms in the lungs. 7 Mast cells are known to be triggered by viruses. 8″ Inhibition of mast cell‐associated inflammation could be accomplished with natural molecules, especially the polyphenolic flavonoids. 23 The flavone luteolin (not lutein, which is a carotenoid) has been shown to have broad antiviral properties.24, 25, 26” (2)

In Long Covid there may be residual virus but it is possible, maybe probable, that there is simply an overactivation of the mast cell system continuing to react to any food or toxin or even stress. See previous post.

“Colds and flu often last longer for people with Mast Cell Activation Syndrome or Histamine Intolerance. This is because these viral infections can set off a cascade of mast cell reactions lasting weeks or a few months.” (6)

Mast cell activation may vary based on what each individual is more sensitive to, as well as including some more typical problem foods or chemicals that everyone with overactive mast cells might find problematic. Symptoms can include a broad range and include mental health and behavior changes so diagnostic approaches might miss an inflammatory as the cause. See previous post.

Luteolin is found in celery, thyme, green peppers, and chamomile tea. (3) Some with over activity of mast cells might do better with the celery and thyme. Green peppers may be a mast cell/histamine problem food (4) and chamomile tea is a flower which some people with seasonal allergies (mast cell activation) may react to. See reference G10.12, Nrf2 Promoting Foods, chamomile tea is discussed and may be beneficial for people who are not sensitized to its pollen.

The excess Interleukin-6 that is commonly seen in COVID-19 illness may lead to over active mast cells in people who did not have seasonal allergy or Mast Cell Activation Syndrome symptoms for most of their lives (it can be genetic based). “Constant IL-6 exposure can cause the body to form more reactive mast cells.” (5)

The terminology and diagnostic criteria for mast cell over activity is still new. Some problems may include stimulation of mast cells without complete degranulation – release of histamine and other cytokines (IL-6 is a cytokine – a cell signal chemical). The name ‘Mast Cell Mediator Disorders (MCMD)’ has been established for symptoms involving less severe mast cell activity than full degranulation. (7)

How mast cell activation relates to Long Covid survivors may also vary based on personal genetic and other unknown factors in their environment or body burden of toxins (yes, we tend to contain a large mixture of modern toxins and heavy metals, (8)). Histamine containing or promoting foods could be a factor that varies based on a person’s diet and food sensitivities, in addition to mast cell activity throughout the body. Diet information and links were included in the first post about histamine in this series.

Based on the information about MCAS and histamine foods, I have improved my own odd symptoms and it is a huge relief to have found a cause that can be controlled, with some difficulty, and which explains the odd behavior and mood extremes. Histamine is involved in a wide range of brain functions and is involved in balance, not too much or too little activity – homeostatic control. Anxiety or whirling thoughts that only escalate are frightening and calling it a psychiatric problem wouldn’t help a histamine problem get any better. (Histamine’s function was included in the previous post.)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Rafael Osswald, @RafaelOsswald, Tweet about research findings regarding crossimmunity in LongCovid survivors, Nov. 16, 2020 https://twitter.com/RafaelOsswald/status/1328408081487835152?s=20
  2. Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors. 2020;46(3):306-308. doi:10.1002/biof.1633 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267424/
  3. USDA/Agricultural Research Service. “Luteolin stars in study of healthful plant compounds.” ScienceDaily. ScienceDaily, 16 July 2010. https://www.sciencedaily.com/releases/2010/07/100708141622.htm
  4. Hidden in Plain Sight: Histamine Problems, westonaprice.org, https://www.westonaprice.org/health-topics/modern-diseases/hidden-in-plain-sight-histamine-problems/
  5. Mast cells: MCAS, genetics, and solutions, geneticlifehacks.com, https://www.geneticlifehacks.com/mast-cells/ https://www.geneticlifehacks.com/mast-cells/#Other_substances_that_activate_mast_cells
  6. Immune Supports and Supplements that May Reduce Risk of Cold or Flu in Mast Cell Activation Syndrome and Histamine Intolerance. mastcell360.com, https://mastcell360.com/immune-supports-and-supplements-that-may-reduce-risk-of-cold-or-flu-in-mast-cell-activation-syndrome-and-histamine-intolerance/
  7. Theoharides TC, Tsilioni I, Ren H. Recent advances in our understanding of mast cell activation – or should it be mast cell mediator disorders?. Expert Rev Clin Immunol. 2019;15(6):639-656. doi:10.1080/1744666X.2019.1596800 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003574/
  8. Gennings C, Ellis R, Ritter JK. Linking empirical estimates of body burden of environmental chemicals and wellness using NHANES data. Environ Int. 2012;39(1):56-65. doi:10.1016/j.envint.2011.09.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249606/
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Glyphosate increases histamine, both may be a factor in COVID19

Recent posts include a long one on glyphosate, biofuel, and liver disease and how it may be increasing inflammation in severe COVID19; and two other posts (a, b) are about how an immune allergy type reaction increases histamine and a variety of symptoms, and which may be a factor in LongCovid. Foods and the health of our intestinal microbiome, bacteria and other microbes, can also increase histamine directly or indirectly. Some foods contain histamine and others cause more histamine to be produced. Glyphosate residue may also cause an increase in histamine. (1)

Genetics may be a factor in who is more at risk for having excess histamine. There is an enzyme needed to break down the excess histamine from foods, within the intestinal tract, which some people may not be able to make. It can be purchased as a supplement and taken with meals. Other people may have overactive mast cells which are the type of immune cell that produces histamine throughout the body. (1 , 2)

If the mast cells are overactive, MCAS – Mast Cell Activation Syndrome, symptoms may be more severe than a seasonal allergy type of histamine reaction and may include: “rashes, hives, itching, flushing, fainting, headache, abdominal pain, nausea, vomiting, gastroesophageal reflux disease (GERD), fatigue, chronic pain, trouble breathing and many more.” (2) To complicate trying to figure out if this is a problem for oneself or a patient the overactivity of mast cells may also be associated with other complex conditions that have varied symptoms too, including: “allergies, autism, autoimmune disorders, cancer, diabetes, Ehler-Danlos syndrome, postural orthostatic tachycardia syndrome (POTS), fibromyalgia, Lyme disease, mastocytosis, migraines and obesity.” (2) Add the various symptoms together and a person might have a confusing mixture of “twenty to thirty symptoms” and feel “extremely ill.” (2)

Lab tests frequently are not helpful for many of the conditions or MCAS and it may also be unclear whether a person is having histamine symptoms because of intestinal digestion or microbiome problems or due to overactive mast cells throughout the body. Severity of symptoms may be worse if the problem is related to mast cell activation throughout the body. Treatment approach would also be different. Some people might be helped by use of the digestive histamine enzyme while others wouldn’t need it. Both types, digestive histamine excess and mast cell over activity, would be helped by decreasing histamine containing foods or ones that increase release of histamine from mast cells. Eliminating all histamine from the diet would be impractical if not impossible. Reducing the amount might make a significant difference though in reducing the negative symptoms. More details about identifying the type of problem with lab tests or other clinical indicators and an elimination diet description are available here: westonaprice.org. (2)

Glyphosate as a stimulator of histamine release (1) would create a different list of foods to avoid. See the previous post “a long one on glyphosate,” the list of tips are summarized at the top of the post, so the full length can be skipped if desired.

Over active mast cells may involve cannabinoid deficiency. Mast cells have both Cannabinoid Receptor Type 1 and Type 2 on the cell surface and when activated they cause an inhibition of the mast cell.

“Mast cells contain CB1 and CB2 receptors, which when activated inhibit mast cell release (R). Research shows that cannabinoids can suppress mast cell degranulation. … Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. ” (3, 4)

“We have previously shown that exposure of mast cells to cannabinoids that bind to both CB1 and CB2 cause a net suppression in the proinflammatory responses.” […] “At short time points, ligation of either CB1 or CB2 leads to a suppression of cAMP levels. However, over a longer exposure time course, the cAMP responses that follow ligation of the two receptors are diametrically opposed. These results allow us to draw two conclusions. First, the results imply that CB1 and CB2 receptors are not redundant when co-expressed in mast cells. Secondly, the results suggest that the two receptors couple to distinct signalling pathways that diverge downstream of the Gαi/o proteins to which they are both coupled.” (4) – that may suggest that a short time, small amount of THC & CBD may not help suppress the mast cells, by increasing cAMP sufficiently, a longer exposure, larger dose is needed – and that both the CB1 and CB2 receptor types need to be activated for the suppression of mast cell. CBD activates CB2 receptors and THC activates CB1 receptors.

“CBD alone without THC maybe ineffective at treating dysfunctional mast cells because THC has a strong binding affinity for both CB1 and CB2 receptors, cannabidiol (CBD) has no particular binding affinity. Instead, many of the therapeutic benefits of CBD are created through indirect actions.” (3)

Edibles or smoke? “However, when it comes to MCAS patients who are more severe, they tend to not tolerate ingesting the Medical Cannabis oil or edibles but may can inhale the actual Organic Medical Cannabis Flower and find great relief from MCAS symptoms.” (3)

More information about mast cells and what they do is included in Mast Cells: MCAS, genetics and solutions. geneticlifehacks.com (1) Viruses can activate mast cells, which then release histamine and other inflammatory cytokines and chemicals. The immune mast cells are also called granulocytes because when activated they release little packets, granules, full of the inflammatory chemicals. Flu virus has been found to activate mast cells and mast cell inhibitors helped reduce lung damage and mortality in severe cases of influenza. Too much inhibition during an active infection might not be helpful though, because the goal is to kill the virus infected cells or other pathogens that can activate mast cells. (1)

What does histamine do?

“Brain histamine promotes wakefulness and orchestrates disparate behaviors and homeostatic functions.” […] “Dysfunctions of the histaminergic system may also contribute to the pathogenesis of multiple sclerosis and its murine model of experimental autoimmune encephalomyelitis,” […] “Histamine neurons send broad projections within the CNS that are organized in functionally distinct circuits impinging on different brain regions.” (5)

Histamine promotes wakefulness, so an excess may lead to insomnia problems, and it affects a lot of varied behaviors and balance of functions throughout the body, disparate – a wide range of behaviors, which suggests why there can be such a wide range of symptoms, and homeostatic – balance of body functions – no longer as able to stay at an even center, too tired, or too excited, too cold or too flushed, numbness or pain – roughly. Too itchy too often.

“Histamine itch and non-histamine itch are mainly mediated by TrpV1 and TrpA1 respectively. In addition, Trp channels can be coupled to cytokine receptors, toll like receptors or may even be directly activated by pruritogens.” (6)

Inflammatory bowel disease (IBD) can involve overactive mast cells and excess histamine activating Trp channels in the intestines, (1), leading to sudden diarrhea and/or pain. “Pruritigens” refers to other chemicals that directly activate Trp channels such as horseradish or Latex that cause itching, (pruritus). Others may cause the bowel symptoms of IBD including cinnamaldehyde from cinnamon, capsaicin from hot pepper, curcumin in turmeric, and other chemicals in spices or herbs like ginger, cloves, and mint. Previous post 1, post 2/webpage G3.5-3.6.2, G5.

Yes, it is not easy to figure out what you can eat if you have Mast Cell Activation Syndrome, or to safely use as skin care products or medications as some of the ingredients might be Trp channel activators.

Medications that may help reduce mast cell activation in the condition of Irritable Bowel Syndrome, similar to Inflammatory bowel disease but less severe, include mast cell stabilizers and “a medication to reduce prostaglandin E2 synthesis (e.g. a COX2 inhibitor) stopped the hypersensitivity in the animal model of IBS. [ref]” (1) Pomegranate peel extract and other antioxidants may act in part through COX2 inhibition. (previous post) Prep tips for pomegranate & the peel: G13.

Mast cell activation may also be involved in autoimmune diseases including Multiple sclerosis, Type 1 Diabetes, and Rheumatoid arthritis. (1) The excessive release of cytokines and inflammatory chemicals can lead to cell damage in surrounding tissue. Mast cells tend to be located within specific tissue areas of the body or along epithelial layers (skin and membrane linings of blood vessels or other tissue), rather than be free moving like some other types of immune white blood cells. (1) Some people may have overactivity in some areas of the body rather than throughout the entire body.

Regarding COVID19 illness, the cytokine interleukin 6 (IL-6) tends to be present in excess, (8), and it is a mast cell activator. (1) Vitamin C can help inhibit IL-6. (7)

Psychological stress causes mast cells to release their histamine and other chemicals – uh oh, time to think serenely about that. (1)

Tips to worry less – can you do anything about them? If no, try to let them go. Writing worries on notes and putting them in a worry jar is one idea – you did something about it. You can look through your worries later. If yes, plan your time – 1. write down your goals, long term – 5-10 years, mid length, this year, and short term, this day/week/month, and 2. make an action plan, what steps to take today, write a list. 3. Do your plan, cross off your list items. It can feel more organized and good to check off your short term goals, and more peaceful to have a plan. (9)

Regarding the complexity of Mast Cell Activation Syndrome, or histamine from food – writing down your symptoms and daily food, beverages, and other lifestyle issues that standout from your routine can help to start seeing a pattern of which foods or habits might be adding to the problem. Elimination diets are quiet simple to start and need to be followed for a couple weeks to get the body cleared out of the potential problem foods and hopefully start feeling better, whether itchy, headaches, fatigue, brain-fog, or pain, numbness, or other symptoms. Then add only one thing back and see if symptoms return. Symptoms may be fairly immediate, or the next day or two so gradual reintroduction will be easiest to track whether it seems to cause symptoms.

Lab tests and other help and medication may be nice too, if available, but an elimination diet can be done fairly easily and safely. Stick to a variety of foods from the different food groups and read bottles on any supplements or medications to check for ingredients that might also be trigger substances ‘starch’ is usually wheat or corn based unless specifically labeled like tapioca or arrowroot starch. Other post (a) includes links with a food diary and information about elimination diets for histamine issues. Not all people have exactly the same sensitivities and there can be an additive effect, many problem foods on the same day as stress – may become a flare up. Some of the lists vary and some are more restricted than others, but most have similarities in the worst risk foods. Starting with eliminating some of those and seeing if you start feeling better can also be a way to work towards learning what are problem foods for you personally.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Mast cells: MCAS, genetics, and solutions, geneticlifehacks.com, https://www.geneticlifehacks.com/mast-cells/
  2. Hidden in Plain Sight: Histamine Problems, westonaprice.org, https://www.westonaprice.org/health-topics/modern-diseases/hidden-in-plain-sight-histamine-problems/
  3. Www.TickedOffMastCell.Org, Medical Cannabis: Mast Cell Activation Syndrome, 10/24/2019, ibcnj.com https://ibcnj.com/medical-cannabis-mast-cell-activation-syndrome/
  4. Small-Howard AL, Shimoda LMN, Adra CN and Turner H, Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells. Biochem. J. (2005) 388, 465–473 https://anandaenterprises.com.au/wp-content/uploads/2019/12/Anti-inflammatory-Potential-of-CB1-mediated-CAMP-Elevation-in-Mast-Cells.pdf.pdf
  5. Passani MB, Panula P, Lin JS. Histamine in the brain. Front Syst Neurosci. 2014;8:64. Published 2014 Apr 28. doi:10.3389/fnsys.2014.00064 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009418/
  6. Sun S, Dong X. Trp channels and itch. Semin Immunopathol. 2016;38(3):293-307. doi:10.1007/s00281-015-0530-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798920/
  7. Härtel C, Puzik A, Göpel W, Temming P, Bucsky P, Schultz C: Immunomodulatory Effect of Vitamin C on Intracytoplasmic Cytokine Production in Neonatal Cord Blood Cells. Neonatology 2007;91:54-60. doi: 10.1159/000096972 https://www.karger.com/Article/Abstract/96972#
  8. Grifoni E, Valoriani A, Cei F, et al. Interleukin-6 as prognosticator in patients with COVID-19. J Infect. 2020;81(3):452-482. doi:10.1016/j.jinf.2020.06.008 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278637/
  9. Gerry McCann, How to Manage Your Time Worry Less and Discover more Happiness, youtube.com, https://youtu.be/RgBb4xNrM-s
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Histamine excess – self help through diet.

Some foods may be particularly beneficial for helping people who tend to have too much histamine. Personal strategies from a non-medical sufferer are available here: Shutting Down Histamine Reactions (Quickly) healinghistamine.com.

Foods or herbs suggested include: Apple, Fennel, Watercress, Parsley, Broccoli, Cauliflower, Ginger, Thyme, Rosemary, Turmeric, and the phytonutrient quercetin. healinghistamine.com. Without looking for further reference links – that list does include many foods and herbs that I have found helpful over the years and currently. Fennel is available as a vegetable, celery like, and also as crunchy seeds.

Having learned of the link between foods and histamine levels while writing the last post, it has helped to avoid the foods that are mentioned, or reduce them. A bad reaction for me, can be very odd behavior and anxiety. Histamine excess symptoms of congestion and seasonal pollen allergies have been a long term problem for me and many of the foods recommended to avoid I had already learned to avoid, but others I wasn’t aware of the connection.

Bad mood changes are later in the day or the next day or two, so making a connection between a food and a symptom can be difficult. It can be simpler to keep a basic meal pattern and only change one thing at a time, so it is easier to recognize a link between symptoms the next day and a new food.

Health is worth some work.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Yasmina, Shutting Down Histamine Reactions (Quickly), healinghistamine.com, https://healinghistamine.com/shutting-down-histamine-reactions-quickly/