A reader ask me to do a post on the COVID vaccines and people with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis. The risk of death is a significant factor in making a personal decision. This is different than most vaccinations; we need to look afresh at this decision and not run off pro forma decisions for things like measles or extremely low risk-of-infection diseases (polio)

• Measles risk of death 2 in 10,000 or 0.02%
• For flu: [cdc]
  • 18-49: 0.02%
  • 50-64: 0.05%
  • 65+: 0.85%

There are possible side-effects, which appear to be transitory for typical people.

 A review of unblinded reactogenicity data from the final analysis which consisted of a randomized subset of at least 8,000 participants 18 years and older in the phase 2/3 study demonstrates that the vaccine was well tolerated, with most solicited adverse events resolving shortly after vaccination. The only Grade 3 (severe) solicited adverse events greater than or equal to 2% in frequency after the first or second dose was fatigue at 3.8% and headache at 2.0% following dose 2. Consistent with earlier shared results, older adults tended to report fewer and milder solicited adverse events following vaccination

PFIZER AND BIONTECH CONCLUDE PHASE 3 STUDY OF COVID-19 VACCINE CANDIDATE, MEETING ALL PRIMARY EFFICACY ENDPOINTS 18 Nov, 2020

I did a prior post on POTS as a consequence of vaccination. Fortunately, that is moot since most people with ME/CFS already have POTS! It is important to note that positive benefit can happen with some vaccines: Effects of  vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome.[1998] that “Fifty percent [of ME/CFS] were rehabilitated successfully and resumed half-time or full-time work.”

There is concern on aluminum in vaccines and ME/CFS as documented in this 2016 post. With subsequest studies

• Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system [2019]
  ” Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity.”
• Aluminum in vaccines: Does it create a safety problem? [2018] “The only problem that deserves attention is the suggested relationship between Al oxyhydroxide-containing vaccines and macrophagic myofaciitis or myalgic encephalomyelitis/chronic fatigue syndrome. Currently, definitive conclusions cannot be drawn on these risks and further studies must be conducted. Until then, Al remains the best solution to improve vaccine efficacy.”
• Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease[2016] Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction.

More Recent Studies

• Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination? [2019] which states “Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.”
  • Like POTS, FM already has this side-effect.

Which Vaccine has Aluminum?

For people in the US, we have a list of all vaccines and their ingredients here. You will see Human Papillomavirus (HPV) (Gardasil 9) cite above, contains amorphous aluminum hydroxyphosphate sulfate.

• Prolonged exposure to low levels of aluminum leads to changes associated with brain aging and neurodegeneration [2014]
• Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer’s disease and age-related neurodegeneration [2015]
• Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production [2012]

Bottom Line

The key issue is whether there is aluminum in the vaccine. If there is, it may worsen existing symptoms (especially neurological issues). The bad news is that appears that the current COVID-19 vaccines some contains aluminum (alum) and others do not.

• COVID-19 vaccines: neutralizing antibodies and the alum advantage [2020]
• …Sinovac – PROFISCOV [2020] does contain it.
• Pfizer’s covid-19 does not appear to contain it.
• Moderna vaccine does not appear to contain it either.

So the traditional and documented issue with vaccines (the aluminum in it) does not apply to two of the Covid vaccines. This implies that for FM, CFS/ME, there is not a supportable evidence-based reason to decline it.

For all ages, the risk of death is significantly higher than for the flu: [see cdc numbers above]

• 18-49: 0.02% vs 0.1 to 0.4% i.e. 20x greater risk
• 50-64: 0.05% vs 0.5 to 3.6% i.e. 72x greater risk
• 65+: 0.85% vs 6.3% to 20%, i.e. 24x greater risk

The side effect risks are low and appear to be transient. “Long Covid” – the name given to a CFS-like syndrome after a COVID infection is likely to make any existing ME/CFS or FM much worst. This is estimated that 10% of people are prone. The probable model is that long covid has resulted in a stable gut bacteria dysfunction (for a similar documented-over-several-years similar scenario see this post)

One study of people hospitalized with COVID-19 in Italy found that 87.4% reported experiencing at least one symptom, often fatigue or shortness of breath, 2 months after discharge. Among people with milder infections, however, the prevalence of long COVID has been unclear. Data from the COVID Symptom Study app suggest that 1 in 10 people with the illness experience symptoms for 3 weeks or more

COVID-19 Symptoms: Longitudinal Evolution and Persistence in Outpatient Setting [2020]

Get the vaccine — there is no evidence-based reason not to (especially if there is no aluminum in it). Not taking the vaccine means significant risk of death and likely more severe CFS/ME or FM.

Post Script – I had COVID… Should I get the vaccine?

Answer is a simple yes. Protection with the vaccine is expected to last longer… Think of it as a booster shot!

Recently I have seen a lot of difference of opinions on social media on these issues. There are several blogger who write on this, for example:

• Alison Vickery
• Healing Histamine
• The Histamine Friendly Kitchen
• Which foods are high in histamine?

I was well trained at University to always work from primary sources (hence the joys of learning at least some greek, latin, french, german, danish for history courses). Bloggers are secondary and often tertiary sources – with the risk of reading more into stuff then there may actually be, or spinning the data to gain readers.

On the flip side, some of their advice comes from experience. The unfortunate aspect of experience is that there is no control for placebo effects, or anti-placebo effects, or effects due to other factors with the person.

You may also wish to read DAO and Probiotics, a prior post

To me, the primary sources are two grades:

• Individual specific studies (which suffer from a variety of bias risks)
• Review Articles (unlike bloggers, these are peer reviewed)

Wikipedia lists the following as Mast Cell Stabilizers, most are prescription drugs

• β2-adrenergic agonists
• Cromoglicic acid
• Ketotifen
• Loratadine
• Desloratadine
• Methylxanthines^{[citation needed]}
• Olopatadine
• Rupatadine
• Mepolizumab
• Omalizumab
• Pemirolast
• Quercetin Plant Flavonol (see below)
• Nedocromil
• Azelastine
• Tranilast
• Palmitoylethanolamide
• Vitamin D^[3]

The drug bank list of Histamine H1 Antagonists, Non-Sedating provides a similar link with the KEGG providing nice diagrams here, with the following enzymes:

07216 Catecholamine transferase inhibitors

07219 Cyclooxygenase inhibitors

07024 HMG-CoA reductase inhibitors

07217 Renin-angiotensin system inhibitors

07218 HIV protease inhibitors

• “Aspirin enhanced histamine release from basophils via increased Syk kinase activation” [2013]

 There is no evidence to suggest that sensitization against drugs occurs more frequently among patients with presumed histamine intolerance compared to patients with normal tolerance to histamine. However, preclinical data suggest interactions between some drugs and histamine catabolism. Nevertheless, the clinical relevance of these findings remains unclear as histamine in humans can be catabolized by different pathways[Editor: DAO and HNMT]. There are no drugs for which induction or worsening of histamine intolerance has been established clinically.

Drug hypersensitivity in patients with presumed histamine intolerance and mast cell activation disease [2019]

In terms of citizen science, we find some strong statistical associations for some bacteria shifts

The Review

Mast Cell Stabilizers

• Twenty-first century mast cell stabilizers [2013] See Table 1 “Naturally occurring mast cell stabilizers”
  • I have a page that links to what contain various flavonoids here, with the amount (and mast cell stabilizers labelled)
    • Often people work off “contains” only, ignoring the amount, for example
      • Apigenin: Kumquats has 21 mg/gram and mangos 0.01 mg/gram — a 2000x difference!
  • Example: Apigenin
• PubMed reports nothing for probiotics that have this effect. Nor for bifidobacterium, nor lactobacillus
  • For Bacillus, we find evidence of histamine release [1975], exactly the wrong response

DAO Response

There are chemicals/vitamins that DAO and  Histamine N-methyltransferase (HNMT) ( the key natural histamine removers) need to act upon histamines. These include:

• “Vitamin B6 is a collective term for all 3-hydroxy-2-methylpyridines which act as vitamins. Vitamin B6 substances like pyridoxine, pyridoxal, pyridoxamine, and their phosphorylated metabolites are all equally effective. Pyridoxal-5-phosphate and pyridoxamine-5-phosphate fulfill the functions of a coenzyme in the organism [for activation of DAO].” [2014]
  • Effect of pyridoxine on histamine liberation and degranulation of rat mast cells [1979]
• Impact of oral vitamin C on histamine levels and seasickness [2014]
  Note: “Histamine (p < 0.01) and DAO levels were increased after the intake of vitamin C (p < 0.001)”
  • The p values suggests that DAO increased significantly more than histamine.
  • This may be the source of QAnon belief that citric fruits/vitamin C is bad.
• “A cross-over study in former East-Germany on patients who had infection-related asthma found that 5 g/day vitamin C decreased the proportion of participants who had bronchial hypersensitivity to histamine by 52 percentage points (95% CI: 25 to 71).” [2013]
• “copper …. did significantly increase two enzyme activities (SOD and DAO)” [1997]
• “diamine oxidase (DAO) activity were both increased (linear, p = 0.0004, 0.001, respectively) with Defatted Rice Bran…” [2019]

Negative Impacts

Caution: DAO production seems to increase with gut permeability issues (GPI). Thus something that improves GPI may not actually decrease DAO production, the change of DAO may be a side effect.

• “selenium-enriched yeast …significantly decreased the serum concentrations of diamine oxidase (DAO)” [2020] – unclear if the yeast or the selenium was the primary cause.
• “Tannic acid … reduced diamine oxidase (DAO) activity”  [2020] ( Tea, coffee, wine, chocolate)
• ” Antimalarial drugs that inhibit histamine N-methyltransferase also inhibit putrescine catabolism in vivo and DAO activity in vitro” [1981]
• “putrescine supplement…. increase in putrescine at 1 h and in diamine oxidase (EC 1.4.3.6) activity within 3-6 h” [1986]
  • “putrescine is found in virtually all foods of plant origin, and is particularly abundant in fruits and vegetables, notably citrus fruits (1,554 nmol/g) and green peppers (794 nmol/g) (9, 61). There are also high amounts of putrescine in wheat germ (705 nmol/g) and soybean sprouts (507 nmol/g) (37, 70).” [2019]

Histamine Production

Many probiotics produce histamines, for a list see our commercial probiotic list. For many probiotics, we could not find PubMed studies. Lactobacillus buchneri has been implicated in histamine-poisoning[1991].

Foods

Fermented foods are usually uncertain for which bacteria are fermenting it. As we see above, many produce histamine. Studies of commercial Kefir have found that the listed bacteria and the actual are usually in disagreement. Bottom line: no fermented food. This includes sauerkraut, soy, miso, red wine and salami[2020] [1991] .This usually extends into no left-overs, most items left in the fridge (or out) indefinitely– get covered in furry green/black coats. This extends to many cheeses [2020][1995], with Feta Cheese being a possible exception [2020]. For cheese, the same cheese name (like Stilton and Camembert cited below), from one producer may be fine and from another bad — the difference is which strains (not species) of bacteria was used. This also applies to yogurts. For “wild Culture cheeses” it is Russian Roulette for histamines.

Very fresh fish can be safe, but they are prone to producing histamine quickly once skinned [2020].

This also applies to items like nuts and beans that are not fresh.

“Citrus fruits are high in histamines” [Internet Legend?] – alas, I could not find any usable studies. I did find this

In this study, aqueous extracts of peels of best known citrus fruits namely grapefruit (Citrus paradisi), lemon (C. limon), lime (C. aurantifolia) and orange (C. sinensis) were used. Depending on polyphenols content, the extracts were graded as orange > lemon > lime > grapefruit. Effects of the extracts on the release of histamine from rat peritoneal exudate cells (PECs) was measured to know anti-allergic activity. All extracts inhibited the release of histamine from rat PECs induced by the calcium ionophore A23187

Anti-histamine release and anti-inflammatory activities of aqueous extracts of citrus fruits peels [2013]

• “Nasal spray from lemon and quince (LQNS) is used to treat hay fever symptoms and has been shown to inhibit histamine release from mast cells ” [2016]

Other Histamine Producing Foods

In researching another possible internet myth, pineapples and banana. I found a summary of a study which could easily be misread to imply histamine issues. After some effort, I found the full text of the article and shows the results of their lab tests below. The summary stated “Histamine, tyramine, noradrenaline, serotonin and other pressor amines occur in fruits and fermented foods such as bananas, pineapples, cheese and wine. ” It does not state that each is found in every fruit and fermented food

Grasping for straws?

“Abnormal association between mast cells and nerve fibers, and increased release of tryptase and histamine have also been described in IBS patients [7],” [2017] has led to the not-demonstrated belief that what improves IBS also improves histamine. i.e. Beneficial effects of Saccharomyces boulardii CNCM I-745 on clinical disorders associated with intestinal barrier disruption [2019]

Highest Mast Stabilizer Foods

As mentioned above, we should not ignore the amount, fortunately the database behind Microbiome Prescription, allows us to compute across all natural mast cell stabilizers and get concrete numbers.

By amount of Mast Cell Stabilizers

Food	mg/gram
Spices, parsley, dried	4523.25
Spices, celery seed	841.05
Capers, canned	303.89
Spices, saffron	205.48
Dill weed, fresh	68.48
Thyme, fresh	47.75
Elderberries, raw	27.35
Kumquats, raw	21.87
Peppermint, fresh	18.05
Cranberries, raw	16.15
Cranberries, dried, sweetened	12.83
Blueberries, cultivated (highbush), raw	9.53
Blueberries, frozen, unsweetened	7.55
Cranberry sauce, whole, canned, OCEAN SPRAY	6.51
Pitanga, (surinam-cherry), raw	6.2
Acerola, (west indian cherry), raw	5.79
Figs, raw	5.47
Currants, european black, raw	5.16
Raisins, golden seedless	5.11
Prickly pears, raw	5.04
Apples, raw, with skin	4.27
Apples, Red Delicious, raw. with skin	3.87
Blackberries, raw	3.85
Apples, Gala, raw, with skin	3.8
Apples, Golden Delicious, raw, with skin	3.69
Spices, marjoram, dried	3.5
Lemons, raw, without peel	3.07
Olives, ripe, canned (small-extra large) – May be high in histamine [2000]	2.8
Rosemary, fresh	2.55
Apples, Granny Smith, raw, with skin	2.54
Cherries, sweet, raw	2.53
Mulberries, raw	2.47
Cranberry sauce, canned, sweetened	2.44
Apples, Fuji, raw, with skin	2.36
Apricots, raw	2.26
Gooseberries, raw	2.11
Applesauce, canned, unsweetened, without added ascorbic acid (includes USDA commodity)	2
Juice, lemon, canned or bottled	1.83
Plums, dried (prunes), uncooked	1.82
Kiwifruit, green, raw	1.81
Cherries, sour, red, raw	1.71
Strawberries, raw	1.61
Raspberries, raw	1.48
Jujube, raw	1.26
Raspberries, frozen, red, unsweetened	1.14
Juice, pomegranate, bottled	1.11
Apples, raw, without skin	1.07
Strawberries, frozen, unsweetened	0.98
Grapefruit, raw, pink and red, all areas	0.94
Dates, deglet noor	0.93
Sauce, pasta, spaghetti/marinara, ready-to-serve	0.92
Watermelon, raw	0.91
Oranges, raw, navels	0.91
Plums, raw	0.9
Peaches, raw	0.88
Pears, raw	0.84
Oranges, raw, all commercial varieties	0.77
Juice, grape, canned or bottled, unsweetened, without added ascorbic acid	0.75
Melons, cantaloupe, raw	0.72
Nectarines, raw	0.69
Juice, apple, canned or bottled, unsweetened, without added ascorbic acid	0.58
Olives, pickled, canned or bottled, green May be high in histamine [2000]	0.56
Juice, lime, raw	0.51

By Number of different Mast Cell Stablizers

Different flavonoids may have different responses, hence the most varied should also be considered.

Food	Flavonoids Counts
Raspberries, raw	6
Strawberries, frozen, unsweetened	3
Oranges, raw, all commercial varieties	3
Apples, raw, with skin	3
Blueberries, cultivated (highbush), raw	3
Blueberries, frozen, unsweetened	3
Cranberries, raw	3
Kiwifruit, green, raw	3
Lemons, raw, without peel	3
Mangos, raw	2
Melons, cantaloupe, raw	2
Oil, olive, salad or cooking	2
Cranberry sauce, canned, sweetened	2
Currants, european black, raw	2
Dill weed, fresh	2
Elderberries, raw	2
Gooseberries, raw	2
Grapefruit, raw, pink and red, all areas	2
Capers, canned	2
Cherries, sour, red, frozen, unsweetened	2
Cherries, sour, red, raw	2
Cherries, sweet, raw	2
Cranberries, dried, sweetened	2
Apricots, raw	2
Bananas, raw	2
Blackberries, raw	2
Oranges, raw, navels	2
Peaches, raw	2
Peppermint, fresh	2
Pitanga, (surinam-cherry), raw	2
Prickly pears, raw	2
Raisins, golden seedless (because of age, histamine risk)	2
Raspberries, frozen, red, unsweetened	2
Strawberries, raw	2
Thyme, fresh	2
Watermelon, raw	2
Rosemary, fresh	2
Spices, celery seed	2
Spices, parsley, dried	2
Acerola, (west indian cherry), raw	2

Bottom Line

I will gladly take comments citing gold standard sources (PubMed with full test), please do not add comments about so-and-so saying something is bad. I dislike QAnon medicine.

The above should give a framework for diet and cooking, as points

• Use items high in mast cell stabilizers
• No fermented foods or left overs
• No ‘old raw’ ingredients (i.e. nuts, beans, etc) – unfortunately, most of these do not have “Picked dates” on them. Bad storage (i.e. high humidity, temperature) is also a factor.
  • Dried fruit/vegetables have significant histamine risk
  • Canned food is unclear, but there are cases of problems from some manufacturers[2010].
• Fresh frozen is usually fine. We buy blueberries originating at a far 4 miles away. We know that the temperature is cool when they are harvested and thus the risk of bacterial growth on them is low. Likely much lower than “fresh blueberries” at the market that was shipped from Chile and have been on display for 3 days.
  • Find out when fruit, vegetables etc are delivered to your market, you want to shop the next day — avoiding all old looking items
• Peel fruits etc, immediately before consumption. Skins evolved to protect the contents from bacteria (i.e. histamine producing) growths

Whenever you hear an avoid (example list)— do your homework on it. Use PubMed exclusively. One of the best items for mast cell stabilization is Kumquats, which is on many avoid lists because it is in the citric family…. another QAnon recommendation.

IBS/Gut permeability appears to be a significant co-factor.

Evidence please! Studies, not the volume of people repeating rumors!

A reader with an autism child who has seen increasing anxiety asked for me to do an update on Anxiety. Given that it is a child, I raise my selection criteria to human studies, ideally on children. I have excluded Cognitive Behavior Therapy and Drug studies. My prior posts (often citing mice studies) are:

• Panic Attacks, Anxiety and the microbiome [Jul,2019]
• Anxiety and the Microbiome [Sept, 2016]
• An Alternative Model for Depression and Anxiety [Aug, 2019]

“Gut bacteria influence behavior, and both depression and anxiety symptoms are directly associated with alterations in the microbiota.” [Psychobiotics: Mechanisms of Action, Evaluation Methods and Effectiveness in Applications with Food Products 2020] It supplies a list of studies where depression or anxiety is reduced by probiotics. Probiotics that cites anxiety improvement include:

• Bifidobacterium longum
• Bifidobacterium breve
• Lactobacillus casei Shirota (Yakult)
• Lactobacillus plantarum
• Lactobacillus rhamnosus
• Faecalibacterium prausnitzii

Vitamins

• Vitamin D supplementation improves anxiety but not depression symptoms in patients with vitamin D deficiency [2020]
• Tryptophan supplements lacks clinical human studies, but appears to be a low risk item, especially if serotonin levels are lower. [2017] [2020]
  • Note: Walnuts are a source for tryptophan and magnesium [WebMD] — Walnuts and Magnesiums are on this child suggestions list from Microbiome Prescription.
• “Root of the Ayurvedic drug W. somnifera (Aswagandha) appears a promising safe and effective traditional medicine for management of schizophrenia, chronic stress, insomnia, anxiety, memory/cognitive enhancement, obsessive-compulsive disorder” [2020]
• ” herbal combination containing St. John’s Wort, Valerian, and Passionflower….
  

• “Exercise as an intervention for anxiety and depression has been demonstrated in both of the animal studies and human clinical trials. “[2020]

Bottom Line

Vitamin D supplement will not show short term improvement, it takes time to raise the level. (Lots of )Fresh walnuts and Aswagandha would be my first choice for my child. Then keeping Yakult handy, available on request, to the child. Lots of walks (since playground play is likely not viable in this age of Covid)

As with all medicines, natural or otherwise, please consult with experts who are experienced in their actions, interactions, contraindications and potential side effects before starting this or any other supplement program.

A reader requested me to do a review of the literature on probiotics and DAO as a result of my post, The Dilemma of D-Lactate Free Probiotics. As background on why DAO is important for some people, see:

• Diamine oxidase supplementation improves symptoms in patients with histamine intolerance 2019.
• Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial [2019]

The purpose of this post is to focus on DAO (and not treating histamine issues).

Returning to DAO and probiotics, the news is not good:

• “Rats that received oral C. butyricum or butyrate had reduced intestinal injury and plasma levels of DAO, LPS, and inflammatory cytokines.” [2020]
• “Streptococcus thermophiles…decreased endotoxin (ET), D-lactate (D-LA) and diamine oxidase (DAO) content in serum. [2020]
• ” the serum DAO activity and D-lactate concentration significantly increased by fluoride were also reduced (P < 0.05) by…Lactobacillus johnsonii [2020]
• ” DAO, endotoxin and D-lactate levels were significantly reduced following chronic ethanol consumption.” [2019] — Have lots of alcohol to reduce D-lactate!
• “the Lactobacillus plantarum group exhibited reduced serum levels of diamine oxidase (DAO) compared with the p-control group” [2019]
• ” Bacillus amyloliquefaciens …  significantly decreased activity of DAO compared with aureomycin group. [2018]
• “Bifidobacterium or Lactobacillus … reduced plasma DAO and D-lactate. [2014]

The latest incursions into the probiotic market of claims have posited the amelioration of oxidative stress via potent antioxidant attributes or limiting the administration of probiotics to those species that do not produce D-Lactic acid (i.e., claims that D-Lactic acid acidosis is linked to chronic health conditions)..there is no place in science and medicine that supports unsubstantiated claims. Extravagant industry based notions continue to fuel the imprimatur of distrust and skepticism that is leveled by scientists and clinicians at an industry that is already rife with scientific and medical distrust and questionable views on probiotics. 

Probiotics, D-Lactic acidosis, oxidative stress and strain specificity [2017]

Histamine Intolerance: The Current State of the Art [2020] is a very informative read

• “DAO (EC 1.4.3.22), also called histaminase or amiloride-binding protein, is a copper-dependent amino oxidase encoded by the AOC1 gene located on chromosome 7 (7q34-36) [14,15,16]. ” – so raising copper levels above average may be helpful (but not in excess).
  • Note that this refers to KEGG Enzyme, a recent addition to the Microbiome Prescriptions – alas, none of the bacterias or fungi associated with this is reported in current uploads.
• There is an alternative,  histamine-N-methyltransferase (HNMT). “Thus, depending on its location, the histamine present in the body is deaminated or methylated by the action of the enzymes DAO and HNMT, respectively “
  • ” Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain…Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. ” [2019]
• ” DAO deficiency has also been linked to certain functional gastrointestinal disorders, such as carbohydrate malabsorption and nonceliac gluten sensitivity (NCGS) [63,73,77,78,79]. “
•  It has been estimated that approximately 20% of the European population regularly take DAO-inhibiting drugs, which significantly increases the number of people susceptible to the adverse effects of dietary histamine [28]

This article gives a nice, high level summary

It is important to note that not only probiotics can reduce DAO levels, but many common supplements can too:

Bottom Line

Avoid probiotics unless there is a very compelling reason to use them (i.e. solid studies), Vitamin B1 and Vitamin C. Radical ways to improve DAO levels: lots of fluoride and alcohol (not recommended).

IMHO, the promoter of the probiotics products claiming help for histamine is under a moral obligation to demonstrate with a study that they work. For these products, a study with 15 control and 15 with brain fog/high d-lactate by lab, is a very very low cost study. Take DAO and D-Lactate readings at start for all, give them the probiotics for 30-90 days, remeasure… then publish. BEAUTIFUL MARKETING MATERIAL. The absence of such publications strongly suggests that this is now pure marketing hype (based on a logical idea and being “sold” on logic and not on evidence based studies). For D-Lactate study likely was done with no (or negative) results – which is exactly what was reported in the study below [that did get published, likely because it was a registered trial].

“Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons’ 2018 – very similar product to below. “A small, negative correlation was observed between change in D:L lactate concentration ratios and change in Streptococcus count for the total sample (r _s  = − .243, p = .142). ” This is NOT STATISTICALLY SIGNIFICANT ( p < 0.01 is what we want to see). 

Probiota Histiminix

This product claims ” contains probiotic species that have been carefully selected to exclude those that are known to increase histamine in the gut.” They omit to state that it probably decrease DAO. It contains:

• Bifidobacterium infantis
• Bifidobacterium bifidum
• Bifidobacterium longum
• Lactobacillus salivarius
• Lactobacillus plantarum (study cited above states this species reduced DAO)
• Bifidobacterium lactis
• Bifidobacterium breve

Post Script for those with Histamine issues

This page may be useful, it includes how to check for DNA mutations that can result in low DAO or HNMT.

Addendum

Using KEGG for DAO and HNMT, we do find that DAO and HNMT are produced (i.e. have the genes to produce) by the following which are not technically probiotics (not bacteria), but are called such by some people.

• Fungi
  • DAO
    • Ascomycetes
    • Basidiomycetes
    • Microsporidians
  • HNMT
    • Ascomycetes
    • Basidiomycetes
    • Microsporidians

Ascomycetes in both cases contains Saccharomycetes, and these specific strains (both available as a “probiotic” ):

• Saccharomyces cerevisiae (budding yeast)
• Kluyveromyces marxianus

There have been no studies of these on human histamine impact. There are reported allergic reaction (rare).

Feedback

A reader forward this image

I looked at the sources of this information — food processing. Such studies are very very difficult to work from — because of murky causality. Is the observed change due to antibiotics produced by them inhibiting the bacteria producing histamines. We are also dealing with a very high oxygen environment (compare to the body). What we need to answer the questions are human studies…. where they are tested, is the effect an increase or decrease of DAO. So far (see above), lowering of DAO.

A reader asked me to do a review of Spectrumceuticals Pro4-50 D-Lactate Free Probiotics which contains

•  L. rhamnosus,
• B. lactis,
• B. breve and 
• B. longum. 

Custom Probiotics offers a similar one labeled with the strains.

• L. Rhamnosus, Strain LR-32
• L. Salivarius, Strain LS-33
• B. Lactis, Strain BL-04
• B. Bifidum, Strain Bb-06
• B. Infantis, Strain Bi-26
• B. Longum, Strain BL-05

The latest incursions into the probiotic market of claims have posited the amelioration of oxidative stress via potent antioxidant attributes or limiting the administration of probiotics to those species that do not produce D-Lactic acid (i.e., claims that D-Lactic acid acidosis is linked to chronic health conditions)..there is no place in science and medicine that supports unsubstantiated claims. Extravagant industry based notions continue to fuel the imprimatur of distrust and skepticism that is leveled by scientists and clinicians at an industry that is already rife with scientific and medical distrust and questionable views on probiotics. 

Probiotics, D-Lactic acidosis, oxidative stress and strain specificity [2017]

We should note a few things from the literature:

• ” Gut permeability markers (D-lactate and diamine oxidase (DAO))  …. the serum DAO activity and D-lactate concentration significantly increased by fluoride” [2020]
  • Translation: No fluoride toothpaste or fluoridated water (beware of bottled water – it’s often sourced from civil fluoridated water systems)
• “The indicators of intestinal mucosal barrier function, such as D–lactate, endotoxin, and diamine oxidase, were significantly improved and the systemic inflammation (interleukin 10) was attenuated after probiotic [live Clostridium butyricum plus Bifidobacterium infantis] therapy. “
• “D-lactic acidosis is characterized by brain fogginess (BF) and elevated D-lactate and occurs in short bowel syndrome….  SIBO was more prevalent in BF than non-BF group.  After discontinuation of probiotics and a course of antibiotics, BF resolved and gastrointestinal symptoms improved significantly (p = 0.005) in 23/30 (77%).”  [2018]
• “Compared with control, d-lactate content, diamine oxidase activity, and adrenocorticotropic hormone level in serum decreased significantly [with Bacillus licheniformis]” [2013]
• “a stand-alone synbiotic treatment was started, specifically Bifidobacterium breve Yakult and Lactobacillus casei Shirota as probiotics, and galacto-oligosaccharide as a prebiotic. Serum D-lactate levels declined, and the patient has been recurrence-free for 3 years without dietary restriction.’ [2013]
• ” she was treated with sodium bicarbonate and oral antibiotics. The probiotics the patient had taken were likely the cause of D-lactic acidosis and should therefore be avoided in patients with short bowel syndrome.” [2009]

The reader requesting this review cited “Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons’ 2018. Which used the above mixture. “A small, negative correlation was observed between change in D:L lactate concentration ratios and change in Streptococcus count for the total sample (r _s  = − .243, p = .142). ” This is NOT STATISTICALLY SIGNIFICANT ( p < 0.01 is what we want to see). In fact, a chart in it illustrated the problem of using averages with the microbiome.

Bottom Line

The apparent reason for the promotion of D-Lactate Free probiotics is to reduce D-Lactate levels. There is no gold standard (or even silver standard) evidence that the above probiotics will do that. The dominant successful way of treating D-Lactic Acidosis is with antibiotics and avoidance of probiotics.

The best documented, all probiotic treatment is:

• Clostridium butyricum plus Bifidobacterium infantis

Promoter’s Moral Obligation

IMHO, the promoter of these products is under a moral obligation to demonstrate with a study that they work. For these products, a study with 15 control and 15 with brain fog/high d-lactate by lab, is a very very low cost study. Take DAO and D-Lactate readings at start for all, give them the probiotics for 30-90 days, remeasure… then publish. BEAUTIFUL MARKETING MATERIAL. The absence of such publications strongly suggests that this is now pure marketing hype (based on a logical idea and being “sold” on logic and not on evidence based studies). A study likely was done with no (or negative) results – which is exactly what was reported in the above study [that did get published, likely because it was a registered trial].

The Dilemma

The literature indicate that reducing D-Lactate also reduces DAO. Insufficient DAO is associated with Mast-Cell Activation and Histamine issues. There is a need for a balance here. A tightrope that may need to be carefully walked.

Sleep Consequences

Sleep issues in ME/CFS may be connected to excessive D-Lactic acid (A known characteristic of ME/CFS)

Results and conclusion: Administration of L-lactate does not influence sleep-wake cycle of experimental animals. At the same time, its artificial optical analog D-lactate induces the significant (as compared to the control) decrease in wake (34.8% to 26.5%) and increase in slow wave sleep (57.4% to 69.2%). It has been suggested that D-lactate may be the antagonist of one or several L-lactate receptors.

[D-lactate as a novel somnogenic factor?] [2020]