Mast Cells Function as Sensors of Food Quality

IgE-Mast cell mediated allergy: a sensor of food quality
“allergic sensitization triggers the formation of avoidance behavior”, food can contain toxic noxious substances in different amounts and our bodies have ways of directly sensing it and responding to protect itself, including extra mucous production, nausea, vomiting, diarrhea, malabsorption, increased peristalsis.  These protective responses can be in response to our bodies sensing the toxicity via smell, taste, chemosensors in the gut.  This is a system that senses food quality and is more general and doesn’t adapt over time.

“Type 1 allergic reactions can induce similar symptoms as already known sensors of food quality. This similarity suggested that type 1 allergic reactions may also act as a ‘food quality control system” that allows learning and behaviour adaptation.³ The great advantage of involving the immune system would be its ability to recognize a nearly infinite number of distinct substances in a very specific manner, which is an original property of the adaptive immune system.” , “early type 1 allergic reactions trigger persistent allergen-specific avoidance behavior” , mice that were deficient in IgE and/or mast cells didn’t develop avoidance behavior.  “Type 1 allergic reactions promote protective antigen avoidance behaviour via IgE armed mast cells.”

“In response to allergic stimulation, cytokines from Tfh cells promote antibody class switch and antibody secretion by B cells, which yield antibodies of various isotypes, including IgE and IgG. IgE arms mast cells with an antigen-specific receptor.”, “during the early preclinical allergic response, mast cells are sufficiently activated to release leukotrienes, which triggers long-lasting allergen-specific avoidance behavior.”  If the exposure to the allergen persists IgE levels may increase and it increases its affinity to the allergen and “trigger strong mast cell activation and allergic disease.”

“In the absence of IgE or mast cells, allergen ingestion is increased, eventually leading to severe immunopathology.”

“IgE production is dependent on IL-4 from T follicular helper (Tfh) cells. This cytokine is sufficient to induce low affinity IgE, which however does not induce severe allergic symptoms, while additional cytokines from Tfh13 cells, including IL-13 and IL-21, are required for the development of high affinity IgE and anaphylaxis”

“High affinity IgE-mediated mast cell activation is the major mechanism for the induction of severe type-1 allergic reactions.” “murine IgG1 (human IgG4) antibodies which are also induced by IL-4, can trigger anaphylaxis too, though only in the presence of higher amounts of antigen” 

“Antibodies of the subclasses IgG2 and IgG3 are not IL-4 dependent, may not contribute to the pathology of type 1 allergic reactions, but can mediate severe inflammation via the activation of the complement system and various innate effector cells.”

“most allergic symptoms are absent in IgE deficient mice, even after forced uptake of high amounts of allergen, they still develop severe anaphylaxis, probably involving antibodies of other subclasses.”

“This work reveals a protective role of IgE-mediated mast cell activation, acting via modification of behavior.”

“even early allergic symptoms are associated with the activation of areas of the brain involved in the response to aversive stimuli.” 

“the induction of allergen avoidance behavior required only mild allergic reactions mediated by IgE, which precede the development of gut allergic inflammation. Evidence was provided, that activated mast cells affect behavior through the release of cysteinyl leukotrienes and the induction of growth and differentiation factor 15 by colonic epithelial cells, eventually sensed by the nervous system.”

“early IgE-mediated allergic reaction triggers avoidance behaviour while chronic allergen ingestion results in IgE-mediated disease.”

“The ratios between the levels of allergen specific IgE and the levels of allergen specific antibodies of other subclasses, correlate better with the development of severe allergic symptoms than the levels of IgE alone.”

“This reflects the fact that antibodies of other subclasses such as IgG1 or IgA can inhibit the severe allergic reactions induced by high-affinity IgE.”

“this mechanism may also be relevant in non-allergic individuals, who nevertheless produce subclinical quantities of IgE, potentially sufficient to cause mild mast cell activation and behavioural change, but without triggering allergic pathology.”

Immune sensing of food allergens promotes avoidance behaviour
https://www.nature.com/articles/s41586-023-06362-4

Mast cells link immune sensing to antigen-avoidance behaviour
https://www.nature.com/articles/s41586-023-06188-0

Food allergy as a biological food quality control system
https://www.cell.com/cell/fulltext/S0092-8674(20)31677-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420316779%3Fshowall%3Dtrue

Identification of a T follicular helper cell subset that drives anaphylactic IgE
https://www.science.org/doi/10.1126/science.aaw6433

B-cell receptor physical properties affect relative IgG1 and IgE responses in mouse egg allergy
https://www.mucosalimmunology.org/article/S1933-0219(22)01761-5/fulltext

T follicular helper cells
https://www.immunology.org/public-information/bitesized-immunology/cells/t-follicular-helper-cells

Eosinophilic GI Disease

 Eosinophilic GI Disease (EGID) is a group of conditions that occur when there are elevated levels of eosinophils in segments of the GI tract, either the esophagus, stomach, small intestines or colon.  These conditions are called Eosinophilic Esophagitis (EoE), Eosinophilic Gastritis or Gastroenteritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EC or EoC).  I have heard reference to Eosinophilic Duodenitis Eosinophilic Rectitis but I don't think either are official conditions.  The esophagus is the one part of the GI tract that doesn't normally have eosinophils, whereas the rest of the GI tract does.  This has led some to speculate that EoE is a different entity than the other EGIDs.  

EGIDs are diagnosed by biopsy.  Tissue samples are collected during endoscopy or colonoscopy, and then sent to a pathologist who looks at the samples under a microscope to identify the presence of eosinophils.  If the numbers are too high, a diagnosis is made.  Symptoms vary depending on the form of EGID a person has, and can be mild to severe.  In EoE, a common symptom, the one that often leads to diagnosis, are food impactions in the esophagus that require medical care to remove.  Symptoms of lower EGIDs tend to be vague such as cramping and pain, vomiting, nausea, diarrhea, food intolerances and a severely restricted diet, malnutrition, and bone pain (usually in the legs).  

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis

Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Molecular analysis of duodenal eosinophilia

Elimination diets are often used by doctors to identify problem foods, as there are no tests to identify eosinophilic triggers.  Treatment often begins by having the patient avoid identified (or suspected) triggers.  If this doesn't adequately control symptoms, various medications can be used, including topical steroids such as Budesonide or Fluticasone (steroids that is swallowed), a PPI (Protono Pump Inhibitor), Singulair, or oral steroids to control flares.  A type of medication called biologics are starting to be used for some EGIDs, in particular Dupilumab (brand name Dupixent).  Eosinophils are the same cells that tend to be responsible for asthma so many of the same medications are used.  Some people describe EGIDs as "like asthma but in your GI tract".  If those treatments fail, it is not uncommon for people with EGIDs to require artificial nutrition such as elemental formula, a feeding tube, or even TPN (IV nutrition).  People with EoE can develop strictures in the esophagus, areas where the tissue has scarring which narrows the width of the esophagus.  This can be treated with dilations, a procedure in which the area is mechanically stretched.

Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics

The leading center for diagnosis and treatment of EGIDs, especially EoE, is Cincinnati Children's Hospital (they also work with adults with EGIDs) 

Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE

Food-specific IgG4 is associated with eosinophilic esophagitis

Common and disparate clinical presentations and mechanisms in different eosinophilic gastrointestinal diseases

Histopathology of Eosinophilic Gastrointestinal Diseases Beyond Eosinophilic Esophagitis
"EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and TH2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs. The level of expression of certain genes associated with TH2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC. Current immune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease."

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders—A Comprehensive Review
"Eosinophils, a specific type of leukocyte derived from CD34+ CD125+ stem cells in the bone marrow, are crucial in defending against pathogens, such as bacteria and parasites. Additionally, they play a pivotal role in modulating humoral immune IgA and cellular T-cell responses, and in maintaining tissue homeostasis.

In the context of EGIDs, the abnormal accumulation of eosinophils is primarily driven by interleukin-5 (IL-5), interleukin-4 (IL-4), and interleukin-13 (IL-13). These cytokines are primarily produced by type 2 helper lymphocytes (Th2) in response to exposure to aeroallergens and food allergens. The overproduction of interleukins is further amplified by dysregulated cells in the innate immune system, including Group 2 innate lymphoid cells (ILC2s) that mature directly in tissues like the GI tract or lungs, plasma cells, and mast cells.  Pathogenesis of Th2 inflammatory drive in Eosinophilic Gastrointestinal Disorders (EGIDs), especially EoE. Exposure to initial food antigens triggers lymphocyte-Th2 activation, resulting in the accumulation of eosinophils in the esophagus. Following stimulation with Eotaxin 3, eosinophil degranulation promotes acute damage to the esophageal epithelium, followed by subsequent chronic fibrotic remodeling of the esophagus, which is dependent on TGF-beta.

Th2 cytokines, particularly IL-13, along with other inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and other chemokines, play a direct role in the activation and degranulation of eosinophils. Eotaxin-3 serves as the primary chemokine involved in these processes and contributes significantly to eosinophilic chemotaxis and accumulation in GI tissues. The release of proteins from eosinophilic granules, including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and major basic protein (MBP), leads to acute cytotoxic and oxidative damage to the tissue. This acute damage results in compromised barrier function through the downregulation of Desmoglein 1 (DSG1), Filaggrin (FGN), and the Epidermal Differentiation Complex (EDC).
The course of acute eosinophilic Th2 inflammation is typically self-sustained and progressive, often leading to chronic damage. This chronic state is often driven by T regulatory lymphocytes’ activation, accompanied by the recruitment of other cell types, including mast cells and basophils [26]. The persistent inflammatory insult can result in sub-mucosal fibrotic tissue deposition and muscular hypertrophy, primarily induced by Transforming Growth Factor beta (TGF-beta). 

A recent study on colonic biopsies conducted by Shoda et al. revealed that EoC is distinct from other EGIDs, with pathophysiological mechanisms that are not completely dependent on allergic inflammatory reactions [186]. The study identified 987 differentially expressed genes that were overexpressed in EoC tissues, thereby defining the “EoC transcriptome”.  Interestingly, the pathogenesis of EoC seems to have only a weak correlation with Th2-related allergic pathogenesis.  (A)dults typically experience chronic abdominal pain and watery diarrhea [25,179,180]. Additional symptoms can include nausea, vomiting, and weight loss. The presence of atopy history in EoC patients often complicates the clinical picture with conditions like asthma, food allergies, rhinitis, or eczema.

The depth of eosinophilic infiltration in the colonic wall allows for the identification of three disease patterns [147].

The mucosal involvement (type 1), defined as eosinophil infiltration of the mucosa, is the most common. This type often follows a continuous disease course (>6 months) without remission, with patients exhibiting symptoms such as bloody diarrhea, microcytic iron-deficiency anemia, and protein-losing enteropathy [5].

Transmural involvement (type 2) occurs when eosinophils infiltrate the muscular layer. It is associated with symptoms like abdominal spasms, pain, and a possible impact on intestinal motility. Complications such as intestinal obstructions, strictures, volvulus, and perforations may occur. The course of the disease in this form is typically recurrent [5].

The serosal subtype (type 3) is the rarest and occurs when eosinophilic infiltration reaches the serosa. This form can be associated with more severe symptoms, including eosinophilic ascites and intense abdominal pain [5].

Radiological signs include intestinal wall and mucosal fold thickening and submucosal edema [150,153]. Mucosal thickening, stenosis, and sub-mucosal edema form the basis of the “halo sign,” characteristic of EoC. The “arachnoid limb-like sign” may also be observed via radiological imaging [150]. In cases of transmural involvement, stenosis, particularly at the cecum, may be observed.

 

In approximately 70% of EoC cases, no alterations in the colonic mucosa are observed during endoscopic evaluation [183,187,188]. However, when abnormalities are present, they typically involve the colon segmentally, with only about 10% of patients presenting with pancolitis [14,25,183]. The endoscopic findings of EoC are often non-specific and do not correlate with the severity of symptoms [7].

 

Drug-induced colitis, triggered by antiplatelet drugs (clopidogrel, aspirin, and ticlopidine), Non-Steroidal Anti-Inflammatory Drug (NSAIDs) (especially ibuprofen), and estrogenic-progestogen agents is another cause of colonic hypereosinophilia [194,195].  Among connective tissue diseases, rheumatoid arthritis uniquely exhibits patterns of colonic eosinophilia [200]. 

 

In addition to hypereosinophilia, other microscopic characteristics that typify EoC histology include extensive degranulation, eosinophilic micro-abscesses, architectural distortion, fibrosis with mucosal atrophy, loss of mucin, and follicular lymphoid hyperplasia, often accompanied by lymphocytes and plasma cells [187,188].

 

According to the strongest evidence, a PEC with more than 50 eosinophils per HPF in the right colon, more than 35 eos/HPF in the transverse colon, or more than 25 eos/HPF in the left colon, along with a consistent clinical and symptomatic profile, indicates a diagnosis of EoC [14] 

 

adults typically receive steroid anti-inflammatory therapy, such as prednisone or budesonide, as the initial treatment [170,180]. If adults experience a relapse after discontinuing prednisone, indicating steroid-dependent disease, Budesonide Controlled Ileal Release (CIR) can be an effective maintenance therapy. Budesonide CIR has the advantage of primarily topical activity, minimizing the long-term adverse effects associated with steroids [202].

Immunomodulators like azathioprine and methotrexate also represent alternatives to maintenance therapy for EoC. Additionally, Montelukast, a leukotriene receptor antagonist, is beneficial in maintenance therapy due to its ability to block eosinophil homeostasis and prevent their infiltration into the intestinal wall [131]. Fecal microbiota transplantation has been suggested as a rescue strategy in EoC, though this evidence is limited to case reports [203]. Emerging therapies for EoC have mainly been tested in animal models. Studies evaluating the efficacy of anti-Siglec-F antibodies (targeting a sialic acid-binding immunoglobulin superfamily receptor) and anti-CCR3 (cysteine–cysteine chemokine receptor 3) antibodies have shown promising results [204,205]. Future therapeutic options are anticipated with the validation of biological drugs like dupilumab, reslizumab, and mepolizumab, which are currently undergoing testing.

 

 

 

 

Dietary Fats and Oils

Sources of oils and fats

Microbes in intestines convert fiber into short-chain fatty acids.  This should be vegetable fiber, NOT grain fiber or capsules/drink.  

Salmon Roe - richest source of omega-3 fatty acids (EPA and DHA), contains 1800 of EFAs in one ounce of salmon roe.  Excellent support for the neurological system.  Also high in other nutrients as well.

Salmon Roe – Unsurpassed for Nourishing the Brain

Speak - This is a supplement that is a combination of oils that supports brain function, especially in regards to speech.

Specific Oils and Fats

Black Seed Oil is a mast cell stabilizer.

Chia Seed - contains omega-3 fatty acids and other essential fatty acids including alpha-linolenic and linoleic acid, oleic acid, and palmitic acid.

CLA (Conjugated Linoleic Acid) found in red meat and grassfed dairy, has anti-tumor properties.  

Coconut Oil contains Lauric Acid, an antiviral, and Caprylic Acid, which is antifungal.  

Cod Liver Oil (CLO) Source of omega-3 fatty acids oils as well as vitamin A and vitamin D.  Omega-3 fatty acids increase brain-derived neurotrophic factor (BDNF) which supports growth of new neurons.  They are also anti-inflammatory, especially in the brain. 

Lard is a natural source of vitamin D and choline and contains some vitamin E.  Avoid lard that has been hydrogenated.  

Olive Oil is an excellent source of omega-9 fatty acids, including oleic acid.  It has the highest proportion of monounsaturated fatty acids of all of the liquid vegetable oils.  It contains 13% of RDA of vitamin E and about 10% of RDA of vitamin K.  The extra-virgin variety has a higher mount of polyphenols, which are natural antioxidants.  

What Does Research Actually Say About Healthy Fats? 

Is Saturated Fat Bad For You?
Ketogenic diet therapy doesn't have to include any saturated fat; many people eat a vegan keto diet or one that is vegetarian without dairy, or some other specialized form of keto.  It's possible to make a keto diet that is compliant with almost any other restriction, such as vegan, vegetarian, Mediterranean, carnivore, and others.

Saturated fat, the estimated absolute risk and certainty of risk for mortality and major cancer and cardiometabolic outcomes: an overview of systematic reviews
Absolute risk is much more informative than relative risk- relative risk sounds more catchy but doesn't actually tell you as much.  When thinking about what a study means for you, whether its conclusion means you need to make changes, depends on the quality of evidence and not just the presence or absence of evidence.  This paper found that the evidence supporting a risk from consuming saturated fat was low or critically low quality.  When looking at the results of reducing or replacing saturated fat in terms of cancer mortality, the authors found that the evidence showed a range of 8 fewer deaths to 3 additional deaths per 1,000 people, and the certainty of evidence (quality) was low to very low.  So no clear-cut link between saturated fat consumption and risk of death from cancer.  When considering the impact of saturated fat in the diet and cardiac deaths, they found a rate of two deaths per 1,000 people with low to moderate certainty.  This does not support the strength of the message we get through doctors and public health to avoid saturated fat.

There are other factors to consider when seeing if the results of a study means anything for you individually.  To illustrate this point, consider one study that was included in this meta-analysis (with moderate quality evidence) that found 24 fewer deaths per 1,000 people from all-cause mortality in a treatment group that reduced saturated fat intake.  We need to look at the details to see what the implications are.  Most people being studied are eating the standard American diet, high in ultra-processed foods, and get their saturated fat from sandwiches, desserts and sweet snacks like cookies, cakes, ice cream, pastries; and rice and grain-based dishes like pasta and pizza, and milk and yogurt which is usually sweetened and flavored.  These foods are all high in sugars and simple starches.  Natural foods, including plain meats, cheeses, butter, etc are lower on the list.  The question then is how do you eat- if you eat lots of junk food, fast food, and processed food, then this study might apply to you.  If you already eat a diet primarily of whole foods and low processed foods then these results probably have no relevance for you.

"Nutrition science is full of low quality evidence that applies to a general population eating a low quality diet".  As a patient, we all deserve to have care providers who treat us as individuals.

A short history of saturated fat: the making and unmaking of a scientific consensus 

Dietary Saturated Fats and Health: Are the U.S. Guidelines Evidence-Based?

Inflammation and Mast Cell Activation Syndrome

Inflammation and mast cell activation syndrome
(My notes for an interview by Dr John Campbell with Dr Tina Peers)

She learned about MCAS because her daughter suffered terribly with eczema and other symptoms that a doctor identified as Histamine Intolerance and MCAS, and treatment made a huge difference for her.  Dr Peers then began recognizing the syndrome in many of her own patients and providing them with answers, many of whom had given up on ever understanding their various chronic health issues.  Her basic level guidance is for patients to take anti-histamines (blocking both H1 and H2 receptors), supplements including vitamin C (for its anti-histamine property), and following a low histamine diet. 

The world leader in mast cell disease research is Dr Molderings at Bonn University.  Mast cell diseases aren't taught in medical school so it's up to patients to tell their doctors about it if they have it.  There are 2 conditions- Histamine Intolerance, which occurs when a patient doesn't produce enough diamine oxidase (an enzyme in our stomachs that reduces the amount of histamine in our food), and MCAS, which is when a person's mast cells release too much histamine too easily.  Most of her MCAS patients are also diamine oxidase deficient (leading to increased absorption of histamine from food) so they get a "double whammy".  In the medical literature, the incidence of Histamine Intolerance is approx 3-5%, but the incidence of MCAS is between 17-20% (According to Dr Molderings). 

She also does genetic testing with her patients to look at their methylation markers and their histamine metabolism- she finds that her MCAS patients rarely have normal diamine oxidase production (the enzyme that breaks down histamine in the gut) and tend to have KIT gene mutations (the genes involved in coding for mast cells).  There are 50 known variations of KIT genes.  Symptoms and syndromes she ties to MCAS include eczema, rosacea, Chronic Fatigue Syndrome (ME/CFS), migraine and other headaches, rash, urticaria, psoriasis, IBS, diarrhea, fibromyalgia, other joint problems, bloating, nausea and vomiting, interstitial cystitis, POTS, and are hypermobile.  She says 80% of MCAS patients are hypermobile (may have EDS) and 80% are female, and 30% have interstitial cystitis. 

Dr Campbell gives a simple overview of mast cells- they are a type of white blood cell that resides in tissue rather than circulating.  They trigger an inflammatory process when we want them to, including heat, pain, redness and swelling, which brings increased blood supply and nutrients to a damaged or infected area to help the healing process.  Mast cells store histamine to release when needed, but they also store another 1,000 cytokines.  They are concentrated in areas where our bodies are in contact with the outside world including our skin, lining the nasal passages, sinus passages, and respiratory system, they line the entire GI tract, they line the urogenital tract; she compares them to bouncers at a club who are just inside the door to stop "undesirables" from coming in.  

In MCAS they become overzealous and pick a fight with all sorts of things, sometimes almost anything, that they come in contact with.  When they react (degranulate), they release one or some or many of these different cytokines (often called mediators) and in various combinations, and they can release 350 chemokines which pass messages to other mast cells to join the reaction (this is how you get systemic reactions aka anaphylaxis).  Mast cells also line our nerves, and histamine is also a neurotransmitter.  Mast cells in the stomach (chromogranin cells) release stomach acid.  Histamine plays essential roles in the body, but we need it to be carefully regulated so that we have only what we need, where we need it, and for how long we need it.  

MCAS patients have excessive histamine lingering, as well as other chemicals that can cause bruising (heparin), elastase 2 causes membranes to break down, clotting factors contributing to clot formation.  There is always inflammation and there may or may not be allergic-type reactions, including anaphylaxis, and dystrophisms which are formations of new tissue (abnormal tissue growth).  Examples include cysts, often in the breast and pancreas (can also include skin tags, scar tissue, and fibroids).  MCAS patients can also have poor wound healing.  The symptoms a person experiences will correspond with where the over-reactive mast cells are concentrated, such as asthma occurring in people with abnormal mast cells in the lungs (in these cases inhalers may not work because the mechanism is different).  For people with concentrations of mast cells in their skin, things as simple as their clothes rubbing on their skin or pressure from waistbands can cause itching and rashes or bruising.

Dr Campbell asks, given the enormous variation in presentation, how do you suspect and diagnose MCAS?  Dr Peer responds that you recognize patterns of inflammatory symptoms, they often have sensitivities including to things touching skin such as tags, as well as a very heightened sense of smell and aversion to bright lights and loud noises.  You also have to consider what other conditions might also produce the pattern of symptoms the patient is presenting with.  Testing for cytokines can help but need to be developed more.  The more the mast cells are triggered, the more sensitive the person can become over time.  Infections can make MCAS worse.  She says there is "consensus 1" criteria, which requires a positive blood test for specific markers and rules out many people, and "consesnsus 2" criteria that don't require the blood test. Instead, consensus 2 says that if the provider has a reasonable suspicion of MCAS that they can try some of the basic treatments and lifestyle changes, including some basic medications, and if the patient improves significantly, it can be inferred that they do have MCAS.  

There is a website called "what the bleep can I eat .com" that has a good list of histamine levels in foods.  It's worth noting that there is a lot of innacurate information online about histamine levels in foods.  The site lists about 200 foods that have no, or very low histamine levels.  Some of the very high histamine foods include tomatoes, bananas, avocados, spinach, gluten, tea and coffee, green tea, alcohol, chocolate (the last 3 also block diamine oxidase production).  Processed foods tend to be high in histamine, as well as leftovers (anything being re-heated or left around for awhile) because bacteria present on foods converts the amino acid histidine to histamine.  You can think of a "histamine bucket" in the sense that it takes a certain amount of exposure to add up to the level that triggers a reaction, so a person may get away with a food one day but not another day.  

A person can take diamine oxidase supplements when eating to help reduce the histamine load (DAO supplements)- as an aside, these often contain ingredients that are problematic for MCAS people so be careful with them.  Pea shoots have a high level of diamine oxidase and eating some of them before a meal can also help.  In the big picture MCAS people do best on a ketogenic or paleo diet, with fewer carbohydrates, because these diets are so anti-inflammatory.  In addition to dietary changes, some supplements help, including vitamin C which has anti-histamine and antibiotic properties, and is anti-inflammatory.  Vitamin D with K2 is also important, as is magnesium, CoQ10, l-carnitine (acetyl), and iodine, things to support the mitochondria.  

MCAS people get mitochondrial dysfunction which then limits energy production.  Our cells have thousands of mitochondria in each one- our mitochondria produce 70-80kg of ATP every day (this is because as soon as we make it, it's gone, so it's made at a high frequency). Our mitochondria are 32% of our body weight.  Our heart has the highest density of them, and then the liver.  The post-exertional malaise, the hallmark symptom of ME, is due to mitochondrial dysfunction such that they can't produce ATP at the rate the person's body needs it.  Most of us (in the UK and America?) have low iodine levels in our bodies.  Iodine is important for the glands, including breast, thyroid, thymus, and prostate.  She instructs her patients to take 2 to 3 drops of Lugol's 15% before bed, in water.  It supports mitochondria but it also keep the upper gut sterile, which it should be.  Seaweed is a good food source, surprisingly, fish does not.  

So much inflammation comes from the gut, there are so many mast cells in the gut.  Getting the inflammation in the gut under control is a really important part of getting MCAS under control and managed because the inflammation in the gut spreads to other parts of the body.  As an aside, Dr Campbell mentions that an oncologist he knows has told him that a lot of cancer seems to come from chronic inflammation, including the gut, and that iodine supplementation can reduce the chances of developing cancer.  Mitochondrial dysfunction also seems to be critical in getting cancer, because it's the mitochondria that signal cell death when a cell has mutated and is growing out of control.  Inflammation in the gut leads to leaky gut, which means that whole proteins can get into the bloodstream instead of their breakdown products, amino acids.  Inappropriate proteins in the bloodstream wreak havoc, including triggering allergies.  

The lining of the gut is only one cell thick, and their are mast cells directly behind those cells.  If the mast cells swell, they can cause cracks to form between the cells lining the gut (leaky gut).  The first 20 feet of our guts are supposed to be sterile, but since our modern diets include sugar, dairy, and some other things, bacteria that should be killed are instead being fed and multiplying, and causing inflammation.  Eliminating all sugars and refined carbohydrates would be best for most people, but people with MCAS should be low-histamine ketogenic.  Sugars and carbs are addictive- instant gratification.  We want a microbiome, but it should be in the colon.  Taking iodine won't affect that part of the gut.  Eating in season when possible.  You can break the addiction to sugar in 2 weeks- there is a gene that switches off.  Good probiotics help.

Figuring out a medication regime for each person is a slow process of trial and error.  She suggests starting with the over-the-counter anti-histamines, one at a time, in higher doses than on the box.  Once you've found one that works, add in famotidine, which is an anti-histamine for H2 receptors (mostly in the gut, but also in the heart and brain).  After that, mast cell stabilizers are added.  Quercetin at 500mg 3x a day is easy because it's available OTC.  Prescription meds in this category include Ketotifen (in America this has to be compounded because there is no commercial version for oral use), working up to 1mg at night.  If that doesn't help, there is Rupatidine- people take one or the other.  The third medication is Gastrocrom (cromolyn sodium), that stays in the gut.  MCAS with IBS symptoms tend to do well on Gastrocrom.  Each patient takes their own cocktail of medications and treatments.  LDN (Low Dose Naltrexone) is very helpful for many people with MCAS.  

Dr Peet is also using medicinal mushrooms for their immunomodulatory capabilities, to help calm the mast cells.  She emphasizes that the mushrooms must be very high quality.  Mushrooms themselves are high in histamine, but extracts can be made that leave the histamine behind.  The sunshine mushroom is a mast cell stabilizer, reducing histamine and cytokine release from mast cells.  She recommends the company Hefasta Terra, a Spanish company- their products are organic and tested, no fillers, and they grow the mushrooms themselves.  They also do clinical research.  She recommends Myco Sol (sunshine mushroom) and Myco 5, which contains sunshine mushroom, reishi (balances hormones, lowers anxiety, improves sleep, anti-inflammatory, analgesic), chaga (kills cancer cells), shiitake and mistake (treats mycotoxins).  Lion's Mane mushroom crosses the blood-brain-barrier and can stimulate growth of neurons.

Mast cells can live for 2 to 4 years- some are replaced sooner, but it can take patience to heal from severe MCAS for this reason.  New mast cells can become over-reactive when they enter tissues where the existing mast cells are already edgy, this can perpetuate the problem.  Dr Peet says that CIRS (Chronic Inflammatory Response Syndrome) from mold can co-occur with mast cells and can look nearly identical to MCAS but she implies that it needs to be considered separately.  Lyme Disease and Epstein-Barr (HHV-5) can also be very similar.  She says you don't want to miss any of those if they are comorbid with the MCAS.  

Tryptase is an enzyme that is released by mast cells when they degranulate under certain circumstances, and is the source of a great deal of controversy in the MCAS world.  In 2012, a consensus statement (consensus statement 1) was put out by some of the doctors and researchers who had been working on mast cells stating that there needed to be an elevation in serum tryptase for MCAS to be diagnosed.  The year before that, another statement (consensus statement 2) had been put out by about 40 of the doctors and researchers working in the field who made a broader definition of MCAS that was based on the patients they were seeing which was more flexible in its diagnostic criteria.  The authors of consensus statement 2 argued that in many parts of the world, it's not always possible to get a serum tryptase level measured, and they noted that many patients who they were treating with success didn't have elevated serum tryptase levels anyway.  Statement 1 excludes many people with the profile of MCAS and denies them treatment.  Many people feel that if the treatment works, that is good evidence that MCAS is present.

Metabolic and Mental Health

 What are Metabolism and Metabolic Health, and How Do They Impact Mental Health?
"Metabolism is the set of life-sustaining chemical reactions in organisms.  The three main things that metabolism does is convert the energy in food to energy that is available to power the cell and therefore the organism, the conversion of elements in food into the building blocks to make proteins, lipids, nucleic acids and carbohydrates, and the elimination of metabolic waste.   Another definition of metabolism is "all the physical and chemical processes in the body that convert or use energy".  Metabolism is how we use our food to create energy.  If we consume more calories then we need we need to store the excess energy.  We store some as glycogen in the liver, but most is stored in our fat cells.  It makes sense that our bodies would have evolved with uncertainty about when we would have food and how much we would have, so we would have needed to store up excess for times when we didn't have enough.  

Metabolic dysfunction usually results from too much food intake or eating foods with a poor ratio of nutrients to calories.  If we consistently eat more calories/energy than we need, our bodies first store the excess in our fat cells but they eventually get full, and then we store fat in our organs, called visceral fat (such as fatty liver). Visceral fat interferes with the function of the organ in question and leads to disease states such as type 2 diabetes.  We need to have low levels of insulin in order to access and use the energy stored in fat.  Insulin levels rise when we eat, especially if we eat sugars and simple carbs.  When our insulin levels are high this signals our body to store energy because we have plenty for now.  The state of having high insulin levels from frequent eating is called hyperinsulinemia.  If the state of hyperinsulinemia persists our cells become less responsive to insulin, producing a state called insulin resistance.  This means too much sugar stays in the blood and not enough is available for energy use.

There can also be a connection between mental health and the gut microbiome.
Never fear, the gut bacteria are here: Estrogen and gut microbiome-brain axis interactions in fear extinction

Mitochondria and Mental Health

Brain Energy, Mitochondria, and Mental Health
Dr Chris Palmer, MD, Harvard Psychiatrist

A major change in psychiatry has been going on for awhile now in which more and more clinicians and researchers are recognizing mental health disorders as related to, and sometimes caused by, physical states in the body and therefore using therapies that are meant to address these states.  A primary example of this is looking at brain metabolism (mitochondrial function in the brain).

The Keto diet is a 100 year old, evidence based therapy that can stop seizures that medication can't stop.  This is evidence of how powerful nutrition and diet can be in treating and altering brain function.  Psychiatrists use epilepsy medications to treat people with other mental mental health conditions often, usually off-label, so there's nothing new about using the ketogenic diet to treat other mental health conditions.  Seizure meds are used to treat dementia, eating disorders, anxiety, psychosis, mood disorders, substance use disorders, and others.  

The Brain Energy Theory- Mitochondria do more than just produce energy for cells "mitochondria play a role in directing and allocating resources for cells".  Not all of the food that mitochondria in the brain process is turned into ATP- some is turned into serotonin, dopamine, or cortisol, and they also play a part in regulating those molecules.  Mitochondrial function is one way of understanding the imbalances of the neurotransmitters and hormones in the brain.  They are also involved in regulating inflammation (turning it both on and off) and epigenetics by signaling the nucleus of the cell to regulate the transcription of gene.  They monitor our outer and inner environment; sensing stress levels, food intake, blood sugar levels, and oxygen levels.  

"Mitochondria play a role in our response to trauma- psychological and social stressors."  Trauma and stressors play a role in mental illness, so this connection could be very significant, because while people have known that there is a connection they haven't known exactly what that connection is on a biological level.  He points out that mitochondria seem to be a way to "connect the dots" in the mental health puzzle between factors like trauma, neurotransmitters, sleep, substances like drugs and alcohol (I would add exercise and sunlight too).  These are all things that affect mitochondrial and metabolic health or are affected by it or both.  People with mental health conditions have higher rates of many physical disorders including diabetes, obesity, heart attacks, strokes, and generally have a shorter life expectancy.  This connection also opens up the possibility of more and better treatments.

For people who struggle to believe this connection is real, he explains that mitochondria are what drives metabolism, which is how we take food and oxygen and transform them to keep ourselves alive.  If these processes are disturbed it means illness, and if they are disturbed enough or stop, we die.  Most poisons work by harming mitochondria- that's how they harm or kill you.  Other cellular components can be harmed without nearly as much danger to the organism.  It makes sense that since mitochondria are the most important part of the cell and what keeps it able to perform its function, if they aren't functioning right the cell won't be able to function right.  

Mitochondria can become both under-active AND overactive.  This makes sense because there are mental health disorders involving areas of the brain becoming overactive as well as areas becoming under-active.  If the health of mitochondria impacting the cell's functioning is the cause or major contributing factor to many mental health disorders that would explain why they can be better or worse at different times of day (or different seasons), why they can be worsened by stress and sleep deprivation.  A lot of the details aren't known yet but already the basic insight that mitochondria are central to mental health is transformative of the fields of psychiatry and psychology.

What options are available to support mitochondrial functioning?

There are a huge variety of things available to help mito function including sun exposure, red light therapy, various supplements, glutathione, methylene blue, and more, but these can only help so much if core lifestyle issues aren't addressed.  For example, alcohol is a potent mito toxin so a person drinking a large amount daily is poisoning their mitochondria far beyond what those things can help.  Having healthy mitochondria requires lifestyle changes- eating well and avoiding highly processed foods, sleeping well, exercising, and avoiding excess stress.  

The ketogenic diet and its effect on brain function has been studied for a long time, its known to change neurotransmitter levels, inflammation, the gut microbiome, but Dr Palmer says that he believes the impact it has on mitochondria is its most important therapeutic effect.  The keto diet creates a state in the body similar to fasting, which is known to trigger mitophagy (when the cell breaks down old and defective mitochondria that are replaced by new, healthy ones) and mitogenesis (which is the production of new, healthy mitochondria).  Dr Palmer suggests that these two processes that remove old, defective mitochondria and replace them with more and healthier ones, might lead to long-term healing where a person could potentially go off the keto diet and remain healthy.  People who are on the diet to control seizures will usually be kept on the diet for 2 to 5 years after the point at which their seizures completely stop (some people with seizures must stay on keto for life).  People can experience improvement of mental health symptoms, even very significant improvement or remission in weeks or months.  Psychotic symptoms tend to take weeks if not months to improve especially if severe.  People often wonder if making some changes in their diet, such as eating more fatty fish, will be enough.  Dr Palmer says maybe for people with relatively mild symptoms or conditions, some changes such as eating more fatty fish can help, but he points out that those changes don't stop seizures but the keto diet does, he says  "ketogenic therapy is a unique and powerful intervention".

What about other interventions to support mito health?

Exercise is a really important factor also and should be part of a treatment plan.  The two types of exercise for which there is the most evidence of benefit for mito health are strength training (aka lifting weights, working out to build muscle) and level 2 cardio (which he defines as 3-60 minutes of running, cycling, etc that gets you breathing hard but not out of breath).  Those types of exercise increase the number and health of mitochondria in muscles which then send endocrine signals to your brain that improve brain function.  Exercise alone isn't enough to heal mito, lose weight, or heal type 2 diabetes.  If people exercise more but don't change how they eat they don't get significant or sustained weight loss.  There has been one very well-done study of middle-aged adults who were prescribed exercise.  In addition, half were given the drug metformin to take and the other half were given a placebo.  The group that got metformin didn't get the mito and metabolic benefits of exercise the way the other group did, which is evidence that metformin interferes somehow with mitochondrial biogenesis.  Many other medications, including many psych meds, are known to interfere in mito function and biogenesis, so this should be considered.  Lifestyle behaviors such as drinking alcohol and smoking cigarettes and marijuana are also mito toxins.  

The psych drugs that can do this are mostly the anti-psychotics, which have been known to have metabolic side-effects and neurological side effects.  They can cause significant weight gain (he has seen people gain as much as 100 pounds in 6 months), they can cause type 2 diabetes, they worsen every known risk factor for cardiovascular disease (raise blood pressure, raise triglycerides, worsen LDL levels), and increase inflammatory biomarkers.  

This represents a new way to understand mental illness and what might be happening in the brain, and a new way to treat it.  This is especially important as mental health remains highly stigmatized in the US and research around it receives very little funding in comparison to disorders considered to be physical.  Many mentally ill people are in prisons, shelters, or even on the street.  "There is tremendous injustice, in my mind, in how we treat people with mental illness".  Dr Palmer points out that while psychological and social factors play a role in mental illness, it's no less physical and "real" in that way.  People with mental illness "deserve medically necessary treatment".  If we can get needed care to people in prison or who are homeless and who have mental illness, they won't be in prison or homeless anymore, they can live enjoyable, productive lives. 

 

 

 

 

 

 

Mast Cell Activation Syndrome and the Vagus Nerve

These are my notes from the article "Mast cell activation syndrome and the vagus nerve"
written by Ross Hauser, MD of Caring Medical on February 4, 2023 

Many patients diagnosed with MCAS (Mast Cell Activation Syndrome) also have neck pain that is diagnosed as (or can be described as) upper cervical instability or cervical spine instability.  It is generally assumed that this pain is part of the existing illness, but in this article Dr Hauser explains that the causality could be going the other way.  Many of these patients are also diagnosed with  Chronic Fatigue Syndrome, Myalgic Encephalomyelitis (ME/CFS), POTS, or some other form of Dysautonomia.  When these patients see specialists to see if the neck pain and problems could be causing some of their symptoms, some are then diagnosed with "degenerative disc disease in their cervical spine and a loss of the cervical curve contributing to kyphosis".Dr Hauser explains that:

"Which brings us to an important question, which came first? Autonomic nervous dysfunction or immune-mediated allergy?  At a minimum, we know they are interconnected. A lot of antigen-antibody immune complexes and a host of histamine releases are going to excite the autonomic nervous system throughout and likewise, autonomic nervous system dysfunction makes antigen-antibody reactions more likely. The patient has the symptoms, is it the neck causing them? Is it the allergies?"

He explains that the way cervical instability could lead to symptoms of MCAS, etc, is because it may be causing the vagus nerve to be pinched or compressed in the neck or: "damaged cervical ligaments’ inability to hold the “wandering” vertebrae in place."  The vagus nerve is how signals from the brain reach the viscera (the organs in your torso) in order to control them, so anything that impedes its function can have major consequences:

"When the vagal nerve sensory afferents are dysfunctional, the important body sensors for homeostasis are switched off. Cervicovagopthy or vagus nerve disorder brought on by cervical spine instability, has wide-ranging negative effects on mucosal barriers in the intestines and lungs, producing a large number of inflammatory mediators, including histamine."

Dr Hauser explains that many patients who fit this profile- having MCAS along with many of the following additional diagnoses- EDS (Ehlers-Danlos Syndrome, POTS (Postural Orthostatic Tachycardia Syndrome), Gastroparesis, Fibromyalgia, sleep disturbances, low blood pressure, serious gastrointestinal pain and dysfunction, "When someone has a myriad of symptoms like this, it is of course difficult to believe they all start spontaneously without a common thread linking them together. In a person like this, when all is a mystery, we follow the neurology, we look for short-circuiting messages between brain and body being caused by compression of the arteries, veins, and the nerves that travel through the cervical spine."

Dr Hauser notes that many of the different disorders and symptoms experienced by these patients Do have established connections and that these connections are further evidence of vagus nerve involvement.  A key example of this is the interconnection between the immune system and the gut, mediated by the vagus nerve, in which modulating signals are sent both ways.  Also, regulating signals and neurotransmitters in this system are part of the mechanism that the body uses to turn inflammation on and off.  To explain this he quotes a may 2021 study in the journal Frontiers in Pharmacology:

“Inflammatory bowel disease, irritable bowel syndrome, and severe central nervous system injury (of which the vagus nerve plays a dominant role) can lead to intestinal mucosal barrier damage, which can cause endotoxin/enterobacteria translocation (movement, or better thought of as escaping to other parts of the body) to induce infection and is closely related to the progression of metabolic diseases, cardiovascular and cerebrovascular diseases, tumors and other diseases.”

"The researchers add that repairing the intestinal barrier represents a potential therapeutic target for many diseases. Repair means addressing the dysfunction of enteral afferent nerves, efferent nerves, and the intrinsic enteric nervous system that play key roles in regulating intestinal physiological homeostasis and coping with acute stress. Furthermore, innervation actively regulates immunity and induces inherent and adaptive immune responses through complex processes, such as secreting neurotransmitters or hormones and regulating their corresponding receptors."

"Histamine is synthesized by mast cells, basophils, platelets, histaminergic neurons, and enterochromaffin cells, where it is stored intracellularly and released upon stimulation. It can be found basically everywhere in the body, including the spinal cord and brain. Histamine causes smooth muscle cell contraction, vasodilation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, while it stimulates gastric secretion and nociceptive nerve fibers. Histamine increases secretions such as hydrochloric acid in the stomach and is vital to protecting the lungs and gastrointestinal tract from infections. When histamine levels are high, increased secretions in the lungs, therefore, cause coughing, phlegm production, sneezing, and diarrhea occur in the digestive tract in an attempt by the body to rid itself of an infectious agent or toxin."

When the transmission of nerve impulses along the vagus nerve from the brain are interrupted or stopped, this can limit the body's ability to regulate and maintain homeostasis (balance of systems), which can keep the body from appropriately limiting the inflammatory response.  It also results in higher histamine content of mast cells, mast cells being more responsive to nerve signals to react, which ultimately means a higher level of histamine in the organs systems.  

"The GI tract harbors the largest population of mast cells in the body and is thus the main reservoir of the body’s histamine. The mast cells’ job is to maintain intestinal permeability and make sure that no microorganisms or antigens enter the body. (A dysfunction of this system can lead to Leaky Gut Syndrome and inflammation of the intestines.) The neurological control over mast cells and their various digestive functions is via the vagal influences on the enteric nervous system.  Elevated histamine levels in the body occur when there is an increase in intestinal permeability (regardless of the cause), including that from synthetic foods (industrial food additives, chemicals in food, genetically modified foods), Ehlers-Danlos syndrome (EDS), and cervical spine instability induced cervicovagopathy."

The effects of histamine on gut function, and how this impacts other disease processes especially autoimmune, has been well-studied.  Some common industrial food additives are known to trigger mast cells to make the gut more permeable (increase the amount of space between cells that line the gut and regulate what gets into the bloodstream and what doesn't), allowing larger proteins than usual into the bloodstream.  Once there, these proteins can trigger allergic and other inflammatory responses and are especially associated with autoimmune disease.  

"Histamine intolerance results from excessive histamine and a decreased ability to absorb or neutralize it.  Elevated levels of histamine give symptoms that mimic allergic reactions, and these include diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritis, flushing, and skin lesions. A true allergy is tied to IgE-mediated histamine release, which is to be differentiated from histamine intolerance. The latter is associated with some forms of urticaria, eczema, asthma, food sensitivity, migraines, and chronic GI and neurological ailments, including inflammatory and irritable bowel syndromes."

"The reservoir of histamine in the body originates in the gut and comes from the breakdown of food that is ingested or the microbiota-generated histamine. Histamine intolerance is akin to lactose intolerance in that the body is missing a key enzyme to digest a food substance. In histamine intolerance, it is DAO in the digestive tract, a deficiency of which leads to elevated histamine levels in the body. DAO is synthesized by the intestinal villi (enterocytes) and is constantly released from the intestinal mucosa into the gut, as well as the blood circulation, during eating and digestion."

Mast cell dysfunction is also being increasingly recognized as a major part of many neurological and psychiatric disorders, especially neurodegenerative disease.  "What is being suggested is that the Mast cells are causing runaway neurological inflammation by excerpting a disruptive influence (bad messages) on the central nervous system and brain and this is leading to neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease for example." 

"vagal activity, partially driven by gastric mast cells, induces long-lasting changes in corticotrophin-releasing factor signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors."

"What they found was vagus nerve stimulation resulted in a significant reduction of the different inflammatory parameters assessed. They said their results underscore the anti-inflammatory properties of the vagus nerve and the potential of neuro-immune interactions in the intestine.  In other words, if the vagus nerve is working correctly, anti-inflammatory and mast cell activation could be suppressed."

Further Information from Dr Hauser:
Can Chronic fatigue syndrome and Myalgic encephalomyelitis be caused by cervical stenosis and cervical spine instability? 

Postural Orthostatic Tachycardia Syndrome (POTS), the Vagus Nerve and Cervical Spine instability

Treatments for Neck Pain and Cervical Instability: A review of upper cervical instability and symptom treatment with Ross Hauser, MD

Cervical Curve Correction – Caring Cervical Realignment Therapy

Research Articles Cited in this Article (not all):
How to evaluate the patient with a suspected mast cell disorder and how/when to manage symptoms

Diagnosis of mast cell activation syndrome: a global "consensus-2"

Global Classification of Mast Cell Activation Disorders: An ICD-10-CM-Adjusted Proposal of the ECNM-AIM Consortium

Evaluation and Classification of Mast Cell Disorders: A Difficult to Manage Pathology in Clinical Practice

Intestinal Mucosal Barrier Is Regulated by Intestinal Tract Neuro-Immune Interplay

The Gut's Little Brain in Control of Intestinal Immunity

Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model

Vagus nerve stimulation dampens intestinal inflammation in a murine model of experimental food allergy