Mast cell activation syndrome and the vagus nerve

Ross Hauser, MD

There is a connection between neck pain and instability and mast cell activation syndrome.

Over the years we have seen many patients who among their long list of symptoms and ailments include Mast Cell Activation Syndrome. They also had neck pain. For many, their neck pain was seen as a manifestation of their illnesses, rarely was it seen as the cause of their illnesses.

So many of these people took it upon themselves to explore upper cervical instability and cervical spine instability not as another symptom, but rather as the possible cause for their long list of ailments.  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 release 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?

People will tell us that in their own research they came upon the idea that cranial cervical instability may be the cause of their prolonged illness including diagnosis of Chronic Fatigue Syndrome, Myalgic Encephalomyelitis, POTS, and Mast Cell Activation Syndrome. What we observe in our own patients and what we see in people that we talk to who are interested in becoming patients is that among their many symptoms is neck pain. However for some, their neck pain was seen as a manifestation of their illnesses, rarely was it seen as the cause of their illnesses.

So many of these people have taken it upon themselves to explore upper cervical instability and cervical spine instability as not a symptom, but rather a cause. These people then make appointments with Cervicocranial specialists who examine them and take imagining studies. In some of these images, the patients learn that they degenerative disc disease in their cervical spine and a loss of the cervical curve contributing to kyphosis.

When the vagal nerve sensory afferents are dysfunctional, the important body sensors for homeostasis are switched off. Cervical vagaopthy 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 amount of inflammatory mediators, including histamine. This has been demonstrated by a number of recent studies as we will examine below.

Symptoms and complaints of Mast Cell Activation Syndrome

A February 2022 paper in the journal Cureus (1) summarizes the symptoms and complaints of Mast Cell Activation Syndrome:

The most frequent symptoms reported by patients with MCAS are gastrointestinal – crampy abdominal pain, diarrhea, nausea, vomiting; cardiovascular – hypotension, tachycardia, syncope (fainting); cutaneous – pruritus (itchy skin and rash), urticaria (hives), flushing, angioedema (deep welts); respiratory – wheezing, stridor (wheezing or “Darth Vader” sounds when breathing).

Patients with MCAS may have a variable clinical phenotype (diagnosis), affecting multiple organ systems but the key feature is recurrent episodes of severe symptoms (anaphylaxis), with concurrent involvement of a minimum of two organ systems and association with an acute increase of specific biologic mediator levels, considered biomarkers of mast cell activation, mainly the serum tryptase. (Tryptase is an enzyme along with histamine and other chemicals, released from mast cells when they are activated as part of a normal immune and allergic response).

The difficulty in diagnosis Mast Cell Activation Syndrome –  Idiopathic mast cell activation syndrome

A January 2022 case study presented by Dutch physicians wrote (4): “Idiopathic (sudden development from an unknown cause) mast cell activation syndrome (MCAS) is one of the causes for recurrent complaints. The diagnosis is sometimes delayed but also often made incorrectly.

Case: (A) patient presented with recurrent attacks of itching, redness of the skin, diarrhea, and near collapse. During an attack, his serum tryptase level rose significantly. We could not identify an underlying trigger. A diagnosis of idiopathic mast cell activation syndrome was made. He was successfully treated with a combination of H1 (blocking the production of histamine) and H2 blockade (stopping the production of stomach acids). Conclusion: MCAS is characterized by recurrent complaints. To make the diagnosis a significant rise in mast cell mediators (serum tryptase) is required. Given the diversity of symptoms, many patients with somatically unexplained symptoms are wrongfully believed to be suffering from MCAS.

Somatically unexplained symptoms

Somatically unexplained symptoms are sometimes generally classified into two groups – “we don’t know” or “It’s all in their head – psychiatric problems are suspected.” Yet people tell us of multiple skin biopsies, extensive dermatologists, immunologists, allergist visits, and extensive steroids. Some tell us that their vagus nerve has been damaged by infection or other means and MCAS, insomnia, anxiety, sensitivity to cold, ear fullness, and digestive problems. Some will have more extensive testing and tell us about their diagnosis of POTS, Dysautonomia, and hypermobile Ehlers Danlos Syndrome.

Inflammatory bowel disease and irritable bowel syndrome

A May 2021 study in the journal Frontiers in Pharmacology (2) wrote:

“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.

The parasympathetic vagal nerve has been put forward as an integral part of an immune regulation network

A 2013 paper in the journal International Scholarly Research Network Gastroenterology from Dr. Wouter J de Jonge describes the role of the vagus nerve in the immune system. (3)

“The gut immune system shares many mediators and receptors with the autonomic nervous system. Good examples thereof are the parasympathetic (vagal) and sympathetic neurotransmitters. . . Earlier and more recent studies in neuroscience and immunology have indicated the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems.

Sympathetic immune modulation (Simply the workings of the immune system in the “fight or flight response) is well described . . . (more recently) the parasympathetic vagal nerve has been put forward as an integral part of an immune regulation network via its release of Ach, a system coined “the cholinergic anti-inflammatory reflex.” (This is the part of the nervous system that helps control and regulate inflammation)

A prototypical example is an inflammatory reflex, comprised of an afferent arm that senses inflammation and an efferent arm: the cholinergic anti-inflammatory pathway, that inhibits innate immune responses.”

The last sentence represents the ying and yang concept of the central nervous system’s turning on and turning off inflammation.

One of the body’s more important immune modulators and neurotransmitters, histamine has wide-ranging effects.

Histamines are chemicals produced by the immune system to get rid of allergens, toxins, or substances that cause an immune response or allergic reaction. Itching a rash is a histamine response, sneezing is a histamine response. However, when your body overreacts to this stimulus, an antihistamine is typically called for to calm down the immune response symptoms. When increased levels of histamines become unmanageable histamine-induced illnesses can be caused, which include histamine intolerance, mast cell activation syndrome (MCAS), and even IgE-mediated serious allergic diseases. During activation, the mast cells release histamine. Hence the name mast cell activation syndrome (MCAS).

Above I wrote that cervical vagaopthy 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 amount of inflammatory mediators, including histamine.  Increased levels of histamines cause histamine-induced illnesses, which include histamine intolerance, mast cell activation syndrome (MCAS), and even IgE-mediated serious allergic diseases. During activation, the mast cells release histamine.

Increased levels of histamines cause histamine-induced illnesses, which include histamine intolerance, mast cell activation syndrome (MCAS), and even IgE-mediated serious allergic diseases. During activation, the mast cells release histamine.

Cervical spine instability, the vagus nerve, and histamine

Cervical spine instability caused by damaged cervical ligaments’ inability to hold the “wandering” vertebrae in place can be the structural etiological basis or co-morbidity in all these illnesses through its effects on the vagus nerves. While histamine intolerance may just need an adjustment of histamine-containing foods in the diet, MCAS and IgE-mediated allergic diseases necessitate more aggressive treatments.

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 cervical vagopathy.

In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part tight junctions play in autoimmune diseases’ pathogenesis has been extensively described.

It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. The effect of synthetic foods, including industrial food additives, chemicals in foods, and genetically modified food has been shown to increase intestinal tight junction permeability.

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.

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.

The level of histamine correlates with the symptom produced.

What we see in this table is the measured histamine effects according to plasma histamine concentration. (5)

Histamine (ng/ml Nanograms per milliliter) of:

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.

The diagnosis of histamine intolerance can be made by noting elevated levels of histamine in the blood and low levels of DAO activity.  The most common symptoms from histamine intolerance are digestive and include bloating, postprandial fullness, diarrhea, and abdominal pain. When placed on a histamine-reduced diet, an improvement in symptoms occurs. DAO activity and a lowering of histamine levels support a successful diagnosis.

This is summed up in an April 2021 paper in the journal Nutrients on histamine intolerance. (6)

“Histamine intolerance is assumed to be due to a deficiency of the gastrointestinal enzyme diamine oxidase (DAO) and, therefore, the food component histamine not being degraded and/or absorbed properly within the GI tract. Involvement of the GI mucosa in various disorders and diseases, several with unknown origin, and the effects of some medications seem to reduce gastrointestinal DAO activity. Histamine intolerance causes variable, functional, nonspecific, non-allergic GI and extra-intestinal complaints. Usually, evaluation for Histamine intolerance is not included in differential diagnoses of patients with unexplained, functional GI complaints or (other) disorders and diseases. The clinical diagnosis of Histamine intolerance is challenging, and the thorough (patient account, history, and diary) of all Histamine intolerance-linked complaints, using a standardized questionnaire, is the mainstay of Histamine intolerance diagnosis.”

With unknown origin – is it dysfunction in the nerves and immune cells’ ability to communicate that causes Mast Cell Activation Syndrome?

In the past decades, researchers have come to the opinion that immune cells and nerve cells talk to each other. An April 2019 study in the journal Neuroscience (7) offers a brief explanation

“Inflammation in the nervous system, termed “neuroinflammation,” has become increasingly recognized as being associated with neurodegenerative diseases. Early attention focused primarily on morphological changes in astrocytes (the glial cells (cells of the central nervous system) in the brain that are closely associated with neuronal synapses) and microglia glial cells that clean up dead brain cells; however, brain and central nervous system resident mast cells are now receiving attention as a result of being “first responders” to injury.

Mast cells also exert profound effects on their microenvironment and neighboring cells including behavior and/or activation of astrocytes, microglia, and neurons, which, in turn, are implicated in neuroinflammation, neurogenesis, and neurodegeneration. Mast cells also affect disruption/permeability of the blood-brain barrier enabling toxin and immune cell entry exacerbating an inflammatory microenvironment.”

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.

The next step is the parasympathetic nervous system – the domain of the vagus nerve

A 2015 paper in the journal of Methods in Molecular Biology (8) gives us this connection between the parasympathetic nervous system and regulating immune responses.

“Often considered as the archetype of neuroimmune communication, much of our understanding of the bidirectional relationship between the nervous and immune systems has come from the study of mast cell-nerve interaction. Mast cells play a role in resistance to infection and are extensively involved in inflammation and subsequent tissue repair. Thus, the relationship between mast cells and neurons enables the involvement of peripheral and central nervous systems in the regulation of host defense mechanisms and inflammation. Recently, with the identification of the cholinergic anti-inflammatory pathway, there has been increased interest in the role of the parasympathetic nervous system in regulating immune responses.”

Vagus nerve – parasympathetic dysfunction

The cause of vagal or parasympathetic dysfunction has many symptoms including a depressed or overactive immune system and systemic inflammation. A cause of these symptoms that is often overlooked is a structural injury to the cervical spine.

Bad vagus signals cause chronic gastrointestinal distress by way of gastric mast cell

A March 2021 study in the Journal of Clinical Investigation (9) insight wrote: “Functional dyspepsia is associated with chronic gastrointestinal distress and with anxiety and depression.” What the researchers in this paper wanted to demonstrate was that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. In animal research, these investigators found Functional dyspepsia is characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, and found that vagal activity – in response to gastric distention – was increased in the animals with Functional dyspepsia.

It was observed that was Functional dyspepsia was associated with gastric mast cell (overactivation) and increased expression of corticotrophin-releasing factor (peptide hormone that affects the response to stress) and decreased brain-derived neurotrophic factor genes (peptides or proteins that support neuron growth) in the central amygdala (the area of the brain where emotional behavior resides). Subdiaphragmatic vagotomy (the removal of the vagus nerves in laboratory rats) reversed these changes and restored effective behavior to that of controls. In conclusion, 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.

Restoring vagus nerve function

In the above study what was being suggested was that the vagus nerve was sending bad signals into the digestive system causing dysfunction. The proof of this was that if you removed the vagus nerve portion that leads to the GI tract, you could stop functional dyspepsia in the laboratory animals. Removing the vagus nerve is obviously not ideal in humans. However, removing the vagus nerve dysfunction is.

In a September 2019 paper in the journal Allergy (10), researchers noted the importance of the vagus nerve “as an important modulator of the intestinal immune system.” In this paper, the researchers wanted to know to what extent the vagus nerve impacts the inflammatory response to food allergy is still unclear.  To do this, the researchers removed the vagus nerve or used vagus nerve stimulation to increase its function, and then the mice were given a challenge that they were sensitive to. Then they looked for signs of food sensitivity in the mice to included elevated mast cells.

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.

Skin rashes, eczema, psoriasis mast cells, and their interaction with nerve cells.

A September 2019 study in the Frontiers in Cellular Neuroscience (11) looked at the “intimate interaction between mast cells and sensory nerves.”

“The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial (welt) reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves.  . . Even though mast cells are well recognized for their role in allergic skin wheeling and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. “

Again we see “mast cell-sensory nerve communication” is essential for regulating the immune response to skin disorders. Throughout this article, I focused on Mast Cell Activation Syndrome and its inflammatory response as culprits in the symptomology some people suffer from. As with many medical disorders, trying to find the source of the patient’s health challenges can daunting, specifically in cases of a long list of symptoms and conditions related to a dysfunctional immune system and possible vagal involvement. Mast Cell Activation Syndrome response caused by cervical instability may be one possible explanation.

What are we seeing in this image?

A Digital Motion X-Ray or DMX is a tool we use to help understand a patient’s neck instability and how we may be able to help the patients with our treatments. In the illustration below a patient who suffered from upper cervical instability demonstrated hypermobility of the C1-C2.

A Digital Motion X-Ray or DMX is a tool we use to help understand a patient' neck instability and how we may be able to help the patients with our treatments. In the illustration below a patient who suffered from upper cervical instability demonstrated hypermobility of the C1-C2. This hypermobility can result in common symptoms of neck pain, headaches, dizziness, vertigo, tinnitus, concentration difficulties, anxiety and other symptoms common in TMJ/TMD patients.

Repairing the ligaments and curve for a long-term fix

The goal of our treatment is to repair and strengthen the cervical ligaments and get your head back in alignment with the shoulders in a normal posture.

What are we seeing in this image?

In this illustration, we see the before and after of neck curve corrections. Ligament laxity or looseness or damage, whether the cause is from trauma, genetic as in cases of Ehlers-Danlos syndrome, ultimately causes a kyphotic force on the cervical spine, stretching the posterior ligament complex of the neck. As can be seen in the x-rays of this image, patients with a whiplash injury, Joint Hypermobility Syndrome, and Ehlers-Danlos syndrome can have their cervical curve restored with Prolotherapy Injections and the use of head and chest weights.

In this illustration we see the before an after of neck curve corrections. Ligament laxity or looseness or damage, whether the cause is from trauma, genetic as in cases of Ehlers-Danlos syndrome, ultimately causes a kyphotic force on the cervical spine, stretching the posterior ligament complex of the neck. As can be seen in the x-rays of this image, patients with a whiplash injury, Joint Hypermobility Syndrome, and Ehlers-Danlos syndrome can have their cervical curve restored with Prolotherapy Injections and the use of head and chest weights, documented below.

In this video, a demonstration of treatment is given

Prolotherapy is referred to as a regenerative injection technique (RIT) because it is based on the premise that the regenerative healing process can rebuild and repair damaged soft tissue structures. It is a simple injection treatment that addresses very complex issues.

This video jumps to 1:05 where the actual treatment begins.

This patient is having C1-C2 areas treated. Ross Hauser, MD, is giving the injections.

Summary and contact us. Can we help you? How do I know if I’m a good candidate?

Cervical instability is explained throughout this website: I would like to direct you to these articles to continue your research:

We hope you found this article informative. Just like you, we want to make sure you are a good fit for our clinic prior to accepting your case. While our mission is to help as many people with chronic pain as we can, sadly, we cannot accept all cases. We have a multi-step process so our team can really get to know you and your case to ensure that it sounds like you are a good fit for the unique testing and treatments that we offer here.

Please visit the Hauser Neck Center Patient Candidate Form

References

1 Leru PM. Evaluation and Classification of Mast Cell Disorders: A Difficult to Manage Pathology in Clinical Practice. Cureus. 2022 Feb 13;14(2). [Google Scholar]
2 Xin-yu Y, Han-yu Z, Xu H, Fang W, Peng-wei Z, Yan-jun Z. Intestinal mucosal barrier is regulated by intestinal tract neuro-immune interplay. Front Pharmacol. 2021 May 31;12:659716. doi: 10.3389/fphar.2021.659716. eCollection 2021. [Google Scholar]
3 de Jonge WJ. The gut’s little brain in control of intestinal immunity. International Scholarly Research Notices. 2013;2013. [Google Scholar]
4 van Daele PL, Hermans MA, Elberink JH, van Wijk RG. Idiopathic mast cell activation syndrome. Nederlands tijdschrift voor geneeskunde. 2022 Jan 24;166:D5844. [Google Scholar]
5 Maintz L, Novak N. Histamine and histamine intolerance. The American journal of clinical nutrition. 2007 May 1;85(5):1185-96. [Google Scholar]
6 Schnedl WJ, Enko D. Histamine intolerance originates in the gut. Nutrients. 2021 Apr;13(4):1262. [Google Scholar]
7 Jones MK, Nair A, Gupta M. Mast cells in neurodegenerative disease. Frontiers in cellular neuroscience. 2019 Apr 30;13:171. [Google Scholar]
8 Forsythe P. The parasympathetic nervous system as a regulator of mast cell function. Mast Cells. 2015:141-54. [Google Scholar]
9 Cordner ZA, Li Q, Liu L, Tamashiro KL, Bhargava A, Moran TH, Pasricha PJ. Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model. JCI insight. 2021 Mar 22;6(6). [Google Scholar]
10 Bosmans G, Appeltans I, Stakenborg N, Gomez‐Pinilla PJ, Florens MV, Aguilera‐Lizarraga J, Matteoli G, Boeckxstaens GE. Vagus nerve stimulation dampens intestinal inflammation in a murine model of experimental food allergy. Allergy. 2019 Sep;74(9):1748-59. [Google Scholar]
11 Siiskonen H, Harvima I. Mast cells and sensory nerves contribute to neurogenic inflammation and pruritus in chronic skin inflammation. Frontiers in cellular neuroscience. 2019:422. [Google Scholar]

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