The Neuroimmune Loop: Th1, Th2, Histamine, Microglial Cells and the Vagus Nerve
Hello, I am Julie Donaldson and I am a clinical nutritionist with functional medicine training. I specialize in restoring balance in complex, chronic and acute health conditions. I welcome you to peruse other articles that may be of interest to you in your health investigation!
"Anyone can acquire a lot of information and take a lot of courses. But true knowledge and understanding is only won through experience. When you find those rare qualities along with honesty, integrity, caring, compassion, and commitment in your health practitioner, then you've found a rare combination that guarantees your success. Julie is that person.”
- William Wolcott
The Powerful Intersections Between the Immune System, Inflammation and Neurological Impairment
In this article, the immensely powerful connections between these body functions will be reviewed. Great advances and paradigm shifts have occurred in the understanding of how the brain/nervous system and the gut/immune system are impacting each other. In between the two lies the Vagus nerve, an integral part of this complex picture. Let’s explore the holistic health approaches around this complex loop.
The brain and neural processing
Body inflammation, essentially, is "injury" - injury to any tissue from any outside source, inclusive of impact or pathogen. When that injury is unresolved, it creates chronic inflammation.
Body inflammation leads to stress chemistry inciting brain inflammation. What follows is diminished Vagus nerve output which then loops back to more body inflammation.
What are some of the possible injuries we can suffer that can initiate this damaging loop?
tissue hypoxia, including cardiovascular events and loss of nitric oxide supplies
insulin resistance
oxidative stress
mold and mycotoxins
building & chemical toxins
pathogens such as viruses and chronic bacterial infections
Rheumatoid arthritis and Crohn’s Disease
traumatic head or brain injuries, concussions and PTSD
chronic personal/interpersonal stress with potential cortisol overload
poor detoxification function/histamine buildup, including the inability to clear sugars, alcohol & perfumes
In all of these disease and injured states, we have the potential alteration of the following body processes:
Body inflammation. One of the primary drivers of brain inflammation is body inflammation. Inflammation also causes impaired neuronal metabolic integrity. It is noteworthy that TNFα and IL-1β, two important inflammatory “ON” signals, are both primary pro-inflammatory cytokines that are upregulated in the context of brain inflammation.
Neuroinflammation. Increases in pro-inflammatory cytokines in the body create upregulation of brain inflammation. Systemic IL-1β can cause central nervous system (CNS) inflammation once it enters the brain, linking systemic inflammation and immune activation with brain inflammation
Microglial cell activation: Our bodies produce immune cells called macrophages. The job of the macrophage is to seek out and ingest foreign material. Microglia are the resident macrophages of the CNS. Microglia are exquisitely sensitive to brain injury and disease and are tasked with performing continuous surveillance on neurons . The pruning of synapses by microglia is an essential part of normal brain development. They do this by palpating. Activation of microglial cells is initiated by the movement of phosphatatdyl serine (PS) from the inside of the neuron cell wall to the outside. (PS is a very important phosphate-based lipid which protects the nervous system The phosphate/lipid combination provides fluidity in two dimensions combined with mechanical strength against rupture.) When it leaves the inner membrane of the neuron, however, microglia palpate the substance and initiate consumption of the neuron. Brown and Neher describe several factors that can drive PS to flip to the outside membrane, promoting apoptosis of neurons by microglia. These include ATP depletion, inhibition of phosphatidylserine translocases by oxidative stress, and increased calcium levels (latter may be impacted by heavy metal toxicity and/or thyroid imbalances). (NOTE: The official discovery of the glymphatic system in the brain occurred in 2015 at UVA’s Center for Brain Immunology and Glia. The meningeal lymphatic vessels consist of both interstitial fluid and cerebrospinal fluid which provide a conduit that enables communication between the brain parenchyma and cervical lymph nodes. This deepens the relationship between the immune and nervous systems.) Many clinically modifiable comorbidities have a common thread, in that they all influence neuron-microglial interactions.
Neuronal death. Surveillance by microglial cells of healthy and unhealthy neurons is happening billions of times daily, typically with a high degree of accuracy. But in an inflammatory state, the signaling tips in favor of gobbling vs. leaving neurons alone. The error rate which is naturally inherent in the process also becomes increased and tipped in favor of neuron consumption. This becomes very, very problematic for the overall health of the brain and nervous system, especially when microglial cells think that neurons are dying when they don't fire often enough...Loss of neuronal firing rate will at some point yield a loss of the neuron’s ability to generate enough electrical activity to adequately inhibit its consumption by microglial cells. This can occur as a consequence of impaired neuronal metabolic integrity, when the neuron cannot generate enough ATP to sustain its firing rate. Mitochondrial ATP production is required for all cells to function, including neurons. If the neuron cannot produce ATP, it cannot continue to pump PS from its outer membrane to its inner membrane; nor can it produce adequate neurotransmitters, growth factors, or other microglial “OFF” signals. Microglial activation is implicated in a number of neurodegenerative diseases, including Parkinson’s, MS and Alzheimer’s disease. Neuronal metabolic integrity is maintained by stimulation, oxygen and glucose.
Many other types of symptoms can precede this type of disease onset. These can include the following:
brain fog
migraines
mood swings
neuropathy (numbness and tingling) and/or essential tremors, tics
balance and motor coordination issues
Firing and non-firing neurons
The Vicious Cycle of Histamine/Mast Cells, GI Inflammation, Th2 Cell Proliferation and Neuroinflammation
Mast cell degranulation, Th2 cell proliferation, GI inflammation and neurogenic inflammation
As one possible instigator of a negative feedback loop in immunity and neurogenic inflammation, let’s discuss mast cells and histamine.
Th1 cells are the helpful cells that develop from immature T cells in the immune system - they support the body to fight pathogens effectively. Their unhelpful counterpart are Th2 cells. When body inflammation and stress chemistry have a decreasing effect on Th1 cells, the Th2 cells proliferate. Th2 cells then stimulate the degranulation of mast cells which contain histamine. As mast cells degranulate, they also release mitochondrial DNA, which is highly inflammatory, especially in the GI tract. mtDNA then recreates mast cell response in another harmful, repetitive cycle which increases histamine. Histamine erodes the mucosal barrier in the intestines, as well as the blood brain barrier...it is one of the few neurotransmitters that cause consistent opening of the blood brain barrier. This is a very dangerous potentiation, as the barrier exists to protect the brain and its neurons from harmful compounds. The important point is that as histamine goes up, so does neurogenic inflammation. As was stated earlier, this brain inflammation then produces more body inflammation in the way of more histamine, GI inflammation and leaky gut. In response to these changes, the epithelial cells in the blood and gut produce inflammatory cytokines which increase Th2 cells. Once again, it is a very vicious cycle. We must stop the injurious influences and ask how to get inside the neurogenic inflammatory process and quiet it back down.
Some other manifestations of histamine issues you might want to think about are:
insomnia
migraines
mood disorders
asthma
skin conditions
lung illnesses
sinus and eye conditions
interstitial cystitis
IBS
sneezing and allergies
intolerance to high histamine foods and alcohol
Histamine is cleared in the body by way of two different pathways, the MAO/DAO pathway and the ALDH pathway. The MAO/DAO pathway also requires ALDH, so this one is particularly key in our evaluation of clearance or lack thereof. B vitamins and molybdenum are crucial to assess, as well as iron balances in the blood.
Below is a helpful chart for understanding the myriad of possible histamine expressions in the body and the types of histamine present. Personalized testing and evaluation will create the right solutions for your individual manifestations of these issues.
Types and locations of histamine cells
The Beginnings of Vagus Nerve Compromise
The next piece of great import in this conversation is the compromise of Vagus nerve function that begins to occur when disease or injury is unresolved and produces systemic inflammation in the body.
The Vagus nerve is the main nerve in the body which controls the parasympathetic nervous system.
Anatomy of the Vagus nerve
The vagus nerve is responsible for the regulation of internal organ functions, such as digestion, heart rate, respiratory rate and vasomotor activity. It also controls certain reflex actions, such as coughing, sneezing, swallowing, and vomiting. It tonifies the nervous system by balancing the active, stimulated sympathetic nervous system with parasympathetic responses.
Its most important function is afferent, which means inward conduction. The delivery of information from the inner organs such as the gut, liver, heart, and lungs to the brain is also the job of the Vagus nerve. In other words, the inner organs are major sources of sensory information to the brain, via the Vagus nerve.
The connection between the central nervous system (CNS) and the enteric nervous system (ENS), also referred to as the brain–gut axis, enables the bidirectional connection between the brain and the gastrointestinal tract. It is responsible for monitoring the physiological homeostasis and connecting the emotional and cognitive areas of the brain with peripheral intestinal functions, such as immune activation, intestinal permeability, enteric reflex, and enteroendocrine signaling.
Going back to our list of potential offenders/injuries that will initiate these processes, let’s speak for a moment about traumatic brain injury (TBI). Research on TBI provides the widest selection of information on neuro-enteric inflammation. From this, we can decipher common reactions in all types of inflammatory conditions. Research shows that a head injury can alter the immune capacity/function of the digestive tract, and in particular, cause damage to the tight junctions of the mucosal barrier. Modulation of tight junction protein expression may explain, at least in part, the increase in intestinal permeability seen following brain injury. Mazzon and Cuzzocrea demonstrated that the structure and function of tight junction proteins on the intestinal epithelia depends on the regulation and production of TNF-α (Tumor necrosis factor-alpha is a cell signaling protein involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction) . Another possible mechanism to explain the attenuation of tight junction protein expression following TBI may involve intestinal epithelial cell death, since apoptotic cells in the mucosal epithelium have been described in rat TBI experiments.
So, imagine what this means when neurons in the brain respond to inflammation (both GI tract and systemic) with slower/less frequent firing and are then gobbled up by microglial cells, causing the whole system to suppress Vagus nerve activity. All at once, we've got multi-system compromise between signals going out from the brain and afferent feedback returning to the brain. Much of this information involves immune response, so here we witness the neuroimmune loop and its potential for constancy.
Also, when Vagus nerve output is diminished, the sympathetic (fight or flight) branch of the nervous system will preside. This means that the mechanisms of the lungs, gut, liver and kidneys will respond via sympathetic stimulation and stress chemistry. What can happen as a result of this? It's a long list, but some of the most critical answers are:
poor gut motility/SIBO
asthma
emotional stress/depression & anxiety
leaky gut & IBS
brain fog/confusion/headaches
excess appetite and weight gain
food sensitivities
inability to eradicate pathogens
fatigue
insomnia
blood sugar dysregulation
(A special note for those on thyroid medications: Thyrotropic Releasing Hormone (TRH) is expressed in the brainstem and plays a key role in gastric stimulation via the Vagus nerve. Thyroid hormone replacement can dampen TRH, yielding a loss of GI motility.)
Summations and Solutions on Supporting the Neuroimmune Loop
At True Nature, we are constantly concerned with the individual presentation of symptoms, nutrition and testing. Recalling the conversation from above about neurons, production of ATP in their mitochondria and how this allows them to continue firing, we must prioritize one of our primary therapies, Metabolic Typing ® (MT). MT’s unique ability to stabilize homeostatic mechanisms in the body provides the foundation for optimizing mitochondrial function. It is one of the only true forms of personalized nutrition.
The most important homeostatic mechanisms are blood sugar, body temperature, body fluid composition, gas concentrations (oxygen and carbon dioxide), and blood pressure. To maintain homeostasis, levels of glucose, gases and metabolic products all have to be tightly regulated. A series of metabolic processes that begin with nutrition make this possible. Here is a basic outline of those processes:
Digestion
Food is introduced into the oral cavity. The breakdown of proteins, fats and carbohydrates begins with saliva.
Chewed/swallowed food enters the stomach. Gastric juices further digest the food.
Complex carbohydrates are broken down into glucose and other byproducts in the intestines. The glucose is absorbed by the walls of the intestines and enters the blood stream. Amino acids and fatty acids from proteins and fats are also diffused through the plasma membrane to be absorbed by the cells of your body.
Cellular Respiration
Blood with oxygen from the lungs and glucose from the intestines is pumped out to the capillaries where the oxygen and glucose diffuse into individual cells.
Inside each cell, a chemical reaction called glycolysis splits the glucose molecules and produces enzymes and energy-carrying molecules called ATP (adenosine triphosphate). (ATP is the "gas" to every one of your body's trillion cells.)
The Krebs cycle steps use some of the enzymes produced by glycolysis to produce additional enzymes, more ATP and carbon dioxide.
The enzymes produced by glycolysis and the Krebs cycle enter the electron transport chain and produce a large number of ATP molecules. The final hydrogen reaction products combine with oxygen to form water.
Elimination
The carbon dioxide and water diffuse out of the cells into the blood stream and are passed back to the heart through the veins.
The blood is pumped through the lungs to eliminate carbon dioxide and through the kidneys to eliminate surplus water.
Cellular respiration is dependent upon successful completion of the Krebs cycle...
...and that successful completion of the Krebs cycle is dependent upon the right mix of nutrients for your individual metabolism. Because carbohydrates, proteins and fats feed into and are processed differently in the the cycle, this balance deserves careful attention. If we miss a key component (based upon our individual needs and metabolic tendencies) in a meal, we'll fall short of optimal production of ATP. While carbohydrates, proteins and fats are ultimately all converted into acetyl-coenzyme A to complete the cycle, they reach that point via different mechanisms. The Krebs cycle is the most important part of the process of aerobic respiration because it drives the formation of electron carriers. These carriers transport the energy used to create a large number of ATP molecules in the final steps of aerobic respiration.
When metabolic nutrition is fine-tuned and ATP is optimized, our primary responses will be the following (hundreds of other symptoms can improve):
hunger is satisfied for 4.5-5 hours following a meal
cravings disappear or can be easily quieted
good energy
good mood and good mental clarity
better elimination
balance in the nervous system
Assessment of the following is also recommended on an individual basis:
Toxicity must always be taken into account, as it overlaps with the immune and nervous systems; proper testing choices, inclusive of methylation patterns, must also be individualized following symptom assessment
Failures and requirements of the immune system with offending pathogens: Th1 and Th2 symptom assessment as well as appropriate immune, metabolic & pathogen testing are necessary
Specific brain/neuron healing substances and therapies should be considered: binaural beat therapy, cognitive therapy and electrical stimulation therapy are all appropriate considerations in addition to natural medicinal remedies
For PTSD, multi system failure conditions and those with thyroid disease/medication, transcutaneous electrical nerve stimulation therapy (TENS) may be necessary. Please see here for a list of scientific references on this therapy:
https://www.cell.com/cell-reports/pdfExtended/S2211-1247(16)30135-8; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859128/; https://pubmed.ncbi.nlm.nih.gov/25164906/;
As you can see, this is a complex loop and it requires careful, intelligent assessment of individual needs.
Write to us today at Julie@truenaturehealthconsulting.com for more information. We provide holistic telehealth services.