Disclaimer: The information in this article is for educational purposes only and not meant to replace diagnosis, treatment, or prescription by a qualified medical professional.
Despite much research and knowledge that has been gleaned over the years about migraine, it is still a stubborn and formidable beast of a condition that confounds many of medicine’s best practitioners. I coach people with migraine headaches who have seen some of the most accomplished migraine experts in the world – and they still get migraines.
Because migraine headaches are a manifestation of a serious chronic systemic inflammatory process affecting every major organ of the body, there are infinite angles and lenses through which we can try to understand migraine. Migraine is associated with:
- food sensititivies and digestive problems
- environmental chemical sensitivities
- reduced thyroid function (hypothyroid)
- congested liver and gallbladder
- adrenal/pituitary axis imbalances and kidney problems
- neurotransmitter imbalances with attendant mood “disorders” such as anxiety and depression
- cranial nerve activation and cortical spreading depression
- hormonal imbalances (low progesterone to estrogen ratios)
- low antioxidant status (especially glutathione but also melatonin)
- electrolyte and consequent blood pressure imbalances (caused mostly by compromised kidney function)
- beta-amyloid plaque/lesions
- low blood pressure
- blood sugar imbalances
- blood platelet aggregation (“sticky blood”)
- lymphatic congestion
- compromised mitochondrial function
- peripheral neuropathies
- increased risk of stroke
- hypermobile joints and lax connective tissue around blood vessels (Ehlers Danlos Syndrome)
- neck and muscular tension
- unresolved trauma
- chronic stress
- And the list goes on and on
So, where to start in this constellation of symptoms?
The list above is long, and yet I see all of them as being symptoms of the root cause of migraine.
If you ask the experts, you’ll see that they are still debating whether migraine starts in the gut as a digestive and enzymatic problem, is caused by circulatory issues (dilated or constricted blood vessels), or if it originates in the brain itself (cortical spreading depression). Let’s not loose sight of the fact that it’s all one integrated system. Since the vagus nerve connecting gut and brain is a two-way circuit I’m not sure why this ultimately matters (although 80% of the nerve transmission is from gut to head). Researchers at Harvard Medical School have found that:
. . . even “non-sick” humans harbor over 200 organisms in the brain. Those numbers don’t even include the virome (viruses). And we know that a bunch of herpes viruses can also survive in the brain . . . Linked in with that model is the gut microbiome because the gut microbiome and the brain microbiome communicate a lot via the vagus nerve. There’s lots of traffic, with bacteria in the brain/gut talking to one another via this highway all the time. Some products of gut fermentation like Short Chain Fatty Acids (SCFAs) literally travel the Vagus Nerve (physical translocation). Immune cells in the brain need these gut microbial SCFAs to mature correctly. Conversely, certain bacteria in the gut live exclusively off chemicals generated in the brain that are transported to the gut. Vagus Nerve traffic may include bacterial signaling molecules called quorum sensing molecules. In this sense microbes in the gut and microbes in the brain may be “talking,” and possibly reaching decisions about what to do next. (Source).
No matter what the experts say, we know that migraine in a large number of people is triggered by foods and improved when these foods are eliminated. We also know that other factors like sleep deprivation and stress can cause migraine without a food trigger. These are not incompatible viewpoints (or even different types of migraine, necessarily) because as we know, migraine is a systemic inflammatory condition. In a constant state of inflammation, triggers can and do come from any number of directions and reinforce each other through infinite nonlinear feedback loops.
We need to start thinking of the body as a whole intelligent system, rather than a machine prone to breaking down in specific areas and ways. Perhaps finding the solution to chronic migraine headaches depends on a new way of thinking that transcends these either/or traps (either originating in the head OR originating in the gut; either nutritional OR genetic; either caused by blood vessel dilation OR trigeminal nerve activation, etc etc).
The Downstream Effects of a Disrupted Microbiome
From the research I’ve done into migraine, I believe that the root cause factor that most contributes to migraine is imbalances in the body’s microbiome – and NOT just the microbiome of the gut. Since the gut, blood vessels, and brain all have a microbiome, there’s no reason why migraine can’t start in any one of these places – and then spread to other areas of the body.
Researchers only very recently discovered that these different biomes, by way of bacterial colonies of biofilm, can communicate with one another through electrical signalling (not just chemical signalling) across different species of bacteria and regions of the body. Therefore, assaults to any part of the the microbiome – whether gut, brain, or blood – by antibiotics and other factors that influence microbiome health will affect the rest of the microbiome elsewhere in the body. This change in the microbiome causes a long cascade of effects:
- nutritional deficiencies (especially of B vitamins) which leads to
- enzyme deficiencies which leads to
- compromised amino acid metabolism which leads to
- elevated levels of glutamate, histamine, and nitrate as well as
- elevated ammonia (from nitrate), which, due to enzyme deficiencies, doesn’t convert to urea for excretion. This elevated ammonia may have effects on
- venous and arterial endothelial tissues – ie, undermining the ability of the blood vessels to expand and contract as needed, and/or leading to the tendency for smaller capillaries to be “leaky”. Chronically dilated blood vessels and leaky capillaries can lead to the escape of excess blood proteins fibrinogen, albumin, and globulin from the capillaries and into the interstitial space of the lymphatic system. This congested lymph (including brain lymph of the glial cells, ie, the “glymphatic system”), combined with the elevated levels of ammonia, glutamate, and CGRP, leads to:
- systemic edema, swelling, inflammation, and encephalopathy, (aka “Migraine”). This systemic inflammation makes:
- greater demands on antioxidants and
- compromises cellular respiration, which in turn leads to
- reduced mitochondrial function.
There you have it in a nutshell. I believe that the process that we call “migraine” is a result of these major setbacks (originating from one original setback: compromised microbiome and B vitamin deficiences). The cascade of problems downstream results in all of the comorbid symptoms mentioned previously (gallbladder congestion, food sensitivities, etc). When this process goes on for years and years, a state of deep depletion results that is hard to overcome.
The Greatest Assault to the Microbiome: Antibiotics
Antibiotics literally means “anti life.” The average person will get 44 doses of antibiotics in their lifetime – even while the CDC says that 30% of all antibiotics administered in the US (totaling 47 million prescriptions) are unnecessary or prescribed incorrectly (Source).
But us moderns are exposed to many antibiotics above and beyond antibiotics administered as medication. Another major source of antibiotics is through our food. Both pesticides and herbicides are antibiotics. Antibiotics are also administered to animals raised for meat in their feed, which is also the leading cause of antibiotic resistance.
These antibiotics don’t only affect our microbiome – some of them even directly affect how we metabolize amino acids like glutamate. For example, one of the most ubiquitous antibiotics we are subject to is the herbicide Roundup (generic term: glyphosate).
Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. . . The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. . . .
Glyphosate has been shown to activate NMDA receptors in rat hippocampus, and this has been proposed to be in part due to glyphosate’s ability to act as a ligand in place of glycine, in addition to glutamate (as the other ligand), whose overexpression is induced by glyphosate. . . (Source)
After 4.5 years of researching migraine headache, I’m convinced that a microbiome disrupted by environmental chemical assaults and medications are the cause. What is happening to our guts is happening to our soil and vice versa. Isn’t it ironic (and sad) that it is the medical and food systems which are most compromising us? These are the two systems that should most be supporting our health.
B Nutrient Deficiencies and Brain Inflammation
There are many ways that nutrient deficiencies caused by compromised gut health can lead to brain inflammation, but here I just want to focus on B vitamins and the role they play in brain inflammation.
According to Dr. Stasha Gominak, a neurologist specializing in sleep disruptions and migraine, B vitamins are needed by the body at night to do deep level healing and repair during REM sleep. To start with, many migraineurs have disrupted sleep patterns and reduced REM sleep, making this repair difficult. But in the presence of B vitamin deficiencies, this repair can’t take place. Improved sleep hygiene, gut rehabilitation and B vitamin supplementation is the answer.
Dr. Gominak puts forth evidence that our biome is meant to be our primary source of B vitamins, and that food is supplemental to this source. She has demonstrated that when our gut flora become compromised by antibiotics or other assaults, they can be rehabilitated by being in the environment they prefer – and that environment is the environment that they normally produce, ie, a b-vitamin “soup” ( in this case, provided by B vitamin supplementation).
Since B vitamins are essential for enzymatic function (and the breakdown and metabolism of histamine, glutamate, and nitrate), a B vitamin deficiency leads to a buildup of these inflammatory molecules. These disrupted enzymatic processes also affect all organs downstream, as well as fatty acid metabolism, carbohydrate metabolism, and neurotransmitter function.
Amino Acids and Migraine: Glutamate, Histamine, Nitrogen
So, what is it that brain inflammation without a food trigger and brain inflammation with a food trigger have in common? Elevated levels of the amino acids glutamate, histamine, and nitrate.
Amino acids are molecules that help to bring nutrients into the cell. Amino acids are synthesized by bacteria in our gut, and by enzymatic processes in our liver and in our cells, which in turn require vitamins to do their job – especially B vitamins.
Glutamate is an amino acid which acts as an excitatory neurotransmitter. The body can make it, but you can also ingest it in food (in msg, tomatoes, fermented foods, bone broth, etc).
“Glutamate is very interesting because it’s also an excitatory amino acid in the human brain. In fact, about half of all brain activity is regulated by glutamate. Glutamate is also one of few amino acids that’s charged. So it can’t just get in and out of cells on its own because that’s energetically unfavorable. So you’ve got to have some kind of a proton motor force to actually take up the charged amino acids. And if you’re dealing with a proton motor force then the cell membrane potential is important.” (Source)
The other charged amino acids are lysine, aspartic acid, and arginine. Histidine, glutamine, tyrosine, and tryptophan are polar (proton donors or acceptors) (source).
Similarly, histamine is present in many foods but is also released by the body (from the mast cells, for example). It is broken down by enzymes different than glutamates. Glutamates and histamine build up because the body is lacking the vitamin and mineral building blocks needed to convert it into less harmful forms through metabolic enzymatic processes.
There is nothing wrong with glutamate per se, just as there is nothing wrong with histamine. The problem is the excessive buildup of these amino acids. High levels of all of these usually coincide together and reinforce each other.
Nitrates are another amino acid that build up in the body of migraineurs when insufficient vitamins are available to make the enzymes that break it down. This can be especially problematic for reasons outlined below.
Nitrates and Ammonia
Nitrates, like glutamates, can also be ingested in food. Nitrates are generated from the breakdown of protein but also are present in cured meats (a known migraine trigger) and some vegetables. Nitrates are converted to ammonia in the body, and then processed by the liver where it is neutralized and excreted as urea. However, if the nitrogen scavenging cells of the liver are damaged (by ammonia), and the person has a compromised urea cycle and along with it, ammonia will accumulate in the body. If, on top of this, the person is deficient in vitamins and amino acids, such as niacin or glycine, which normally aid in ammonia detoxification, they will have elevated levels. Nitrogen blocks glycine.
Main sources of ammonia are the colon (through bacterial metabolism of proteins and urea) and small intestine (through bacterial degradation of glutamine). . . . Hepatic transformation of ammonia into urea and subsequent excretion of urea via colon or kidneys prevent entrance of ammonia into the systemic circulation. If the hepatic metabolic capacity is exceeded, or if ammonia bypasses the liver by shunting of blood, circulating ammonia levels increase and elimination of ammonia is shifted to kidneys, brain, and skeletal muscle. Ammonia that reaches the brain can be metabolized by forming glutamine from glutamate, mostly in astrocytes with subsequent transfer of glutamine to neurons, and deamination of glutamine resulting in the formation of the neurotransmitter glutamate. (Source)
Bacteria in our gut also produce nitrates (as well as ammonia), so gut microbiome health directly impacts overall nitrate and ammonia load above and beyond that generated by the diet. Migraineurs have been shown to have more nitrate-producing bacteria in their guts, as well as higher levels of ammonia in their blood.
Many organisms in our gut also produce ammonia. Upper gut bacteria can break down amino acids into nitrogen compounds including ammonia and some produce the enzyme urease which converts urea back into ammonia. . . Some bacteria also produce ammonia or convert urea to help them thrive in our gut, reduce antimicrobial efficiency (if they require a certain pH to be effective) and when overgrown cause dysbiosis. . . Dysbiosis can increase ammonia production within our gut and many people with upper gut overgrowth have liver health issues, which decreases ammonia secretion. Both probiotic bacteria and opportunistic strains produce ammonia. If you are dealing with dysbiosis and are having issues clearing ammonia, it may not matter if you have an overgrowth of a normally probiotic bacteria or opportunistic strains – both can cause issues. (Source)
As mentioned previously, ammonia, once it accumulates, binds with glutamine to form glutamate. The combination of ammonia and glutamate leads to brain swelling, aka, encephalopathy. This is also known as hyperammonemia. Encephalopathy is just a general term to describe brain inflammation from many causes, but it is a central feature of migraine. I believe that ammonia is a largely overlooked factor in migraine headache.
Healing Migraine from the Root
If my hypothesis for the root cause of migraine is correct, then the following steps represent the greatest leverage points for resolving migraine:
- rehabilitating the gut, blood, and brain microbiome;
- while replacing nutrition (mostly B vitamins) lost due to microbiome dysfunction;
- reducing dietary glutamate, histamine, and nitrate load and
- supporting the body to eliminate excess ammonia.
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CGRP – Calcitonin Gene Related Peptide
CGRP (calcitonin gene related peptide) is a neuropeptide responsible for blood vessel dilation. The triptan medications work to abort migraine by inhibiting the neuron’s receptor sites of CGRP, in the presence of elevated levels of CGRP.
Toxicity (ie, Sepsis) and Lymphtic Congestion
Another discovery that only recently came which we should take note of in revising and updating our view of migraine pathology is the discovery that the blood-brain barrier doesn’t (strictly speaking) really exist.