Microbiome Alteration Through Diet as a Treatment for Epilepsy and Seizure Disorders
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A Novel Dietary Treatment Approach for Epilepsy
Working Paper
Katharine Hankus, MA
Abstract
Epilepsy is a serious neurological disease that affects over 65 million people worldwide with that number expected to rise[1]. It is a serious disease causing lifelong disability and a significantly increased risk of mortality. Recent research has highlighted the microbiome as a cause – and treatment – for numerous diseases, including epilepsy. We propose the GAPS nutritional protocol as a therapeutic target for epilepsy because it takes a necessary multifaceted approach to treating the factors that result in epilepsy. The GAPS nutritional protocol decreases intestinal permeability and pathogenic immune responses while rebalancing gut microbiota and treating dysbiosis. Furthermore, recent insight into the mechanisms of action of the ketogenic diet show that it is not the ketones that provide anti-seizure effects, but rather an alteration of intestinal microbiota, anti-inflammatory side effects, and inclusion of medium-chain triglycerides. In particular, it is not necessarily the blood plasma levels of ketones raised by the traditional ketogenic diet or MCT diet, but rather plasma levels of decanoic acid. We also propose that if major diet changes like the ketogenic diet can reduce seizures in severe cases, that moderate diet changes can control seizures in moderate cases. Therefore, an improved diet that is less restrictive and takes into consideration all of the new research has been developed and should be considered as an alternative to the ketogenic diet and anti-seizure medications for epileptic patients. Furthermore, the GAPS nutritional protocol has the ability to immediately suppress seizure activity as well as change the long-term prognosis.
1. Introduction
The intestines are home to hundreds of trillions of microbes with at least 1,000 different species of bacteria, weighing approximately 1-2 kg in total. The importance of the microbiome in human health is becoming increasingly apparent. In addition to regulating digestion, microbes support intestinal epithelia and regulate pathogen levels. When dysbiosis occurs, and pathogenic microbes are in greater numbers than is optimal, a myriad of mental and physical health issues can result, including seizures. [2]
While human microbiomes share common features, the majority of a person’s microbiome is unique [3]. The microbiome begins developing in utero, and is subsequently affected by birthing method. Next, neonatal nutrition contributes to its composition. Finally, growing evidence shows the microbiome is constantly altered by other epigenetic factors including nutrition, antibiotics, stress, hygiene, and infections.
In addition to the composition of the microbiome, the degree of permeability of the intestinal wall plays a significant role in epilepsy. The intestinal wall is composed of epithelial and mucus layers, while its biochemical and immunological factors are also important in epilepsy. The intestinal wall is dynamic FILL IN>>>
There is a certain level of permeability in the intestinal wall, but factors such as inflammation (explain in more detail and other factors) cause the junctions to loosen allowing for microbial products to pass through that are not supposed to. When such foreign products, microbes and antigens pass into the body, the immune system can react and secrete inflammatory mediators.
Therefore, it is imperative to address both gut dysbiosis and intestinal permeability when treating epilepsy. The current nutritional approach to treating epilepsy has not been updated for almost a century, and with this new understanding of the gut-brain axis it is time for the inclusion of a novel dietary approach called the GAPS nutritional protocol.
2. The importance of controlling seizures
*Parth: Should we include this section? If so, needs some work.
In addition to causing short-term complications such as injury, patients with epilepsy are at a 1.6-3 times greater risk of death – and possibly higher in children. (IOM Report, 2013; Forsgren et al, 2005). While death from a seizure itself can occur, from drowning while in a bath or swimming during a seizure, for example, sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in epileptic patients. Studies show a risk of approximately 1 out of 1,000 patients with epilepsy die from SUDEP. [4]
Aside from an increased risk of death, epilepsy can significantly impact a person’s life – cognitively, socially, financially, and otherwise.
“Patients with epilepsy are at significant risk for cognitive impairment and behavioral abnormalities.1 Although it appears safe to say that the likely reason for the cognitive impairment is the neuropathology underlying the epilepsy, it remains unclear whether one of its clinical manifestations, i.e. seizures, can cause cognitive decline per se.” https://www.sciencedirect.com/science/article/pii/S1059131106000380
Whether seizures directly cause cognitive impairment has been a matter of debate, but recent studies are showing a direct correlation. “It appears from these findings that the presence of recurrent seizures in the developing human brain is associated with an adverse and widespread neurodevelopmental impact on both brain structure and function if assessed after a longstanding disease history in the matured brain.” https://www.sciencedirect.com/science/article/pii/S1059131106000380
In addition to neurodevelopmental impact, seizures deplete the body of nutrients, particularly “folic acid, vitamin b6, thiamine, other B vitamins, essential fatty acids, amino acids, magnesium, zinc, manganese, selenium, fat-soluble vitamins and other nutrients.” (p. 79)
3. What are current treatments for epilepsy?
3a. Antiepileptic Drugs
When a patient is diagnosed with epilepsy, a classically trained neurologist will typically prescribe antiepileptic drugs (AEDs). The mechanisms of action are unknown, so often it is trial and error to see how the patient responds.
The first-line of treatment is often valproate (footnote: brand names: Convulex, Depakote, Epilim, Stavzor, and others) for generalized epilepsy, and carbamazepine (footnote: Tegretol, Carbatrol, Epitol, Equetro, and others) for partial seizures. Side effects associated with valproate include “digestive problems, nausea, ataxia, tremors, hair loss, increased appetite and weight gain, problems with blood coagulation, impaired liver and kidney functions, oedema, amenorrhoea, skin rashes, pancreatitis and blood cell abnormalities. Carbamazepine has similar side effects plus dizziness, drowsiness, headaches, confusion and agitation, double vision, anorexia, fever, heart problems, lymph node enlargement, hepatitis and acute kidney failure.” (Campbell-McBride, p.79) Furthermore, AEDs are also known to cause bone structure abnormalities and bone fractures due to interference with bone metabolism.
Additionally, it is extremely dangerous to suddenly stop taking any of these medications as they can affect heart rate and too sudden of a withdrawal can may increase cardiac sympathetic activity during sleep and result in death. Other than the most severe consequence of AED withdrawal, numerous unpleasant withdrawal effects are often noted.
The side effects of AES are extensive and serious. Neurologists and other well-intentioned prescribing physicians believe these risks are preferable to seizures, which demonstrates the importance of controlling seizures.
“Impact of adverse effects of antiepileptic medications (AEDs) such as cognitive side effects (CSEs) on quality of life can be significant.” (https://www.sciencedirect.com/science/article/pii/S1059131115000837)
(Note to editors: All of the quotes in this article need to be flushed out and put into own words...I just put them in as place holders for points I want to make)
“Antiepileptic pharmacotherapy can very well have positive effects on cognition and behavior via control of seizures and interictal epileptic discharges, and/or via improvements of mood and psychiatric comorbidity. However, more frequent and less appreciated are adverse effects of antiepileptic drugs (AEDs), causing new cognitive or behavioral problems or aggravating preexistent neuropsychological impairments.” https://www.tandfonline.com/doi/full/10.1080/14656566.2017.1309025
“When a young child is put on long-term anti-epileptic medication the child is condemned to a plethora of side effects that influence the child’s mental and physical development. On top of that, due to suppression of the brain activity, these children are not able to learn well, they do not do well academically or socially and their personality changes…I have lost count of the loving parents who described their child as a “zombie” due to anti-epileptic medication…there are many cases where the seizures do no disappear with drug treatment but change their character and can become more severe and distressing.” (Campbell-McBride, p.78)
3b. Ketogenic Diet (KD)
“Let food be thy medicine and medicine be thy food.” – Hippocrates
Since the beginning of clinical medicine, starting with Hippocrates, fasting was the treatment for epilepsy. Since fasting is not a viable long-term solution, a search for a diet that mimicked such effects began. Since the brain’s energy source during fasting switched from glucose to ketones, researchers began searching for a diet that allowed the body to produce ketones instead of glucose. A typical Western diet contains mostly carbohydrates, and as a result glucose is burned and the body's fuel source. A ketogenic diet is largely based on fats, some protein, and very limited carbohydrates, resulting in ketones used as the body’s fuel source.
Thus, the ketogenic diet (KD) was developed in the 1920s at the Mayo Clinic and the metabolism of ketones was believed to be the seizure mediating cause. Due to the development of AEDs roughly fifty years later, research and application of the KD diminished. Around 1990, internationally renowned pediatric neurologist Dr. John M Freeman at Johns Hopkins revived the ketogenic diet as an alternative to medications for childhood epilepsy.
The Ketogenic diet (KD) has been the single dietary approach for seizures but recent evidence suggests it is not effective for the reasons previously believed. Since the diet was popularized in the early 20th century, the metabolism of ketones was thought to be the seizure mediating cause. Now, it appears that it is the alteration of intestinal microbiota - not the production of ketones - responsible for anti-seizure effects[5].
“Understanding the therapeutic mechanism of the diet has been challenging (Rho and Sankar, 2008; Rho and Stafstrom, 2011). It was initially assumed that ketone production was the key to the diet’s antiepileptic effect, but there is a poor correlation between serum ketones and seizure control (Likhodii et al., 2000; Thavendiranathan et al., 2000).”
The KD is typically used as a secondary line of treatment, only if anti-seizure medicine does not work. Likely because? it requires a major change of life. It is simpler to take a medication and not worry about everything a patient eats. Although it is available in over 45 countries as a treatment option for epilepsy, most practitioners? (or physicians or neurologists?) report using the KD only as a last resorts, in patients with refractory epilepsy[6].
Notes to editors: Need to revise to give some more credit to ketosis...it does have several benefits including anti-inflammatory effects. So maybe make a distinction between extreme and mild ketosis, and expand on benefits such as the following research published in 2017 that concluded:
“Ketogenic diets act through a combination of mechanisms, which are linked to the effects of ketones and glucose restriction, and to interactions with receptors, channels, and metabolic enzymes. Decanoic acid, a component of medium-chain triclycerides, contributes to seizure control through direct α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition, whereas drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway. Ketogenic diet therapy also affects DNA methylation, a novel epigenetic mechanism of the diet. Ketogenic diet therapy combines several beneficial mechanisms that provide broad benefits for the treatment of epilepsy with the potential to not only suppress seizures but also to modify the course of the epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28141738
“High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.” (Augustin K, et al) https://www.ncbi.nlm.nih.gov/pubmed/29263011
There are currently several variants of the ketogenic diet, with the MCT version being the highest in carbohydrates. Thus we will discuss that diet in detail in the next section.
|
Type of KD |
% Fat |
% Protein |
% Carbs |
|
Classic Keto |
90 |
6 |
4 |
|
Modified Keto |
82 |
12 |
6 |
|
MCT Keto |
73 |
10 |
17 |
|
Modified Atkins |
65 |
30 |
5 |
|
Low Glycemic Index |
60 |
30 |
10 |
While the side effects of AEDs are significant, the KD is not without its dangers either.
Short term side effects include:
- The “keto flu” which isn’t a medically serious condition but can cause a patient to feel unwell and include fatigue, irritability, and GI disturbances.
- Dehydration is a common early-onset effect when starting the treatment with fasting.
“Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia.[7]”
Most complications of the KD are short-term and manageable, however life-threatening complications can occur and it is for this reason that new patients are hospitalized when starting the KD and are monitored very closely.
Long term side effects are not well studied, but there is a concern for:
- Kidney stones due to hypercalciuria,
- acid urine, and
- low urinary citrate excretion.
3c. Medium-chain triglyceride Ketogenic Diet
In 1971, pediatric neurologist and neuroscientist, Peter Huttenlocher, modified the KD to be more palatable and found that by including more medium-chain triglycerides, and allow for more carbohydrates, the anti-seizure effects would remain the same[8].
Although the ketogenic diet has been used for about a century, and fasting for thousands of years in the treatment of epilepsy, new research highlights it is not the production of ketones responsible for anti-seizure effects.
“The short chain fatty acid valproic acid (VPA, 2-propylpentanoic acid), is a commonly used broad-spectrum antiepileptic drug, but is sub-optimal due to numerous side effects…In the search for new seizure control treatments, a recent study suggested that the action of VPA involves modification of phosphoinositol turnover in the social amoeba Dictyostelium discoideum (Chang et al., 2011). Based on this mechanism, a group of medium chain fatty acids including both MCT-diet associated compounds and a novel family of related branched fatty acids were identified as potential new therapeutics for epilepsy.” (https://www.sciencedirect.com/science/article/pii/S0028390812005382)
The medium chain triglyceride (MCT) ketogenic diet was first identified as a treatment for refractory epilepsy in 1971 (Huttenlocher et al., 1971). It has provided one of the most effective therapeutic approaches for children with drug-resistant epilepsy (Liu, 2008; Neal and Cross, 2010; Levy et al., 2012) and has recently been demonstrated to be effective in childhood epilepsy in a randomized control trial (Neal et al., 2009). However, the diet has adverse gastro-intestinal related side effects, such as diarrhoea, vomiting, bloating, and cramps (Liu, 2008). Furthermore, it has also been shown that there is a high attrition rate for the diet, due to many patients finding the diet difficult to tolerate (Levy et al., 2012)
“However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold.”[9]
“The main benefit of the MCTKD is allowing more carbohydrate (CHO) than the CKD [classic ketogenic diet], with resultant increased palatability. Food exchanges are used which allow more food choices and larger food portion sizes, especially fruits and vegetables, in the MCTKD. As patients consume more varieties and larger quantities of food, children have better growth and require fewer micronutrient supplements compared to the CKD. There are also fewer incidents of renal calculi, hypoglycemia, ketoacidosis, constipation, low bone density, and growth retardation. With MCTKD, there is no acidosis or reduction in serum alanine, as in the CKD. In addition, there is a positive effect on lipid levels with a significantly lower total cholesterol/high density lipoprotein (HDL) ratios, compared to the CKD.”[10]
In a study of a single case, researchers in the Neurology Department at Vanderbilt University Medical Center studied the anti-epileptic effects of medium-chain triglyceride supplementation in the form of pure oil on a single patient and “his seizure frequency was markedly reduced from multiple daily seizures to one seizure every four days.” Furthermore, it was observed that his seizures recurred after discontinuing MCT oils, resulting in a conclusion that “MCT oil supplementation may be a more tolerable alternative to the standard ketogenic diet.”
“In the future, MCT supplementation may prove to be an efficacious, safe, and relatively cheap option to reduce seizures without resorting to restrictive diets.”
“However, despite the efficacy of the ketogenic diet in controlling seizures in patients with epilepsy, several studies have shown a poor correlation between blood plasma ketone concentrations and seizure control, and ketones do not acutely block seizure activity in an animal model. An additional study has shown seizure control in the absence of ketosis. These observations challenge the view that ketones alone have a role in seizure control and raise the question of the roles of other components of the diet, particularly fats that are provided at high levels in the diet.” [11]
3d and 3e. Possibly discuss the modified Atkins diet and “low glycemic index treatment” - further proof that seizure control is not dependent upon ketosis.
“A single study from Massachusetts General Hospital in 2005 described an even less restrictive diet: the ‘low glycemic index treatment.’31 This diet restricts carbohydrates to 40–60g/day and does not restrict fluids or protein, but loosely monitors fat and calories. Unlike the modified Atkins diet, the type of carbohydrate is important in this diet, with only carbohydrates with a glycemic index <50 allowed. These carbohydrates include berries and wholegrain breads as opposed to potatoes, white bread, and most citrus fruits. Efficacy is also surprisingly good despite an absence of urinary ketones and only low levels of serum ketones.”
(Good article and graphs here: http://www.touchneurology.com/articles/top-five-advances-use-ketogenic-diets-epilepsy-and-beyond-0)
*One of Koben’s neurologists at the U is an author on a paper cited there - 2006: https://www.ncbi.nlm.nih.gov/pubmed/16901419
“Recently, it has been established that decanoic acid has antiseizure effects at clinically relevant concentrations in vitro and in vivo (Chang et al., 2013; Wlaz et al., 2015) but octanoic acid does not, and with previous in vivo pharmacokinetic data indicating that decanoic acid penetrates the blood–brain barrier (Oldendorf, 1973), these data suggest that decanoic acid directly contributes to the therapeutic effect of the MCT ketogenic diet. Indeed, in vitro, decanoic acid is more potent than valproic acid [a branched chain fatty acid isomer of octanoic acid, that is commonly used in the treatment of epilepsy (Chang et al., 2013), and which has been shown to act on phosphoinositide signalling in seizure control (Xu et al., 2007; Chang et al., 2012, 2014a)].”
“Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects.” https://www.ncbi.nlm.nih.gov/pubmed/26608744
New research at the University College London and Royal Holloway University of London shows now that the antiseizure effects of the MCT diet are from the decanoic acid component of the MCT diet, not diet-derived ketones. (Chang, P, et al)
Professor Matthew Walker, right, University College London, and co-author of the study, told Epilepsy Society: ‘This is likely to have a large impact on the dietary treatment of epilepsy as it may be possible to use diets enriched in decanoic acid and avoid many of the unwanted side-effects of the present MCT ketogenic diet.
Katrin Augustin, one of the researchers from Royal Holloway said that the research changes the way we think about nutrition.
‘We are showing for the first time that dietary fats can alter brain function,’ she said. ‘What we eat may not only affect our physical health but also our mental function, which means we may be able to regulate brain function by changes in our diet.
‘Finding a direct action for fatty acids explains why ketosis often does not correspond to seizure control, and that could be very reassuring for both patients and clinicians. It means that low ketone levels may not at all be a reason to discontinue the diet.’
From: https://academic.oup.com/brain/article/139/2/431/1753724
4. What the newest research says about the cause of epilepsy.
“While research on the gut-brain axis is still in relative infancy, certain basic rules have begun to emerge. It appears as though specific neurological pathways evolved to respond to the effect of microbial populations, while others are unaffected by microbiome ‘‘instruction’’ and subject to purely genomic or other environmental cues. Interaction with host-associated microbial communities, either directly via microbial metabolites or indirectly by the immune, metabolic, or endocrine systems, can supply the nervous system with real-time information about the environment. These cues converge to control basic developmental processes in the brain such as barrier function, immune surveillance, and neurogenesis. The mechanistic understanding of how different microbial populations, beneficial or pathogenic, govern these and other functions related to health and disease holds promise in the diagnosis, treatment, and prevention of specific neuropathologies. Determining how a microbiome, changing with Westernization and other environmental factors, impacts a human population with growing rates of neurodevelopmental disorders and increasing life expectancy represents an urgent challenge to biomedical research and to society.”[12]
Reword: “Complex and bidirectional, the communication pathways between the gut microbiota and the brain play an important role in human health and disease. Mutualistically associated, the gut hosts an environment potentiating microbiota growth, while microbiota maintains homoeostasis within the body and overall health. Gut–brain and brain–gut communication occurs by means of neural (autonomic and enteric nervous systems), endocrine, metabolic and immune systems (Zhou and Foster, 2015). Disruption of one such system may have pathological consequences.”
1. Not Ketones. Above we established that ketones are not the primary mechanism of action in the KD diet.
2. Medium-Chain Triglycerides and decanoic acid??? are crucial in seizure control. As a result, a modified diet was created called the MCTKD diet.
3. Systemic inflammation causing neurotoxicity is a pathogenic cause of seizures via gut-BBB axis. Once thought of as simply a predisposing factor, it is now considered a biomarker. Intestinal inflammation is now recognized to be able to trigger brain inflammation and seizures. BBB permeability is also affected, if not controlled, by the intestinal microbiome.[13] Just as the gut-brain axis is becoming understood, new animal research is showing the connection between the gut-BBB axis. As long ago as 2010, inflammation and BBB disruption was cited as a possible mechanism for epilepsy[14].
“...examine the several ways the microbiome is known to interact with the CNS barriers. Bacteria can directly release factors into the systemic circulation or can translocate into blood. Once in the blood, the microbiome and its factors can alter peripheral immune cells to promote interactions with the BBB and ultimately with other elements of the neurovascular unit. Bacteria and their factors or cytokines and other immune-active substances released from peripheral sites under the influence of the microbiome can cross the BBB, alter BBB integrity, change BBB transport rates, or induce release of neuroimmune substances from the barrier cells. Metabolic products produced by the microbiome, such as short-chain fatty acids, can cross the BBB to affect brain function. Through these and other mechanisms, microbiome-BBB interactions can influence the course of diseases as illustrated by multiple sclerosis.” [reference:
https://www.ncbi.nlm.nih.gov/m/pubmed/29169241/]
4. Hyperpermeability of the intestinal wall plays a role in epilepsy. Nutritional factors that affect intestinal permeability occur through tight junction down regulation, histone deacytalase inhibitors, ENS modulators, malnutrition, and toxins in our food. Other environmental factors that decrease integrity include gastrointestinal viruses, chronic inflammation and autoimmunity, dysbiosis of micribiota, and other toxins.
[12]
5. Gut microbiota are crucial in epilepsy.
“Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior.”[15]
6. Insight into the Microbiota-Gut-Brain Axis and Vagus Nerve
* Parth and Sandra: obviously this section is not written out yet and needs some work but I included some key information to build on.
Anti-epileptic effects of vagus nerve stimulation have been proven for over a century, while just recently the mechanism of action has been understood to be anti-inflammatory[16]. The new research into VNS further supports the role of GI-tract inflammation critical in seizure control and bidirectional communication through the microbiota-gut-brain axis.
“The microbiota, the gut, and the brain communicate through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve (VN), the principal component of the parasympathetic nervous system, is a mixed nerve composed of 80% afferent and 20% efferent fibers. The VN, because of its role in interoceptive awareness, is able to sense the microbiota metabolites through its afferents, to transfer this gut information to the central nervous system where it is integrated in the central autonomic network, and then to generate an adapted or inappropriate response. A cholinergic anti-inflammatory pathway has been described through VN's fibers, which is able to dampen peripheral inflammation and to decrease intestinal permeability, thus very probably modulating microbiota composition. Stress inhibits the VN and has deleterious effects on the gastrointestinal tract and on the microbiota, and is involved in the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) which are both characterized by a dysbiosis. A low vagal tone has been described in IBD and IBS patients thus favoring peripheral inflammation. Targeting the VN, for example through VN stimulation which has anti-inflammatory properties, would be of interest to restore homeostasis in the microbiota-gut-brain axis.[17]”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808284/
“The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the cholinergic anti-inflammatory pathway; CAP).”[18]
https://www.ncbi.nlm.nih.gov/pubmed/23360102
“The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the cholinergic anti-inflammatory pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve.”[19]
https://www.ncbi.nlm.nih.gov/pubmed/23360102
7. If major diet changes like the ketogenic diet can reduce seizures in severe cases, than moderate diet changes can control seizures in moderate cases.
An extremely restrictive diet is now used as the last resort in epileptic patients - only when AEDs do not work. Currently there is no middle ground, per se, for patients without severe, refractory epilepsy. We believe this logic needs to be revisited. If diet has a major impact in epilepsy in the most severe cases, we propose that moderate diet changes be the first line of treatment for patients with mild-moderate cases of epilepsy.
Through both research and successful first-hand case studies with the GAPS nutritional protocol, we have seen and heard of thousands of cases were the GAPS nutritional protocol arrested and reversed symptoms of epilepsy.
5. Explanation of the GAPS nutritional protocol
Dr. Natasha Campbell-McBride, MD, MMedSci (neurology), MMedSci (nutrition), coined the term Gut and Psychology Syndrome (GAPS) to describe disorders of the brain caused by abnormal microbial flora in the gut. In 2004, Dr. Campbell-McBride fine-tuned the Specific Carbohydrate Diet developed in the 1920s and developed the GAPS nutritional protocol to treat neurological and psychological conditions by re-establishing normal gut flora, decreasing intestinal permeability, and restoring proper digestive function. Dr. Campbell-McBride was a practicing neurologist for seven years when her son was born. At age three he was diagnosed with autism. She was shocked to find a dismal perception of his outlook among her colleagues. Due to the severity of his gastrointestinal symptoms, she pursued another graduate degree in nutrition. She focused heavily on the digestive system’s pathology and the gut-brain axis. Combining her experience in neurology with an increased understanding of the digestive system, she was able to develop the GAPS nutritional protocol. After she healed her son from autism, she opened a clinic in England to treat other autistic children. She is currently still practicing and has treated thousands of patients from around the world for autism, epilepsy, and other diseases.
The GAPS nutritional protocol is a restorative, not restrictive, diet. It is divided into six stages. Each stage specifically identifies key foods to incorporate or restrict. In general, stage one is the most limited and each stage strategically adds in more foods.
We propose that the GAPS nutritional protocol is the most (*or an) effective strategy for treating epilepsy with no side effects. We also propose that previous attempts at treating epilepsy have focused on a single cause, whereas the GAPS nutritional protocol takes a necessary, multi-faceted approach. In particular, because recent research highlights it is the alteration of intestinal microbiota – not the production of ketones – which is at the core of efficacy for the ketogenic diet (KD), we propose that the GAPS nutritional protocol is a safer, less restrictive diet for seizure management than the KD.
Furthermore, the GAPS nutritional protocol prevents the passage of microbes and foreign antigens from the gastrointestinal tract into the bloodstream – and most importantly in epilepsy patients, from reaching the blood brain barrier. Dr. Campbell-McBride recognized that it is both the composition of bacteria in the microbiome, in addition to the degree of permeability of the intercellular junctions in the digestive system that play a role in seizure activity.
While nutritional immunology was not new, Dr. Campbell-McBride was on the forefront of cutting edge research into the importance of the microbiome in disorders otherwise thought to be purely psychological or neurological in nature.
Her book, Gut and Psychology Syndrome, was published in 2004 and has since been translated into 18 languages. Medical doctors and other health practitioners around the globe have been using it to cure patients for fourteen years, but it is now time that scientific studies prove its validity. Once it is scientifically validated and there are published studies, the GAPS protocol can be used extensively as a safe and effective cure for epilepsy and other devastating diseases.
6. How the GAPS nutritional protocol compares to the Ketogenic diet and the MCTKD
The GAPS protocol is a multifaceted approach, not a single solution, in addressing epilepsy. The protocol is divided into six stages to address intestinal permeability, inflammation, nutrient absorption, and normalize gut microbiota. We argue that the GAPS nutritional protocol is more effective in achieving – and sustaining – anti-epileptic results than either the KD or MCTKD. Furthermore, the GAPS nutritional protocol is less restrictive and safer, whereas the ketogenic diet poses a risk of serious side effects, the GAPS nutritional protocol has no potential side effects and by stage 6 of the diet it is safe for long-term use.
“GAPS Nutritional Programme has been designed to take control of pathogens in the gut and to heal the gut. As the gut wall heals, the level of toxins and partially digested foods getting through drops dramatically, so the brain has a chance to start functioning normally. At the same time GAPS nutritional protocol provides highly nutritious foods, while making the digestive system fit enough to digest them; these factors quickly remove nutritional deficiencies which could have been contributing to seizure activity.” (p.84).
6a. Similarities between the GAPS nutritional protocol, KD and MCTKD
Microbiota Alteration
While the KD and the MCT KD inadvertently alter gut microbiota, the GAPS nutritional protocol proactively addresses dysbiosis as a critical factor in epilepsy. The first stage of the protocol emphasizes reducing numbers of harmful pathogens, while the subsequent stages replenish healthy bacteria and facilitating tight epithelial junctions in the GI-tract to decrease unhealthy levels of permeability. This order prescribed in the protocol is subtle yet crucial. For this reason, it is necessary for epileptic patients to work with a GAPS trained practitioner or dietician. While the diet may appear simple, there are deliberate intricacies. For example, probiotic supplements and other bacteria rich foods are restricted during the first stage in order to reduce numbers of unhealthy pathogens by depriving them of nutrients. To an untrained practitioner, they may unwisely prescribe probiotics or certain nutrient dense food during the wrong phase. Even certain healthy bacteria (called ???) Can be converted into unhealthy bacteria, which is why restrictions of probiotic supplements and most healthy foods are limited during the first stage of re-establishing homeostasis of the microbiome.
High in medium-chain triglycerides and decanoic acid
Foods rich in medium-chain triglycerides (found in coconut oil and dairy fat) are a substantial part of all diets. The addition of more medium-chain triglycerides to a ketogenic diet has already proven to allow for a modification of the ketogenic diet, referred to as the medium-chain triglyceride ketogenic diet (MCTKD) introduced by Huttenlocher in 1971, with the same efficacy in seizure control.
6b. Differences between the GAPS nutritional protocol, KD and MCTKD
While there are some critical overlaps between the dietary approaches to epilepsy, there are a few crucial differences. Now that scientists have discovered ketosis is not the primary mechanism behind seizure control, a diet permanently low in carbohydrates like the KD and MCTKD is unnecessarily restrictive. A multifaceted approach to address the various factors ? is necessary, however.
The GAPS nutritional protocol reduces systemic inflammation
Anecdotal and now current scientific evidence is linking intestinal inflammation to systemic inflammation, now including the brain. Thus the GAPS protocol recognizes one of the key aspects to reducing brain inflammation and seizures, is to reduce intestinal inflammation.
In agreement with this, the antiepileptic effect of Vagus nerve stimulation (VNS) has been linked with the stimulation of the cholinergic anti-inflammatory pathway [47]. Thus, VNS confirms the role of gut-brain axis and inflammation in seizure controls.
Instead of dramatically restricting carbohydrate sources like the KD diets, the GAPS protocol ultimately only restricts the most inflammatory carbohydrate sources such as gluten. Other, nutrient dense carbohydrate sources like ??? are allowed on the GAPS protocol providing the patient with a more diverse diet than the KD and mitigating nutrient deficiencies.
The complexity and multi-faceted approach of the protocol can be illustrated in the careful restriction, then slow addition of dietary fiber. For instance, dietary fiber is prohibited in the first three stages of the protocol because fiber itself can be a problem in an unhealthy microbiome with a disproportionate composition of bacteria by facilitating the growth of more pathogenic bacteria and aggravating inflammation in the intestinal wall. Through following the first few stages of the protocol, the composition of bacteria will change and the beneficial bacteria will far outweigh the pathogens. Once they do, and the patient has moved on to stage four, easily digestible fiber is slowly introduced because the restorative protocol acknowledges that fiber is healthy in an optimally functioning intestinal system allowing the digestive system to metabolize electrolytes, recycle bile acids and cholesterol, among other integral duties[20].
The GAPS protocol addresses intestinal permeability as a factor in epilepsy, whereas the KD and MCTKD diets do not
While already established that the GAPS protocol proactively addresses intestinal permeability by reducing factors that decrease barrier integrity, and increasing factors that promote barrier integrity, the lower percentage of fat in the GAPS vs. KD diets may also play a role in healthy intestinal permeability. New research shows that high fat diets may be associated with increased permeability due to depletion of intestinal eosinophils[21].
As we have discovered, however, a diet low in carbohydrates does result in marked seizure reduction by altering the microbiota. This restriction in carbohydrates is only necessary to address dysbiosis and can be adjusted after pathogenic populations are controlled. After this the GAPS protocol re-introduces certain carbohydrates at crucial times.
“This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’.”[22]
“Since we now know about the clinical implications, interest in understanding the regulation of this barrier is growing. Two major regulatory factors could be identified, diet/nutrients/prebiotics, and, secondly, the intestinal microbiota/probiotics. Both are related to life style, which suggests that environmental factors might influence the function of the intestinal barrier and thus gut health. The molecular mechanisms that regulate the epithelial tight junction and the paracellular pathway in response to luminal nutrients as D-glucose are less well defined but have been proposed to involve the cytoskeleton including myosin light chain phosphorylation.” [12]
The GAPS nutritional protocol is rich in prebiotics and probiotics, identified as integral to the health of a healthy intestinal barrier. Inulin, for example, ….
Collagen (describe more here…)
Evidence suggests that reduction of tight junction protein expression and degeneration of epithelial barrier integrity is a feature of this permeability.[23]
Furthermore, pathogens are associated with alteration of epithelial tight junctions, likely related to mucous production.
Without the care of beneficial bacteria while under attack from pathogenic flora, the gut epithelium degenerates and becomes unable to digest and absorb food properly, leading to malabsorption, nutritional deficiencies and food intolerances. 19.21,25
Apart from keeping the gut wall in good shape, the healthy gut flora populating this wall has been designed to take an active part in the very process of digestion and absorption. 19,21 So much so, that the normal digestion and absorption of food is probably impossible without well-balanced gut flora. It has an ability to digest proteins, ferment carbohydrates, break down lipids and fibre. By-products of bacterial activity in the gut are very important in transporting minerals, vitamins, water, gases and many other nutrients through the gut wall into the bloodstream. 10 If the gut flora is damaged, the best foods and supplements in the world may not have a good chance of being broken down and absorbed.
“This pathophysiological cascade is now accepted to be of major relevance for the development of metabolic diseases including type II diabetes, cardiovascular diseases and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) [88-93]. Therefore it is tempting to speculate that tools allowing a safe modulation of the intestinal microbiota such as prebiotic food components or probiotic bacteria might be of great interest for future therapy of intestinal barrier-related diseases.” [12]
Short-chain fatty acids produced by fermentation of undigested dietary carbohydrates have been determined to play a role in regulating permeability and TNF-α release [12].
Fructose has been identified as a contributor to increased intestinal bacterial overgrowth and intestinal permeability [12]. In particular, a mouse model shows a correlation between fructose and the reduction in tight junction proteins occludin and ZO-1 while fructose simultaneously increased a bacterial endotoxin in the portal vein [12].
Enteric pathogens often gain access to the body by altering the structure and function of tight junctions to increase permeability of the barrier via the secretion of proteases, which can cleave tight junction proteins or by altering the cytoskeleton [116]. Inflammatory cytokines such as TNFα and IFNγ, which are induced during infection and in IBD, have been shown to increase intestinal permeability in general, although single inflammatory models yielded different results [114] while probiotics and commensals can reverse such inflammatory dysfunctions in human intestinal epithelial cells, e.g. by improving barrier functions or by inhibition of pathogen adherence. [12]
Addressing intestinal permeability and inflammation addresses autoimmune causes of epilepsy
The comorbidity and correlation between autoimmune disease and epilepsy is well documented. Therefore, the autoimmune role in epilepsy must be considered.[24] By following the GAPS protocol that reduces intestinal permeability and systemic inflammation any autoimmune reaction instigating seizures is thereby diminished.
In addition to genetics and environmental factors, the intestinal microbiome and gut-brain axis are increasingly recognized as major contributors to the development and severity of autoimmune disease. For such reasons, treating autoimmune diseases through nutrition (as with the FODMAP diet or the GAPS nutritional protocol) are becoming increasingly common. New treatments to reduce intestinal permeability are also being developed, such as zonulin antagonists.
There has been more scientific research into the role of intestinal hyperpermeability in autoimmune diseases. And based on this research, and numerous case studies, this treatment approach is extremely hopeful. New treatments for autoimmunity are focusing on stopping the disease course by arresting the passage of antigens across the intestinal barrier and re-establishing healthy permeability levels[25].
Another detail of the multifaceted GAPS protocol can be illustrated by the careful restriction, then reintroduction of sucrose. The first three phases of the protocol restrict sucrose – a known disruptor of intestinal wall integrity. The next stage introduces limited quantities of sucrose. And the final stages allow for slightly more only after intestinal wall integrity is restored. To promote continued healing of the intestinal barrier, the diet is rich in its building blocks including prebiotic and probiotic sources. Unlike the KD diets, the GAPS protocol includes certain carbohydrate sources necessary for the development of short-chain fatty acids – also integral in healthy development of the intestine’s epithelial layers.
The GAPS nutritional protocol also restricts known inflammatory foods, such as gluten and pasteurized dairy. While the KD diets do not differentiate between pasteurized dairy and non-pasteurized dairy, the GAPS protocol makes a distinction and restricts pasteurized dairy for two reasons: 1. Pasteurization destroys the beneficial bacteria in milk, and 2. Pasteurization alters the milk protein resulting in an unfamiliar protein that promotes a systemic inflammatory response in patients with hyperpermeable intestinal walls.
Dairy in itself is restricted to fermented, unpasteurized dairy products such as kefir or yogurt during the first five stages of the protocol because these products are easier to digest and lack lactose because it is consumed during fermentation. Without fermented dairy, the casomorphins from the milk protein casein, can cross the GI-tract and the BBB contributing to inflammation[26].
In a recent pediatric case of drug resistant epilepsy, simple elimination of cow’s milk stopped seizure activity[27]. This case highlights the neurological manifestations in the form of refractory epilepsy of systemic inflammation induced by a single milk protein and supports the significance of the gut-brain axis in epilepsy. In particular, in this case, the authors mentioned “that our patient underwent a complex diagnostic workup, with a final diagnosis accidentally given by an ex adiuvantibus therapy, and even when standard allergic tests were normal, highlighting a non-IgE-mediated food reaction. Therefore, first of all, this case suggests giving importance of familial and personal history to any allergic anamnesis and not to exclude any kind of sensitization only by standard tests, because even when negative, they cannot exclude non-IgE-mediated hypersensitivity reactions.”[28]
Differentiation between casein a1 and a1 - EXPAND ON.
“In literature, other similar cases have been described, such as that one of Falsaperla et al., and Vitaliti et al., in which authors suggested that a peripheral inflammation of the GI tract can trigger the GI immune system, with an allergen-mediated activation of local antigen-presenting cells, consequent shift toward Type-II helper T-lymphocytes (Th2) and subsequent secretion of pro-inflammatory cytokines. These pro-inflammatory agents can diffuse in circulation, reaching the BBB and being responsible for its disruption, by mast cells' activation and in loco induction of T-lymphocytes, with consequent CNS inflammation-triggering seizures. Moreover, cow's milk proteins can cause a GI inflammation responsible for the induction of T-lymphocytes specifically sensitized to these proteins, which migrate within the BBB in the context of the “homing” process. Therefore, the absorption of cow's milk proteins through an inflamed GI mucosa, with a consequent migration in the systemic circulation, may trigger those sensitized lymphocytes within the BBB (which had colonized it after a process of homing), with secondary induction of the inflammation cascade in the CNS.”
The GAPS protocol limits the patients exposure to neurotoxins
Dr. Campbell McBride was ahead of her time when she said all seizures are caused by toxins. Fourteen years later we are just now scientifically validating her statements and identifying neurotoxins from the GI-tract as contributory, if not the cause, of neurodegenerative diseases[29]. In a groundbreaking study regarding the cause of Alzheimers disease (AD), it was observed that neurotoxins (X in particular) were abundant in the brain neocortex and hippocampus of AD patients. This study supports Campbell McBride’s theory 2004 regarding GI derived neurotoxins as the source of many neurological diseases.
This is one of the first studies linking microbiome-derived neurotoxins to neurodegenerative diseases. While the last decade of research has produced a plethora of studies linking the microbiome to GI diseases like IBD, IBS, and Chron’s, this study takes us further and shows how toxins in the microbiome contribute to neural degeneration[30].
We propose that a similar study be done in epileptic patients, gaining a better insight into the source of inflammatory signaling in the neuropathology of epilepsy. In addition, further insight into a similar state of self-reinforcing inflammation identified in AD patients should be identified in epileptic patients. In AD patients, pro-inflammatory responses of “chemokines, cytokines, the insoluble Aβ42-enriched peptide deposits, NFTs, apoptotic, damaged and vanishing neurons, and activated microglia, and other related pro-inflammatory signals” serve to maintain a state of inflammation in the brain[31].
Toxins released from the GI-tract is the primary cause of seizures according to Dr. Campbell McBride. All of the work on intestinal permeability and inflammation is designed to reduce toxins being released into the body proper, resulting in many major function disruptions, including seizures.
Inflammation in either (or both) the GI-tract and the vagus nerve leads to poor motility (constipation), resulting in further accumulation of pathogenic material and a condition known as SIBO. Such toxins released into the vagus nerve affect key transmitters like GABA and deplete levels of glutathione.
A recent study into the alteration of the gut microbiota of the KD showed that substantial alteration occurred in just four days on the KD. The UCLA scientists were the first to demonstrate a definite link in a research study between gut microbiota and seizure activity.
They determined that two key strains of bacteria, Akkermansia muciniphila and Parabacteroides spp, were elevated after adherence to the KD and that the two together provided significant anti-seizure effects by altering the profile of circulating metabolites in the GI-tract, consequently altering brain metabolism – specifically levels of GABA relative to glutamate. (One strain alone was not sufficient – suggesting a crucial interplay among bacteria).
“Specifically, reduction in γ-glutamylation of circulating amino acids and elevated hippocampal GABA (γ-aminobutyric acid)/glutamate are associated with seizure protection in mice.[32]”
Section in Neurotoxins missing: *Discuss organic food sources and the reduction of glyphosate. Include research by S. Senneff, MIT.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808284/)
7. Barriers to the GAPS nutritional protocol
It is critical to note that there are no adverse health risks associated with the GAPS nutritional protocol. Currently the first line of treatment for epilepsy is AEDs, but as we outlined above are associated with extensive and serious side effects. The KD and the MCTKD diets are associated with less side effects in comparison, but are not risk free. The GAPS nutritional protocol is therefore the only completely safe treatment for epilepsy.
We do need to recognize that following the protocol is not as easy as taking a prescription like an AED, however. So while we believe it is both safer and more effective than other treatments for epilepsy, we have identified the following barriers to following the GAPS nutritional protocol:
1. Lack of available GAPS certified practitioners. Because the protocol is new, this is probably the most significant barrier. While the number of certified practitioners is growing, we recognize a need for more trained practitioners. Currently you can search for a GAPS practitioner in your area of the world on this website: http://www.gaps.me/find-a-gaps-practitioner.php
2. Financially burdensome. The cost of working with a GAPS practitioner is not always covered by insurance at the moment. We recognize this as a barrier to treatment. Furthermore, grocery costs will likely be higher than an average Western diet.
3. Inconvenient. Due to the labor intensive planning and preparation of many of the meals, we have identified protocol compliance as a barrier to treatment.
Despite these barriers, we agree with Dr. Campbell-McBride:
“As far as dietary treatment is concerned, it is generally easier to treat epilepsy, in children in particular, when there is no medication involved. I do believe that, wherever possible, diet should be the number one choice in childhood epilepsy, before drugs are considered. Children are developing every minute and every day: their bodies and their brains evolve and progress all the time, following an immensely complex programme, set in motion from birth…Drugs interfere with your child’s mental and physical development in a brutal and unpredictable way, which would affect your child for the rest of his or her life.” (Campbell-McBride, p. 87)
Need graphics.
Amazing graphic here of intestinal permeability and CNS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808284/
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