Medical literature of the Assyrians and Babylonians from more than 4000 years ago recorded detailed accounts of epileptic seizures [1]. Today, epilepsy has become a common neurological condition that affects more than 65 million people worldwide. About 1 in 26 people in the United States may develop epilepsy during the course of their lifetime [2]. Epilepsy is a complex disorder characterized by abnormal brain activities that induce seizures. Epilepsy can be genetically inherited or acquired. Current available therapeutics mainly target ion channels or neurotransmitter systems [3]. However, these anti-seizure medications are only effective in about 60% of epileptic patients, providing merely symptomatic relief.
This article will discuss the most current understanding of mechanisms underlying the cause for epilepsy, and possible solutions that can address the core issues affecting epilepsy.
There is a growing consensus that recognizes the gut-brain axis as an important bidirectional system between the intestinal microbiome and the central nervous system involving neural, endocrine and immune pathways [4]. In fact, the health of the microbiome is now associated with neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Multiple Sclerosis, Amyotrophic Lateral Sclerosis [5]; and autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis [6]. In 2018, more than 4,000 studies were published on the subject of the gut microbiota, with emphasis on Its wide influence on metabolic diseases like type 2 diabetes. Even autism [7] and cancer are associated with the microbiome [8].
Ketogenic Diet & Your Microbiome
The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that has been shown to have positive effects in neurological conditions including cognitive decline, dementia, Parkinson’s disease, multiple sclerosis and epilepsy. KD was developed in the 1920’s to treat intractable childhood seizures. At that time there were very few antiepileptic drugs available. Today, as a therapy of last resort for children with pharmacoresistant epilepsy, the ketogenic diet still proves to be extremely effective in that 30% of children with pharmacoresistant epilepsy on KD diets had more than 90% seizure reduction [9]. Whereas 32% of adult patients with drug resistant epilepsy, were able to reduce seizures by more than 50% [10].
Many theories attempt to explain the mechanisms behind the success of the ketogenic diet in controlling seizures. The most plausible one being the supply of an alternate source of fuel for the brain in the form of ketones formed when observing ketogenic diets [11].
A study released in 2018 finally solved the mystery surrounding how the Ketogenic Diet (KD) really works in epilepsy. The researchers in the study discovered that the ketogenic diet was completely ineffective in protecting mice from seizures when the mice were either treated with antibiotics or raised in a germ-free environment. In that groundbreaking study, the authors showed that there is a distinct connection between microbiome composition and the protection against seizures [12].
The researchers discovered that in just four days after being fed on a ketogenic diet, the diversity of the gut microbiota of mice previously kept on a regular diet changed dramatically. The levels of Akkermansia muciniphila increased from 2.8% to about 36.3%; levels of Parabacteroides, Sutterella, and Erysipelotrichaceae were also significantly increased; whereas other strains of bacteria decreased in concentration.
To test their theory even further, the researchers transplanted mice fed on regular control diets with the gut microbiota from mice on KD diets. Not surprisingly, the mice on regular diets were protected from seizures as a result of the transplant. However, if the Akkermansia muciniphila and Parabacteroides were not transplanted together, the seizure protection was lost. Mice fed on KD diets without the specific strains of Akkermansia muciniphila and Parabacteroides had reduced seizure protection compared to mice on KD diets replete with Akkermansia muciniphila and Parabacteroides [12].
Escherichia coli & the Ketogenic Diet
Several months after the publication of the groundbreaking study that linked the relationship between an altered microbiome and its effect on seizure control in mice, a study on the effects of the ketogenic diet on therapy-resistant children was released. Twelve children were placed on a ketogenic diet for three months. At the end of the study period, a comparison of their fecal samples before and after the study period showed that the ketogenic diet significantly influenced the taxonomy and functional composition of the microbiota of these children with severe epilepsy [13].
Unlike the results obtained in the study on mice, the authors found the compositional changes observed might actually not be favorable for gut or overall health, because there was a significant 3.5-fold decrease observed in the health promoting taxa bifidobacteria and E. rectale. At the same time, there was a dramatic three-fold increase in Escherichia coli (E.coli), which can be both commensal and pathogenic [13].
Similar to the study where mice without Akkermansia muciniphila and Parabacteroides showed reduced seizure protections, the authors found 5 out of 12 patients showed a better than 50% decrease in the number of seizures while 10 children demonstrated improved cognition and motor functions [13].
Two outstanding questions seem particularly relevant at this juncture. Why was the shift in microbiota observed in children fed a ketogenic diet so distinctly different from the shift observed in mice on KD?; and why was the ketogenic diet able to increase the concentration of E. coli by close to three-fold?
Deuterium, E. coli & the Ketogenic Diet: A story about Membrane Fluidity
It is understandable that the decrease in carbohydrates in ketogenic diets can reduce bifidobacteria which depend on a diverse range of dietary carbohydrates as substrates for their metabolic processes [14]. On the other hand, E. coli is able to consume either glucose or acetate as substrates [15]. In the case of the KD fed children, the increase of acetate from KD could be the reason for the enhanced growth rates. But since E. coli can survive on both carbohydrates and fats, why would acetate make such a huge difference?
The health of microbiota and even our own cells actually depend upon the balance of elements at a quantum level. One such essential elements is deuterium.
Deuterium exists in nature at a natural abundance of 1 deuterium atom per 6420 hydrogen atoms. When deuterium is combined with oxygen, it forms deuterium oxide, commonly known as Heavy Water (D2O). A normal 50 kg. human body with about 32 kg of water contains enough deuterium to make 5.5 grams of heavy water [16].
Deuterium atoms are naturally incorporated in biomolecules via metabolic processes. These enzymatic exchanges bond deuterium to carbon atoms irreversibly. That means once the bonds are formed, the process cannot be reversed. Whereas the non-enzymatic exchange occurring between deuterium atoms and other atoms like oxygen, nitrogen and sulfur are completely reversible. That means under physiological conditions, non-enzymatic exchanges do not exist. In water (H2O), as soon as the non-enzymatic exchange with deuterium is made, it is reversed almost instantaneously, therefore you will not be able to ‘catch’ a non-enzymatic exchange [17].
It has been observed that Akkermansia muciniphila, Parabacteroides as well as E. coli all incorporate deuterium in their membranes [18]. How do they accomplish that, and most important of all, why would they want to incorporate deuterium in the cell membranes?
NADPH, Fatty Acids & Deuterium
New techniques in optical imaging of continuous metabolic processes using deuterium oxide (D2O) as a chemical tracer revealed definitive evidence that deuterium is incorporated irreversibly during enzymatic exchanges in biological reactions that generates NADPH [19]. NADPH is required for the biosynthesis of amino acids (specifically proline in mammals), deoxyribonucleotides, sterols, and fatty acids [20]. NADPH is the reductant required in all fatty acid synthesis in the human body. NADPH is part of the fatty acid synthase enzyme system responsible for the production of saturated long-chain fatty acids in our body [21].
During cholesterol synthesis, one molecule of cholesterol requires 36 ATP molecules and 26 molecules of NADPH [22]. NADPH is used exclusively as reducing equivalent during cholesterol synthesis. In fact, the first and rate-limiting enzyme in the cholesterol biosynthetic pathway, HMG-CoA reductase, ABSOLUTELY depends on NADPH to deliver hydrogen atoms during the conversion of HMG-CoA to mevalonate [71]. Statin drugs lowers serum cholesterol by inhibiting HMG-CoA reductase [72].
The most important cellular source of hydrogen (H) in fatty acid synthesis is NADPH. NADPH provides more than 50% of H in fatty acids. Most biosynthetic reactions require NADPH rather than NADH, but some organisms like E. coli can derive their H source from either NADPH and NADH. Regardless of the source, the fundamental processes underlying isotopic exchanges remains the same [73].
In heterotrophs like humans and bacteria, NADPH is formed during oxidative metabolism such as the TCA (Krebs) cycle, the pentose phosphate pathway [24], where H is transferred directly from substrate to NADP+ [25]. Therefore, how much deuterium is incorporated in the total pool of NADPH in the body will depend on the substrates in addition to the isotopic effects during the H transfer, as well as the different metabolic pathways involved during energy metabolism. [23].
E. coli, Acetate & Deuterium
It has been observed that E. coli can incorporate deuterium at HIGHER amounts when they are given acetate as substrates. E. coli, is enriched by up to +50‰ when it is fed acetate. On the other hand, when E. coli is given glucose as substrate, it is actually depleted in deuterium by close to -120‰ [23]! A ketogenic diet will create more acetate in the body because acetate is produced from the hydrolysis of acetyl-CoA during the formation of ketone bodies from acetoacetate [26]. Why would increased deuterium incorporation result in a three-fold increase of E. coli in the epileptic children on ketogenic diets rich in acetate [9]?
Scientists have known for the longest time that deuterium in the right proportion is essential for growth and development in living organisms. This balance, known as Isotopic Resonance has been vigorously studied, with emphasis on the biological effects of deuterium at low enrichment levels. Longevity and growth were usually achieved with enrichment levels at around 600 ppm (0.06% heavy water) [27]. It is generally accepted that the perfect “terrestrial” isotopic resonance is closer to 0.03% of deuterium [28].
Bacteria, including E. coli, have been found to show a preference for ultralow deuterium enrichment of under 0.25% in different environments. E. coli exhibited increased growth rates at deuterium concentrations as low as 0.04% [29]. Does this surprise you? After all, life on earth would not have happened without deuterium [30]. How did deuterium protect bacteria close to 4 billion years ago, in totally inhospitable environments where high UV-C radiation bombarded the earth incessantly?
Oxidative Stress, Membrane Fluidity & Deuterium
The fluidity of cellular biomembranes can affect important functions like the regulation of enzyme activity, permeability, transport of nutrients, motion of membrane constituents as well as the osmotic stability of cells. [31]. When viscosity of membranes is increased, membranes become more rigid, negatively impacting cellular processes. When fatty acids in membranes are oxidized, the membranes become more rigid, decreasing fluidity. Degenerative diseases are always associated with higher membrane rigidity [32].
Most people incorrectly assume that just because deuterium oxide (heavy water) has a higher viscosity compared to regular water (H2O) [33], the higher viscosity translates naturally into a more rigid membrane. This is a simple extrapolation that is incorrectly applied and cannot be further from the truth.
In fact, cell membranes that contain deuterated lipids actually have higher fluidity! The lower phase transition temperature of deuterated lipids together with the way deuterated lipids are arranged actually INCREASES the fluidity. The substitution of hydrogen with deuteriums in fatty acid chains effectively alters the chain structure of lipids, making the structures less ‘packed’. This change in structure increases membrane fluidity. A fluid cell membrane is important for cellular integrity because it confers stability and enhanced functionality of proteins associated with the membranes [34].
Membrane fluidity is directly affected by oxidative stress. In patients with coronary arterial disease (CAD), a decrease of 14% membrane fluidity is observed in association with an increase of 13% lipid peroxidation, and signfificant decrease in antioxidant activities of catalase and SOD [35]. Oxidative stress has also been observed to increase membrane rigidity in macrophage [36].
Electromagnetic Radiation Increase Oxidative Stress, Reduce Membrane Fluidity
Electromagnetic radiation, both natural and manmade can generate free radicals. If these free radicals are not neutralized, excess oxidative stress will damage biomolecules. 2.45 GHz microwave commonly found in WIFI devices has been shown to induce changes in the ordering of lipids in cell membranes. These changes shifted the membranes from a more fluid-like phase to a more rigid (ordered) state. These effects were especially prominent in cells that contained melanin [37].
Melanin is known for its capacity to scavenge reactive oxygen species when exposed to ultraviolet radiation as well as visible light. In the process, melanin generates the superoxide free radical. The fact that 2.45 GHz microwaves can affect membrane fluidity through free radical generation from melanin reveals how electromagnetic radiation can affect the health of humans and their intestinal microbiota. Melanin can be found in a variety of bacterial taxa. In anaerobic bacteria, melanin is used as the final electron acceptor instead of oxygen [38].
This also implies that bacteria, especially anaerobic ones like Akkermansia muciniphila, are exquisitely sensitive to oxidative stress, and the REDOX environment of the intestines directly affect their health and proliferation.
REDOX, Microbiota & Epilepsy
Oxidative stress is a state of imbalance between oxidants and antioxidants. A relative excess of oxidants will result in the disruption of redox signaling and molecular damage. Most of the time, our bodies require antioxidants that can donate electrons to neutralize oxidants with unpaired electrons that are seeking to pair up with oxygen in order to stabilize themselves. If these oxidants are successful in grabbing electrons from oxygen molecules they will create dangerous reactive oxygen species (ROS). ROS can be used as signaling molecules that initiate a cascade of biological responses. However, an excess of ROS that is not neutralized in a timely manner will result in oxidative stress, or REDOX imbalance.
Oxidative stress is increasingly associated with a wide range of diseases including cancer [39], autoimmune diseases [40], metabolic dysfunctions [41], and neurological diseases [42]. The role of oxidative stress in epilepsy has been extensively studied. It is believed that seizure generation may be caused by the imbalance between antioxidants and oxidants. Experimental seizure models have shown that endogenous antioxidants have the ability to attenuate seizure generation. [43, 44]
Even though oxidative stress can damage proteins and nucleic acids like ribonucleic acid (RNA), nuclear DNA or mitochondrial DNA (mtDNA), leading to changes in functions in various signal transduction pathways [45], the REDOX environment of the host gut is actually paramount in the shaping of the microbiota. Oxidative stress is now believed to be an important influence in the pathogenesis of intestinal dysbiosis [46].
Healthy Microbiome Requires a Low REDOX Environment
Increasing evidence points to the association between diseases and the alteration of the microbiota as a result of abnormal gut REDOX. It is generally accepted that antioxidants and reducing agents can modify bacterial growth by altering the REDOX potential of the medium [47].
Children with severe acute malnutrition (SAM) often have inadequate diet, leading to low levels of plasma antioxidants and gut microbiota alterations. In these children, their gut environment is highly oxidized. The abnormally high (positive) gut REDOX potential often cause the global depletion of obligate anaerobes and subsequent enrichment of pathogenic prokaryotes in these children [48].
In humans and animals, the gut redox environment and the microbiome it hosts undergo maturation changes that is dependent on age and diet [49]. As REDOX potential decreases in the gut, the level of anaerobic predominance increases [50]. In the few months after birth, human fecal REDOX potential decreases by 450 mV (from +150 mV to -300 mV). At the same time, anaerobic bacteria begin to proliferate and gain dominance [51].
A study on 70 individuals varying in age, geography and nutritional status showed an extremely high variability in their gut REDOX potential, ranging from -137.5 mV to +137.1 mV. Positive fecal REDOX potential was associated with the predominance of aerotolerant bacteria. Whereas individuals with negative REDOX showed a predominance in anaerobic bacteria [51]
The ability of REDOX to modulate bacterial growth is immense. Anaerobic bacteria that normally could not grow in aerobic atmosphere could actually be induced to proliferate when supplied with adequate antioxidants [52]. Critically ill children often display severe gut dysbiosis accompanied by highly perturbed bacterial metabolite compositions [53].
It is entirely possible that the bacteria responsible for protecting mice from seizures were influenced by their gut REDOX environment. It is well known that mice produce ascorbic acid or Vitamin C, whereas humans do not. Could A. muciniphila and Parabacteroides be affected by ascorbic acid levels? If the children in the KD experiment were deficient in ascorbic acid, would that affect the restructuring of microbiota while they are on a ketogenic diet?
Akkermansia muciniphila, Camu Camu & Metformin
Akkermansia muciniphila is currently viewed by most as a biomarker for disease as it has been associated with healthy intestines. Abundance of A. muciniphila in the gut are inversely correlated to diseases like obesity, Type 2 diabetes, gut dysbiosis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and Crohn’s disease [54].
Due to its beneficial influences on the host, many experiments attempt to study mechanisms that may increase the abundance of A. muciniphila. One of these studies used Camu Camu, which contains a high level of ascorbic acid. The authors noticed a significant increase in A. muciniphila when diet-induced obese mice were fed a COMBINATION of Camu Camu and ascorbic acid, but not ascorbic acid alone [55]. Similarly, experiments using polyphenols from grapes also induced a bloom of A. muciniphila in diet-induced obese mice [56].
What may come as a surprise to you is that the prescription drug Metformin, frequently used as treatment in metabolic diseases like Type 2 Diabetes and obesity, has also been observed to enhance the growth of A. muciniphila in both humans and animals [57, 58]. What connects Metformin, Camu Camu and grape polyphenols?
Mucin, Inflammation & Akkermansia muciniphila
Akkermansia muciniphila are oval shaped, gram-negative bacteria that is a strict anaerobe. As such, the REDOX environment of its surroundings will greatly affect its survival. An oxidized, inflammatory environment will be hostile for its proliferation. A. muciniphila rely on mucin found in the mucus layer close to intestinal epithelial to supply sole sources of carbon and nitrogen substrates [59].
Most of the mucin found in human intestines is Mucin 2 (MUC2) proteins that are secreted by goblet cells found in intestinal mucosa. This mucus layer protects the intestinal epithelial cells. Mice bred without MUC2 suffered from decreased intestinal barrier function and increased inflammation, marked by symptoms of colitis [60]. In ulcerative colitis and other conditions where there is acute inflammation such as IBD, goblet cells are often depleted [61]. Depleted goblet cells will result in inadequate mucin supply as substrates for Akkermansia muciniphila.
The studies that observed enhanced levels of A. muciniphila by the use of Metformin, Camu Camu and grape polyphenols all employed diet-induced obese mice. Whereas the study that found ketogenic diet to raise A muciniphila used normal mice subjected to induced seizures. The key here is the use of dietary-induced obese mice, because science has now linked adipocytokines in the pathogenesis of inflammatory bowel disease (IBD) disease [62].
So the question is, what is the connection between Metformin, Camu Camu and grape polyphenols? Because for these elements to increase A muciniphila, these elements must have been able to modulate the inflammatory status of the diet-induced obese mice.
We know that proanthocyanidins and ellagitannins are the common denominators in Camu Camu and grape polyphenols; but where does Metformin fit in?
FOXO3, Intestinal Inflammation & Akkermansia muciniphila
Proanthocyanidins and ellagitannins are polyphenols that are known for their ability to stimulate the genetic expression of FOXO3 [63]. Metformin, known for its use in the treatment of type 2 Diabetes, is also effective in enhancing the expression of FOXO3 [64].
What most people are unaware of, is that intestinal inflammation conditions such as inflammatory bowel disease (IBD), often show a deficiency in FOXO3 expressions. FOXO3-deficient mice exhibit dysregulated lipid metabolism and high levels of intestinal inflammation, characteristic of most inflammatory bowel disease (IBD) [65].
By inducing the expression of FOXO3, Metformin, Camu Camu, and grape polyphenols were able to reduce intestinal inflammation and restore mucin secretion levels, which resulted in the increase of A. muciniphila. On the other hand, normal mice without intestinal inflammation, and adequate REDOX balance, responded to the ketogenic diet through the increase of deuterium incorporation in lipids. The enhanced membrane fluidity probably allowed commensal taxa to proliferate over others.
The study that placed twelve epileptic children on the ketogenic diet for three months did not show the same degree of microbiota restructuring as the KD mice. It is possible that the children were deficient in ascorbic acid and antioxidants that resulted in a higher oxidative stress environment in their intestines. The increased positive REDOX potential in their gut would not have favored the growth of anaerobes like A. muciniphila. Instead, the ketogenic diet allowed for the opportunistic growth of E.coli, which is a facultative anaerobe that can survive equally well in the presence of oxygen [66]. The increased membrane fluidity from increased deuterium incorporation was the mechanism that boosted the enhanced survival of E. coli in a hostile oxidative environment.
If the incorporation of deuterium into lipids in cellular membranes is critical to the health and survival of microbiota, what does it mean for humans?
Myelination, Deuterium & Membrane Fluidity
Membrane fluidity can affect important functions like the regulation of enzyme activity, permeability, transport of nutrients, motion of membrane constituents as well as the osmotic stability of cells [31]. In the context of neurological development, the fluidity of membrane is an important consideration in the process of myelination and remyelination.
Cholesterol accounts for over one-fourth of total myelin lipids in our bodies [67]. The biosynthesis of one molecule of cholesterol requires 36 ATP molecules and 26 molecules of NADPH [22].
Cholesterol is one of the most important regulators of lipid organization in myelin membranes. Cholesterol has the ability to stabilize and regulate membrane fluidity, as well as seal and insulate myelin membranes [68]. Cholesterol helps modulate the arrangement and ordering of lipids in such a way that affects biophysical properties of the membranes. The balance of the lipid orders is crucial because too much ordering will cause rigidity, and slows down the diffusion of membrane proteins as well as reduction in the bending capacity of the membrane [69]. On the other hand inadequate ordering can induce permeability of polar molecules such as ions [70].
Considering the fact that one molecule of cholesterol requires 26 molecules of NADPH, and that deuterium has been shown to be able to affect membrane fluidity, one has to assume the natural abundance of deuterium during cholesterol synthesis must be maintained.
Ten of the twelve drug-resistant epileptic children placed on ketogenic diets showed improved cognition and motor functions [13]. This could be the direct result of improved myelination as a result of enhanced membrane fluidity from cholesterol synthesis during myelin formation. .
It is therefore not unreasonable to assume the incorporation of deuterium at natural abundance into NADPH could enhance myelination in the 10 children with severe drug-resistant epilepsy who showed improved cognition and motor functions [13].
Conclusion
In summary, the maintenance of intestinal health depends on a balanced REDOX environment that allows optimal growth conditions for commensal microbiota. Inappropriate manipulation of deuterium levels to deviate from its natural abundance levels can affect the fluidity and integrity of cell membranes in not only our own organs and tissues, but the trillions of bacteria living within us. The ketogenic diet can enhance deuterium incorporation in cellular membranes as a result of irreversible enzymatic exchanges in NADPH during increased lipid metabolism. Higher membrane fluidity from the incorporation of deuterium offers protection against molecular damage from oxidative stress, especially that created by electromagnetic radiation.
However, our world today contains less deuterium than in the past. As levels of oceans continue to rise, deuterium concentrations continue to drop. Sea levels have risen from -77m 11,500 years ago to +0.2m today. Deuterium in precipitation, which is the source of all our water, comes mainly from oceans. That is why the bones of our ancestors from over 10,000 years ago all contain higher levels of deuterium [30]. As such, we cannot expect to be able to maintain the perfect “terrestrial” isotopic resonance, critical to all life on earth.
Electromagnetic radiation, both natural AND manmade, have the potential to generate excess oxidative stress that is detrimental to our health and that of the trillions of bacteria residing within us. Their health is now deemed to be a critical component in our search for optimal. Without adequate deuterium, we must turn to ascorbic acid, Vitamin C, as the ultimate REDOX balancer, to protect both host and ‘guests’ from excess oxidative stress created by EMR.
Ultimately, the effect of gut microbiota can be complex and sometimes even offer contradictory evidence. To truly take advantage of what a healthy microbiota can achieve, it is important for us to understand not only the ways we can enhance their growth and protect their survival, but the mechanisms through which they exert their influences…… To Be Continued…..
References:
[1] Hallmarks in the history of epilepsy: epilepsy in antiquity. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/19963440
[2] Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/23041175
[3] Mechanisms of action of antiseizure drugs. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/22939059/
[4] Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour | Nature Reviews Neuroscience https://www.nature.com/articles/nrn3346
[5] Gut microbiota in neurodegenerative disorders. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/30658292
[6] The microbiome in autoimmune diseases. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/29920643
[7] Role of the Gut Microbiome in Autism Spectrum Disorders. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/30747427
[8] The cancer microbiome | Nature Reviews Cancer https://www.nature.com/articles/s41568-019-0155-3
[9] Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/23294191
[10] The ketogenic diet in patients with myoclonic status in non-progressive encephalopathy. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/28743048
[11] Ketogenic Diet | Epilepsy Foundation https://www.epilepsy.com/learn/treating-seizures-and-epilepsy/dietary-therapies/ketogenic-diet
[12] The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet https://www.cell.com/cell/pdf/S0092-8674(18)30520-8.pdf
[13] The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy | npj Biofilms and Microbiomes https://www.nature.com/articles/s41522-018-0073-2
[14] Carbohydrate metabolism in Bifidobacteria https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145055/
[15] Acetate fluxes in Escherichia coli are determined by the thermodynamic control of the Pta-AckA pathway | Scientific Reports https://www.nature.com/articles/srep42135
[16] Deuterium https://en.wikipedia.org/wiki/Deuterium
[17] Hydrogen exchange and structural dynamics of proteins and nucleic acids. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031643/pdf/rsta20150378.pdf
[18] Tracking heavy water (D2O) incorporation for identifying and sorting active microbial cells https://www.pnas.org/content/pnas/112/2/E194.full.pdf
[19 Optical imaging of metabolic dynamics in animals. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079036/
[20] Principles of biochemistry https://pubs.acs.org/doi/pdf/10.1021/ed060pA201
[21] Fatty Acids Are Synthesized and Degraded by Different Pathways – Biochemistry – NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK22554/
[22] Cholesterol: A Novel Regulatory Role in Myelin Formation http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.837.1173&rep=rep1&type=pdf
[23]Large D/H variations in bacterial lipids reflect central metabolic pathways https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722351/
[24] The phosphate makes a difference: cellular functions of NADP https://www.tandfonline.com/doi/pdf/10.1179/174329210X12650506623122
[25] Proton translocation by transhydrogenase. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/12788487
[26] Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313038/
[27] On the Effect of Planetary Stable Isotope Compositions on Growth and Survival of Terrestrial Organisms https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215764/
[28] Role of Stable Isotopes in Life—Testing Isotopic Resonance Hypothesis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054155/
[29] Effects of Low-Level Deuterium Enrichment on Bacterial Growth https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102507/#pone.0102071-Zubarev2
[30] Deuterium, Quantum Paradox: Light Water & Magnetism | Doris Loh | Pulse | LinkedIn https://www.linkedin.com/pulse/deuterium-quantum-paradox-light-water-magnetism-doris-loh/
[31] Alterations in membrane fluidity and dynamics in experimental colon cancer and its chemoprevention by diclofenac. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/20336351
[32] Increased oxidative stress and decreased membrane fluidity in erythrocytes of CAD patients. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/24032681
[33] Viscosity of deuterium oxide and water in the range 5° to 125° C https://nvlpubs.nist.gov/nistpubs/jres/42/jresv42n6p573_A1b.pdf
[34] Deuterium isotope effect on the stability of molecules: phospholipids. The Journal of Physical Chemistry, 89(9), 1810–1813 | 10.1021/j100255a054 https://pubs.acs.org/doi/pdf/10.1021/j100255a054
[35] Increased oxidative stress and decreased membrane fluidity in erythrocytes of CAD patients. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/24032681
[36] Effect of oxidative stress on plasma membrane fluidity of THP-1 induced macrophages – ScienceDirecthttps://www.sciencedirect.com/science/article/pii/S0005273612002945
[37] Modification of membrane fluidity in melanin-containing cells by low-level microwave radiation. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/1317176
[38] Melanin synthesis in microorganisms — biotechnological and medical aspects http://www.actabp.pl/pdf/3_2006/429s.pdf
[39] Oxidative stress and cancer: an overview. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/23123177
[40] [Pathological roles of oxidative stress in autoimmune diseases]. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/12690629
[41] Oxidative stress and metabolic syndrome. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/19281826
[42] Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724665/
[43] Role of oxidative stress in epileptic seizures https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606551/
[44] Metabolic Dysfunction and Oxidative Stress in Epilepsy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713334/
[45] Brain aging and neurodegeneration: from a mitochondrial point of view. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/28397282/
[46] Nutrition, oxidative stress and intestinal dysbiosis: Influence of diet on gut microbiota in inflammatory bowel diseases. – PubMed – NCBI. https://www.ncbi.nlm.nih.gov/pubmed/27812084
[47] Titanium (III) citrate as a nontoxic oxidation-reduction buffering system for the culture of obligate anaerobes. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/793008
[48] Increased Gut Redox and Depletion of Anaerobic and Methanogenic Prokaryotes in Severe Acute Malnutritionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869025/
[49] Persistent gut microbiota immaturity in malnourished Bangladeshi children | Nature https://www.nature.com/articles/nature13421
[50] Human gut microbiome viewed across age and geography https://www.nature.com/articles/nature11053
[51] Linking gut redox to human microbiome – ScienceDirect https://www.sciencedirect.com/science/article/pii/S2452231718300150#b0025
[52] Aerobic culture of anaerobic bacteria using antioxidants: a preliminary report. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/24820294
[53] Multi-compartment profiling of bacterial and host metabolites identifies intestinal dysbiosis and its functional consequences in the critically ill child https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699985/
[54] Akkermansia muciniphila in the Human Gastrointestinal Tract: When, Where, and How? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163243/
[55] Treatment with camu camu (Myrciaria dubia) prevents obesity by altering the gut microbiota and increasing energy expenditure in diet-induced obese mice | Gut https://gut.bmj.com/content/68/3/453#F5
[56] Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic healthhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971143/
[57] Metformin Ameliorated Inflammatory Bowel Disease by Enhancing Akkermansia Muciniphila https://www.gastrojournal.org/article/S0016-5085(19)39838-5/pdf
[58] Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut – PubMed – NCBI. https://www.ncbi.nlm.nih.gov/pubmed/27999002/
[59] Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/15388697?dopt=Abstract
[60] Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/16831596
[61] Mucins and inflammatory bowel disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1741691/
[62] The role of obesity in inflammatory bowel disease. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/30352258
[63] Molecular Mechanisms and Bioavailability of Polyphenols in Prostate Cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429226/
[64] Metformin Induces FOXO3-Dependent Fetal Hemoglobin Production in Primary Erythroid Cells | Blood Journal http://www.bloodjournal.org/content/128/22/322
[65] Intestinal inflammation requires FOXO3 and prostaglandin E2-dependent lipogenesis and elevated lipid droplets https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895869/
[66] Escherichia coli – Wikipedia https://en.wikipedia.org/wiki/Escherichia_coli
[67] Cholesterol: A Novel Regulatory Role in Myelin Formation http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.837.1173&rep=rep1&type=pdf
[68] Cholesterol and myelin biogenesis. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/20213556?dopt=Abstract
[69] Effect of cholesterol on structural and mechanical properties of membranes depends on lipid chain saturation. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/19792175?dopt=Abstract
[70] Cholesterol reduces membrane electroporation and electric deformation of small bilayer vesicles. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/15923075?dopt=Abstract
[71] Cholesterol: Synthesis, Metabolism, Regulation https://themedicalbiochemistrypage.org/cholesterol.php
[72] Drug Class Review on HMG-CoA Reductase Inhibitors (Statins): Final Report – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/20496454
[73] Chemical basis for deuterium labeling of fat and NADPH https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748894/
