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Epigenetics, Epilepsy & Oxidative Stress – The Microbiome Connection

Epigenetics, Epilepsy & Oxidative Stress – The Microbiome Connection

Epilepsy is one of the most prevalent neurological conditions found in approximately 50 million people worldwide.  Epilepsy occurs throughout the age-span and is often characterized by spontaneous non-provoked seizures.  

Currently  third generation antiepileptic drugs are designed to suppress neuronal hyperexcitability and thereby, able to suppress epileptic seizures.  Unfortunately, at least one-third of affected individuals continue to experience spontaneous recurrent seizures as the entire arsenal of anti-seizure drugs (ASD) is ineffective in the prevention of development and progression of epilepsy in those patients [1].

Furthermore, this group of patients are at risk for comorbidities from unrelenting seizures such as cognitive impairment, and sudden unexpected death (SUDEP).  In the meantime, chronic ASD treatment can exert temporary or lasting side effects including ASD hypersensitivity syndrome [1].

History of Antiepileptic Drug Development

[Source: Jong M. Rho, H. Steve White  Brief history of anti-seizure drug development Epilepsia Open, 3(s2):114–119, 2018 doi: 10.1002/epi4.1226]

Recent epilepsy research and development has departed from traditional anti-seizure drugs to focus on epigenetics in the prevention of epilepsy and its progression.  The reasoning behind epigenetics is elegant and simple. 

DNA methylation was first associated in the pathogenesis of seizures in the mid 2000’s where in vitro studies demonstrated a decrease of spontaneous excitatory neurotransmission and network activity when enzymes responsible for DNA methylation, DNA methyltransferases, were inhibited pharmacologically [2]. 

Advances within the past decade has shown that genome-wide DNA methylation changes occur in prolonged seizures (status epilepticus), as well as epileptic tolerance, which is an endogenous response system activated in the brain by a seizure episode. [3] 

Current research links mutated DNA sequences in genes that encode neurotransmitter receptors or ion channels in hereditary or generalized epilepsies [4].  The fact that genotype-phenotype correlations are weak, prompts further exploration in other factors that affect genetic predisposition, such as epigenetics.  Common features in epilepsy can now be explained by epigenetic mechanisms including DNA methylation, histone modifications, chromatin remodelling and non-coding RNAs. [5] 

Epigenetic Regulation in Epilepsy

Anti-seizure drug treatment are ineffective in the prevention of seizures in one third of patients who suffer from epilepsy is probably due to the fact that treatment by drugs is basically a pharmacological ‘top-down’ approach, whereas evolution began from the opposite direction.  Organization and complexity of life is built from the utilization of basic metabolites, followed by the introduction of biochemical and epigenetic regulation of genes. As life continued to evolve the need for more complex regulation led to the development of transcription factors and their regulators such as G-protein coupled receptors (GPCR) [13], and protein kinases [14].

[Source: Robert Stone,  The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine Front. Mol. Neurosci., 13 April 2016  https://www.frontiersin.org/articles/10.3389/fnmol.2016.00026/]

Studies now demonstrate clinical and experimental evidence that supports the theory that epilepsy can be prevented by biochemical manipulations that target epigenetic functions that are associated with the development and maintenance of the epileptic state.  Global DNA hypermethylation have been observed in subjects with chronic epilepsy, with the involvement of genes associated with calcium signaling, DNA binding and transcription, programmed cell death and synaptic transmission [6, 7]. 

How do Epigenetics affect Epilepsy?

Epigenetics in simple terms, are the changes in physical structures that support genes.  The term Epigenetics was originally used to describe heritable changes to the genome that are independent of changes to the DNA code.  The current updated understanding of the term epigenetics describe cellular processes that affect medium to long-term readability and accessibility of the genome that would determine changes in the regulation and structure during gene expression that is outside of the direct changes made to the DNA sequence.  

Widespread changes to gene expression have been observed in epileptogenesis where genes are either turned on, or turned off.  The  changes observed all point to causes that underlie pathogenesis of epilepsy, such as neuronal death, gliosis, neuroinflammation and changes to ion channel and neurotransmitter receptors, neural plasticity, and remodeling [8]. 

Mechanisms involved in epigenetic changes include DNA methylation, changes to chromatin structure facilitated by modification of histone proteins and changes to chromatin structure modified by noncoding RNAs.  Each of these categories has been observed to be altered in epilepsy [9].

Of all the epigenetic changes, methylation of DNA, which generally exerts a silencing effect on transcriptional activities, is accepted to have the most enduring effects. 

DNA Methylation

DNA methylation consists of the addition of a methyl group at the fifth position of cytosine (5mC) in a CpG dinucleotide,  which is the most studied epigenetic mark with important functions in the  development, differentiation and maintenance of cellular identity, as well as pathogenesis of disease [10].

Over the past 40 years, changes in DNA methylation have been observed in many human diseases, especially cancer.  DNA methylation patterns are transmitted with high accuracy during DNA replication [11]. Neurological disorders such as autism, epilepsy, Alzheimer’s, brain tumors have been associated with altered expressions and enzymatic activities of DNA methyltransferase (DNMT), enzymes that are responsible for DNA methylation [12].  

DNA methyltransferase (DNMT) plays an important role in the maintenance of DNA methylation patterns during replication because it has the ability to recognize and methylate CpG sites [15].  In vertebrates, DNA methylation is mainly restricted to CpG sites. Non-CpG methylation activities have been detected in pluripotent stem cells [16]. 60-80% of the 29 million CpGs in the human genome are methylated [17]. 

DNA Methylation & Seizures

In 2017, a study revealed the close connection between aberrant methylation of the RASgf1 gene and seizures in epilepsy.  RASgrf1 is paternally inherited that has a differently methylated region (DMR) at the promoter that can silence gene expression. The authors of the study demonstrated clearly that the pharmacological Inhibition of DNA methyltransferase (DNMT) in an acute epileptic rodent model could suppress acute epileptic seizures.  Inhibition of DNMT initially increased methylation of the RASgfr1 gene, with significant inhibition during the latent period, followed by a suppression of RASgrf1 mRNA and protein expression levels during the chronic phase, thus restoring proper RASgrf1 expression levels in the chronic phase [18]. 

In my previous article, Deuterium, Redox & Epilepsy – The Microbiome Connection [19], the distinct association between epileptic seizures and the health and balance of gut microbiota in humans and rodents was clearly delineated. The mechanisms behind the effects however, were not elucidated in the studies discussed. 

Microbiome & Epigenetics

Microbiologists have been studying how our microbiota can shape gene expression for decades. Latest research show convincing evidence that bacteria in our microbiome can alter expression of host genes.  

Data from genome-wide association (GWA) studies show that many common human diseases are transmitted by parents to their offsprings, yet this phenomenon is not fully supported by common genetic variants [20]. One of these missing links is believed to be the influence of microbiome on gene expression as parents and offsprings often share similar conditions that affect the composition of the their microbiomes [21]. 

Epigenetics regulate mechanisms used by our bodies to respond and adapt to stress present in the environment, including oxidative stress, infections, injuries and toxins.  Epigenetics is a fundamental cellular pathway that supports detoxification and the mediation of inflammation as well as the balancing of neurotransmitters [22]. 

In brain development, it is now widely accepted that methylation in epigenetic regulation is a major driving force behind prenatal and postnatal development [23].  We currently do not have all the facts on exactly how microbiota regulates epigenetic gene expression. However, one unmistakable influence exerted by bacteria in our gut is their ability to modulate the very basic element that supports evolutionary process. Metabolites. 

Methylation & Microbiome: The Folate Connection 

Dysbiosis describes the condition where there is a disproportionate increase in pathogenic bacteria in the gut, which may be the cause of various diseases. Dysbiosis can cause alterations in the balance of metabolites which affects epigenetic regulation of gene expression, leading to the pathogenesis of metabolic disorders, cardiovascular diseases, and even cancer [24]. 

In addition to its effects on epilepsy, the balance of microbiota composition in humans have now been associated with a variety of neuropsychiatric conditions including depression, autism [25], Alzheimer’s and Parkinson’s disease [26].  How do bacteria affect epigenetics? They do it through DNA methylation regulation by modulating important metabolites like folate. 

Folate or folic acid, vitamin B9 [27] can be obtained from foods or dietary supplements.  Folate is critical during methylation processes because DNA methyltransfereases (DMNT) is dependent upon folate to support the generation of  Sadenosylmethionine (SAM), the primary methyl donor for DNMT [28]. 

Commensal bacteria like Bifidobacterium and Lactobacillus produce folate and other vitamins [29]. In fact, various strains of probiotic bacteria have been shown to significantly increase folic acid in human subjects in pilot studies [30].

The interesting point about these commensal bacteria that produce folate is that they have been observed to increase folate metabolite production in the presence of increased deuterium.

DEUTERIUM & FOLATE: The Lactobacillus Connection

In the article ‘Deuterium, REDOX & Epilepsy – The Microbiome Connection’ [19], the ability of deuterium to enhance membrane fluidity in commensal microbiota, thereby increasing their relative abundance, offered one explanation as to why bacteria may affect seizures in epilepsy. 

What most people do not know is that deuterium not only increases membrane fluidity in bacteria, it also can stimulate folate production in certain commensal strains like lactobacillus. 

Lactobacillus are lactic acid bacteria known for their abilities to produce B vitamins in the gut, including riboflavin and folate [31]. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Folate deficiency has been linked with increased risk of cardiovascular disease, cognitive dysfunction and cancer via DNA instability [32]  and DNA strand breaks as a result of methylation dysregulation [33].  

Lactobacillus can affect methylation because they produce natural folate derivatives, including 5-methyltetrahydrofolate (5-MTHF) and folylglutamates which have been shown to have higher bioavailability than synthetic folic acid [34]. 

When lactobacillus are grown in deuterium depleted water (8-10 ppm D2O), their production of olate derivatives like 5-methyltetrahydrofolate (5-MTHF) and folylglutamates are REDUCED by up to 40%!  When they are grown in deuterium enriched water, they show elevated levels of folate and derivatives [35].  

Now it is becoming even clearer, why increased deuterium levels from ketogenic diets has a beneficial effect on lowering seizures in epilepsy.  The enhancement of folate production in commensal bacteria facilitates DNA methylation affecting epigenetic regulation that controls genetic expressions underlying the development of epilepsy. 

The generation of metabolites affects not only DNA methylation, but the expression of non-coding RNA

Akkermansia muciniphila & miRNA Modification

Akkermansia muciniphila’s beneficial role in epilepsy and other diseases have been well documented [36, 37].  In 2018, scientists showed for the first time, the ability of A. muciniphila to regulate gene expression through N6-methyladenosine (m6 A) modification of micro RNA (miRNA). 

Noncoding RNAs include long non-coding RNAs, microRNAs (mRNA) and snoRNAs as well as other small RNAs.  Even though noncoding RNAS do not encode proteins, they participate in important biological processes.  

miRNA is a small non-coding RNA molecule with about 22 nucleotides. They regulate gene expression in post-translational processes by binding to target sites.  Science now associates gut microbiota with changes in cellular miRNA profiles during infections by M.tuberculosis, Helicobacter and Salmonella enterica. Commensal and virulent, pathogenic bacteria can alter microRNA expressions that modulates immune responses including proliferation, differentiation pathways that may protect the host against inflammation during infections [38]. 

Akkermansia muciniphila, the bacteria that positively influenced seizure thresholds in epileptic models, has been found to be able to impact m6A-modifications in both the cecum of the large intestines, as well as in the liver.  This is an important groundbreaking discovery, because it shows the effects of microbiota extending beyond the intestines to other organs of the host [39].  

Alterations in the expression of microRNA and their target messenger RNAs have been identified in three experimental models of lesional epilepsy, revealing important molecular pathways that may underlie the development and maintenance of the disease. 

An extensive meta-analysis of dataset available showed 176 miRNAs were detectable in the three models, and 26 of these miRNAs were differently expressed during the latent period, and 5 in chronic epilepsy [40].

Conclusion

There is no doubt that our gut microbiome has the ability to modify our epigenome, directly affecting gene expression [41].  Through epigenetic modifications, which are actually both dynamic AND REVERSIBLE [42], microbiota can modulate the outcomes in the pathogenesis of a variety of health conditions and diseases, including neurological disorders like epilepsy.

The microbiome is a fascinating, highly dynamic ecosystems where human genetics can also affect its composition. This bi-directional crosstalk between microbiome and host has far-reaching implications still to be discovered and fully understood. 

Oxidative stress affects the homeostasis of microbiota in our gut. Interestingly, oxidative stress has been found to affect epilepsy also. Not surprisingly, vitamin C, ascorbic acid, has been shown to be effective against the prevention of seizures in various epileptic models….To Be Continued…..

Have you had your AA today? 

 

References

[1] Brief history of anti-seizure drug development    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293064/ 

[2] Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus http://www.jbc.org/content/281/23/15763.long

[3] Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703365/

[4] Epilepsy genetics: Current knowledge, applications, and future directions – Myers – 2019 – Clinical Genetics – Wiley Online Library https://onlinelibrary.wiley.com/doi/full/10.1111/cge.13414

[5] The Epigenetics of Epilepsy and Its Progression – Rebecca M. Hauser, David C. Henshall, Farah D. Lubin, 2018 https://journals.sagepub.com/doi/full/10.1177/1073858417705840 

[6] The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine Front. Mol. Neurosci., 13 April 2016  https://www.frontiersin.org/articles/10.3389/fnmol.2016.00026/full#B36

[7] Deep sequencing reveals increased DNA methylation in chronic rat epilepsy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028609/

[8] Mechanisms of epileptogenesis and potential treatment targets. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/21256455

[9] Epigenetics and Epilepsy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665035/#A022731C72

[10] DNA methylation: roles in mammalian development. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/23400093

[11] Epigenetic inheritance during the cell cycle. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/19234478

[12] Epigenetics and Epilepsy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665035/#A022731C21

[13] Integration of G-Protein Coupled Receptor Signaling Pathways for Activation of a Transcription Factor (EGR-3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172350/ 

[14] Protein kinase C control of gene expression. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/11693964 

[15] CpG Site https://en.wikipedia.org/wiki/CpG_site

[16] Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25812/

[17] Human DNA methylomes at base resolution show widespread epigenomic differences https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857523/

[18] Association of RASgrf1 methylation with epileptic seizures https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542267/

[19] Deuterium, REDOX & Epilepsy – The Microbiome Connection https://www.evolutamente.it/deuterium-redox-epilepsy-the-microbiome-connection/

[20] Personal genomes: The case of the missing heritability | Nature https://www.nature.com/articles/456018a 

[21] Beyond DNA: integrating inclusive inheritance into an extended theory of evolution. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/21681209/

[22] Epigenetic Dysfunctional Diseases and Therapy for Infection and Inflammation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222695/

[23] Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation – ScienceDirect https://www.sciencedirect.com/science/article/pii/S0301008209000562

[24] Dysbiosis of Gut Microbiome and Its Impact on Epigenetic Regulation | Insight Medical Publishing http://clinical-epigenetics.imedpub.com/dysbiosis-of-gut-microbiome-and-its-impact-on-epigenetic-regulation.php?aid=18979

[25] Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558112/

[26] Colonic bacterial composition in Parkinson’s disease. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/26179554/ 

[27] Folate https://en.wikipedia.org/wiki/Folate

[28] Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262611/

[29] Folate Production by Probiotic Bacteria https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257725/

[30] Quantification of folic acid in human feces after administration of Bifidobacterium probiotic strains. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/18685499

[31] B‐Group vitamin production by lactic acid bacteria – current knowledge and potential applications – LeBlanc – 2011 – Journal of Applied Microbiology – Wiley Online Library https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2672.2011.05157.x

[32] Folic acid deficiency and cancer: mechanisms of DNA instability. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/10746348

[33] Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/8988912 

[34] Folate, folic acid and 5-methyltetrahydrofolate are not the same thing: Xenobiotica: Vol 44, No 5 https://www.tandfonline.com/doi/abs/10.3109/00498254.2013.845705?journalCode=ixen20

[35] Effects of deuterium oxide on folate metabolism in Lactobacillus casei. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/22900307

[36] The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet https://www.cell.com/cell/pdf/S0092-8674(18)30520-8.pdf

[37] Akkermansia muciniphila in the Human Gastrointestinal Tract: When, Where, and How? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163243/

[38] MicroRNAs and bacterial infection. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/23795564

[39] A role for gut microbiota in m6A epitranscriptomic mRNA modifications in different host tissues https://www.biorxiv.org/content/biorxiv/early/2018/12/21/504266.full.pdf 

[40] Epilepsy an Update on Disease Mechanisms: The Potential Role of MicroRNAs https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868323/ 

[41] The relationship between early-life environment, the epigenome and the microbiota. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/26585860

[42] Microbial genes, brain & behaviour – epigenetic regulation of the gut-brain axis. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/24286462

 

 

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Doris Loh

Doris Loh

Doris Loh is an independent researcher and writer specializing in the investigation of familiar and innovative health topics using unique perspectives in traditional and quantum biology. Her training as a classical pianist allows her the freedom to explore concepts and theories with a curiosity that often results in distinctive conclusions. Recent works by Doris are focused on how health and disease are greatly affected by electromagnetic radiation that surround us everywhere we go. Her works on EMF offer insight and solutions to the challenges humans and other living organisms face during this era of change. Major works by Doris include an in-depth series on deuterium, as well as a startling series on the birefringent quantum properties of the major REDOX balancer, Vitamin C (ascorbic acid).

MICROBIOMA E RITMI CIRCADIANI

RITMI CIRCADIANI E IMMUNITA’