The microbiota-gut-brain axis (MGBA) has emerged as a critical frontier in understanding neurological disorders, including epilepsy. Microbial disequilibrium potentially alters brain homeostasis and could potentiate an inflammatory state linking intestinal dysbiosis and intractable seizures. The current study sought to probe the anti-kindling, electrographical, behavioral and neuropathological impacts of combined intervention of probiotics (PRO; 10 ml/kg) and pregabalin (PRG; 10 mg/kg) in PTZ-induced epileptic mice for 21 days. Adult BALB/c mice were kindled via subthreshold dose of (PTZ 40 mg/kg) until mice reached seizure stage of 4-5. After the procedure, mice were tested using a set of behavioral tests, and redox alterations along with cellular pathology were assessed. vEEG monitoring revealed that kindling instigated recurrent polyspikes of high amplitude with generalized epileptic seizures which were markedly impeded in the mice treated with dual regime suggesting potential preventive impact of probiotic therapy on neuronal hyperexcitability. Additionally, combination intervention exerted positive behavioral outcomes as it ameliorated anxiety and depressive-like phenotypes along with cognitive impairments (P < 0.05) vs. PTZ control. Moreover, probiotic and pregabalin therapy incurred gut-microbiota antioxidant neuroprotection and prevented morbid neurodegeneration as evidenced by decreased production of oxidative stressors (MDA and AchE; p < 0.01) and increase in activity of antioxidant factors (SOD; P < 0.01 and CAT; P < 0.05). Furthermore, these commensal species and PRG duo regulates inflammation and halted neuronal apoptosis in CA1 and CA3 subfields of the cornu-ammonis. Overall, our findings support probiotics as an adjuvant therapy to shift treatment paradigms in drug-resistant epilepsy by altering gut-microbiome pathological neural links.

Over 10 million children in the world have epilepsy, with an unknown cause in half of the cases. The gut microbiome has been associated with various neurological disorders, and certain drugs greatly disturb the microbiome. Our aim was to study the association of prenatal and childhood exposure (before the age of two) to antibiotics, proton pump inhibitors (PPIs) and histamine-2 receptor antagonists, and the risk of childhood epilepsy. Using population-based registers, we included all live singleton births in Sweden from 2006 to 2017. Exposure was considered prescription(s) to antibiotics, proton pump inhibitors, or H2-receptor antagonists (separately). Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals. 708,903 mother-child dyads were included, and 0.5% of children had an epilepsy diagnosis. Average follow-up was 3.8 years (IQR 1-6). Prenatal exposure to antibiotics (aHR 1.09, 95% CI 1.01-1.18) and PPIs (aHR 1.38, 95% CI 1.17-1.65) were associated with an increased risk of epilepsy. Exposure to antibiotics (1.11, 95% CI 1.02-1.21), PPIs (3.40, 95% CI 2.47-4.68) and H2RAs (1.65, 95% CI 1.03-2.64) before the age of two was associated with an increased risk of epilepsy after the age of two. Dose response analysis showed that one prescription of antibiotics in pregnancy or early life was not associated with an increased risk of epilepsy, while one prescription of PPIs in pregnancy or early life had an association. To conclude, our results support the hypothesis that microbiome modulating drugs are associated with an increased risk of epilepsy. This needs to be further validated in other studies, ideally including indications for drug use.

Over 70 million people worldwide suffer from epilepsy, a persistent brain disorder. Although there are more than 20 antiseizure drugs available for the symptomatic treatment of epilepsy, about one-third of patients with epilepsy experience seizures that show resistance to pharmacotherapy. Since patients with drug-resistant epilepsy are more prone to physical injuries, psychosocial dysfunction, early death, and deteriorated life quality, the development of safer and more effective treatments is a crucial clinical need. The gut-brain axis and microbiome research advances have provided new insights into the pathophysiology of epilepsy, the resistance to anti-seizure medicine, and potential treatment targets. Inflammation, disturbance of the blood-brain barrier, and altered neurotransmitters are key pathways linked to gut dysbiosis. The characterization of microbial species and functional pathways has advanced thanks to metagenomic sequencing and high-throughput analysis. In this review, we elaborate on the gut-mediated molecular pathways involved in drug-resistant epilepsy, the gut- modulatory therapeutic options, and their combination with antiseizure medications for drug-resistant epilepsy.

There is accumulating evidence suggesting a connection between epilepsy, a neurologic disease with recurrent seizures, and gut microbiota. This systematic review and meta-analysis explores the alterations of GM composition in patients with epilepsy.

A systematic search was conducted up to June 26, 2024, across PubMed, Scopus, Web of Science, and Embase. The study outcomes were α- and β-diversity indexes, and relative abundance at different bacterial taxonomic levels, compared between epilepsy patients and healthy controls. Inverse variance-weighted meta-analysis was performed to estimate the standardized mean difference. We utilized the Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies.

In this systematic review, we included 16 case-control studies encompassing 438 cases and 369 controls, and 12 studies were included in the meta-analyses. α-diversity was not significantly different between epilepsy and control group. Of the 11 studies measuring β-diversity, 8 studies showed that the microbiota compositions of the two groups differed significantly. Verrucomicrobia was significantly higher in the epilepsy group (SMD = 0.39 [0.05, 0.72], p = 0.022) than in the control group. At the genus level, Roseburia (SMD = -0.50 [-0.84, -0.17], p = 0.003), Blautia (SMD = -0.40 [-0.73, -0.06], p = 0.022), and Dialister (SMD = -0.40 [-0.74, -0.07], p = 0.018) were significantly less abundant in patients with epilepsy.

Our findings evince remarkable changes in gut microbiota composition in epilepsy. Bacterial genera that promote neuroinflammation are elevated in epilepsy. Our study revealed the interrelation between GM disruption and epileptogenesis, but the heterogeneity among the included results was high, and further investigation is encouraged.

Accumulating evidence suggests that gut microbiota (GM) plays a crucial role in Alzheimer's disease (AD) pathogenesis and progression. This narrative review explores the complex interplay between GM, the immune system, and the central nervous system in AD. We discuss mechanisms through which GM dysbiosis can compromise intestinal barrier integrity, enabling pro-inflammatory molecules and metabolites to enter systemic circulation and the brain, potentially contributing to AD hallmarks. Additionally, we examine other pathophysiological mechanisms by which GM may influence AD risk, including the production of short-chain fatty acids, secondary bile acids, and tryptophan metabolites. The role of the vagus nerve in gut-brain communication is also addressed. We highlight potential therapeutic implications of targeting GM in AD, focusing on antibiotics, probiotics, prebiotics, postbiotics, phytochemicals, and fecal microbiota transplantation. While preclinical studies showed promise, clinical evidence remains limited and inconsistent. We critically assess clinical trials, emphasizing challenges in translating GM-based therapies to AD patients. The reviewed evidence underscores the need for further research to elucidate precise molecular mechanisms linking GM to AD and determine whether GM dysbiosis is a contributing factor or consequence of AD pathology. Future studies should focus on large-scale clinical trials to validate GM-based interventions' efficacy and safety in AD.

Modern bioelectronic tools are rapidly advancing to detect electric potentials within networks of electrogenic cells, such as cardiomyocytes, neurons, and pancreatic beta cells. However, it is becoming evident that electrical signaling is not limited to the animal kingdom but may be a universal form of cell-cell communication. In this review, we discuss the existing evidence of, and tools used to collect, subcellular, single-cell and network-level electrical signals across kingdoms, including bacteria, plants, fungi, and even viruses. We discuss how cellular networks employ altered electrical "circuitry" and intercellular mechanisms across kingdoms, and we assess the functionality and scalability of cutting-edge nanobioelectronics to collect electrical signatures regardless of cell size, shape, or function. Researchers today aim to design micro- and nano-topographic structures which harness mechanosensitive membrane and cytoskeletal pathways that enable tight electrical coupling to subcellular compartments within high-throughput recording systems. Finally, we identify gaps in current knowledge of inter-species and inter-kingdom electrical signaling and propose critical milestones needed to create a central theory of electrical signaling across kingdoms. Our discussion demonstrates the need for high resolution, high throughput tools which can probe multiple, diverse cell types at once in their native or experimentally-modeled environments. These advancements will not only reveal the underlying biophysical laws governing the universal language of electrical communication, but can enable bidirectional electrical communication and manipulation of biological systems.

There has been growing evidence that perturbations in gut-microbiota-brain axis (GMBA) are involved in mechanisms of chronic sequelae of traumatic brain injury (TBI). This review discusses the connection between GMBA and post-traumatic epilepsy (PTE), the latter being a common outcome of TBI. The focus is on two aspects of post-TBI GMBA dysfunction that are relevant to epilepsy. First are impairments in intestinal permeability with subsequent translocation of gut bacteria into the bloodstream. Specifically, endotoxemia following TBI may have a serendipitous protective effect against PTE through lipopolysaccharide conditioning, which may be leveraged for the development of therapeutic interventions. Second are changes in microbial composition (i.e., dysbiosis). Here, the GMBA-PTE connection is explored from predictive biomarker perspective, whereby the risk of PTE can be stratified based on specific microbial profiles. Finally, microbiota transplantation is discussed both as a tool to examine the role of gut microbiota in PTE and as a prelude to novel approaches for PTE therapy and prevention.

The complex relationship between probiotics and human health goes beyond their traditional function in gut health, generating considerable interest for their broad potential in disease treatment. This review explores the various functions of probiotics, highlighting their impact on the immune system, their benefits for gut and oral health, their effects on metabolic and neurological disorders, and their emerging potential in cancer therapy. We give significant importance to studying the effects of probiotics on the gut-brain axis, revealing new and non-invasive therapeutic approaches for complex neurological disorders. In addition, we expand the discussion to encompass the impact of probiotics on the gut-liver and gut-lung axes, recognizing their systemic effects and potential in treating respiratory and hepatic conditions. The use of probiotic "cocktails" to improve cancer immunotherapy outcomes indicates a revolutionary approach to oncological treatments. The review explores the specific benefits associated with various strains and the genetic mechanisms that underlie them. This study sets the stage for precision medicine, where probiotic treatments can be tailored to meet the unique needs of each patient. Recent developments in delivery technologies, including microencapsulation and nanotechnology, hold great potential for enhancing the effectiveness and accuracy of probiotic applications in therapeutic settings. This study provides a strong basis for future scientific research and clinical use, promoting the incorporation of probiotics into treatment plans for a wide range of diseases. This expands our understanding of the potential benefits of probiotics in modern medicine.

There is growing concern about the role of the microbiota-gut-brain axis in neurological illnesses, and it makes sense to consider microglia as a critical component of this axis in the context of epilepsy. Microglia, which reside in the central nervous system, are dynamic guardians that monitor brain homeostasis. Microglia receive information from the gut microbiota and function as hubs that may be involved in triggering epileptic seizures. Vagus nerve bridges the communication in the axis. Essential axis signaling molecules, such as gamma-aminobutyric acid, 5-hydroxytryptamin, and short-chain fatty acids, are currently under investigation for their participation in drug-resistant epilepsy (DRE). In this review, we explain how vagus nerve connects the gut microbiota to microglia in the brain and discuss the emerging concepts derived from this interaction. Understanding microbiota-gut-brain axis in epilepsy brings hope for DRE therapies. Future treatments can focus on the modulatory effect of the axis and target microglia in solving DRE.

Recent research suggests a potential link between the gut microbiome (GM) and epilepsy. We undertook a Mendelian randomization (MR) study to determine the possible causal influence of GM on epilepsy and its various subtypes, and explore whether cytokines act as mediators.

We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM, cytokines, and four epilepsy subtypes. Furthermore, we assessed whether cytokines mediate the relationship between GM and epilepsy. Significant GMs were further investigated using transcriptomic MR analysis with genes mapped from the FUMA GWAS. Sensitivity analyses and reverse MR were conducted for validation, and false discovery rate (FDR) correction was applied for multiple comparisons.

We pinpointed causal relationships between 30 GMs and various epilepsy subtypes. Notably, the Family Veillonellaceae (OR:1.03, 95%CI:1.02-1.05, p = 0.0003) consistently showed a strong positive association with child absence epilepsy, and this causal association endured even after FDR correction (p-FDR < 0.05). Seven cytokines were significantly associated with epilepsy and its subtypes. A mediating role for cytokines has not been demonstrated. Sensitivity tests validated the primary MR analysis outcomes. Additionally, no reverse causality was detected between significant GMs and epilepsy. Of the mapped genes of notable GMs, genes like BLK, FDFT1, DOK2, FAM167A, ZSCAN9, RNGTT, RBM47, DNAJC21, SUMF1, TCF20, GLO1, TMTC1, VAV2, and RNF14 exhibited a profound correlation with the risk factors of epilepsy subtypes.

Our research validates the causal role of GMs and cytokines in various epilepsy subtypes, and there has been no evidence that cytokines play a mediating role between GM and epilepsy. This could provide fresh perspectives for the prevention and treatment of epilepsy.

Over the past decade, microbiome research has significantly expanded in both scope and volume, leading to the development of new models and treatments targeting the gut-brain axis to mitigate the effects of various disorders. Related research suggests that interventions during the critical period from birth to three years old may yield the greatest benefits. Investigating the substantial link between the gut and brain during this crucial developmental phase raises fundamental issues about the role of microorganisms in human health and brain development. This underscores the importance of focusing on the prevention rather than the treatment of neurodevelopmental and neuropsychiatric disorders. The present review examines the gut microbiota from birth to age 3, with a particular focus on its potential relationship with neurodevelopment. This review emphasizes the immunological mechanisms underlying this relationship. Additionally, the study investigates the impact of the microbiome on cognitive development and neurobehavioral issues such as anxiety and autism. Importantly, it highlights the need to integrate mechanistic studies of animal models with epidemiological research across diverse cultures to better understand the role of a healthy microbiome in early life and the implications of dysbiosis. Furthermore, this review summarizes factors contributing to the transmission of gut microbiome-targeted therapies and their effects on neurodevelopment. Recent studies on environmental toxins known to impact neurodevelopment are also reviewed, exploring whether the microbiota may mitigate or modulate these effects.

Microdeletion of the human chromosomal region 16p11.2 (16p11.2+ / - ) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2+ / -  syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2+ / -  are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2+ / - , as well as the underlying molecular mechanisms.

Mice with the 16p11.2+ / -  showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene.

Our study reveals that 16p11.2+ / -  leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2+ / -  mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome. Video Abstract.

Alterations in the composition and function of the gut microbiome have been reported in idiopathic epilepsy (IE), however, interactions of gut microbes with the enteric nervous system (ENS) in this context require further study. This pilot study examined how gastrointestinal microbiota (GIM), their metabolites, and nutrients contained in intestinal contents communicate with the ENS.

Fecal supernatants (FS) from healthy dogs and dogs with IE, including drug-naïve, phenobarbital (PB) responsive, and PB non-responsive dogs, were applied to cultured myenteric neurons to test their activation using voltage-sensitive dye neuroimaging. Additionally, the concentrations of short-chain fatty acids (SCFAs) in the FS were quantified.

Our findings indicate that FS from all examined groups elicited neuronal activation. Notably, FS from PB non-responsive dogs with IE induced action potential discharge in a higher proportion of enteric neurons compared to healthy controls, which exhibited the lowest burst frequency overall. Furthermore, the highest burst frequency in enteric neurons was observed upon exposure to FS from drug-naïve dogs with IE. This frequency was significantly higher compared to that observed in PB non-responsive dogs with IE and showed a tendency to surpass that of healthy controls.

Although observed disparities in SCFA concentrations across the various FS samples might be associated with the induced neuronal activity, a direct correlation remains elusive at this point. The obtained results hint at an involvement of the ENS in canine IE and set the basis for future studies.

Posttraumatic epilepsy (PTE) is a severe complication arising from a traumatic brain injury caused by various violent actions on the brain. The underlying mechanisms for the pathogenesis of PTE are complex and have not been fully defined. Approximately, one-third of patients with PTE are resistant to antiepileptic therapy. Recent research evidence has shown that neuroinflammation is critical in the development of PTE. This article reviews the immune-inflammatory mechanisms regarding microglial activation, astrocyte proliferation, inflammatory signaling pathways, chronic neuroinflammation, and intestinal flora. These mechanisms offer novel insights into the pathophysiological mechanisms of PTE and have groundbreaking implications in the prevention and treatment of PTE. Immunoinflammatory cross-talk between glial cells and gut microbiota in posttraumatic epilepsy. This graphical abstract depicts the roles of microglia and astrocytes in posttraumatic epilepsy, highlighting the influence of the gut microbiota on their function. TBI traumatic brain injury, AQP4 aquaporin-4, Kir4.1 inward rectifying K channels.

Children with autism spectrum disorders (ASD) or autism are more prone to gastrointestinal (GI) disorders than the general population. These disorders can significantly affect their health, learning, and development due to various factors such as genetics, environment, and behavior. The causes of GI disorders in children with ASD can include gut dysbiosis, immune dysfunction, food sensitivities, digestive enzyme deficiencies, and sensory processing differences. Many studies suggest that numerous children with ASD experience GI problems, and effective management is crucial. Diagnosing autism is typically done through genetic, neurological, functional, and behavioral assessments and observations, while GI tests are not consistently reliable. Some GI tests may increase the risk of developing ASD or exacerbating symptoms. Addressing GI issues in individuals with ASD can improve their overall well-being, leading to better behavior, cognitive function, and educational abilities. Proper management can improve digestion, nutrient absorption, and appetite by relieving physical discomfort and pain. Alleviating GI symptoms can improve sleep patterns, increase energy levels, and contribute to a general sense of well-being, ultimately leading to a better quality of life for the individual and improved family dynamics. The primary goal of GI interventions is to improve nutritional status, reduce symptom severity, promote a balanced mood, and increase patient independence.

The central nervous system manages all of our activities (e.g., direct thinking and decision-making processes). It receives information from the environment and responds to environmental stimuli. Bacterial viruses (bacteriophages, phages) are the most numerous structures occurring in the biosphere and are also found in the human organism. Therefore, understanding how phages may influence this system is of great importance and is the purpose of this review. We have focused on the effect of natural bacteriophages in the central nervous system, linking them to those present in the gut microbiota, creating the gut-brain axis network, as well as their interdependence. Importantly, based on the current knowledge in the field of phage application (e.g., intranasal) in the treatment of bacterial diseases associated with the brain and nervous system, bacteriophages may have significant therapeutic potential. Moreover, it was indicated that bacteriophages may influence cognitive processing. In addition, phages (via phage display technology) appear promising as a targeted therapeutic tool in the treatment of, among other things, brain cancers. The information collected and reviewed in this work indicates that phages and their impact on the nervous system is a fascinating and, so far, underexplored field. Therefore, the aim of this review is not only to summarize currently available information on the association of phages with the nervous system, but also to stimulate future studies that could pave the way for novel therapeutic approaches potentially useful in treating bacterial and non-bacterial neural diseases.

Epilepsy is now conceptualized as a network disease. The epileptic brain network comprises structurally and functionally connected cortical and subcortical brain regions - spanning lobes and hemispheres -, whose connections and dynamics evolve in time. With this concept, focal and generalized seizures as well as other related pathophysiological phenomena are thought to emerge from, spread via, and be terminated by network vertices and edges that also generate and sustain normal, physiological brain dynamics. Research over the last years has advanced concepts and techniques to identify and characterize the evolving epileptic brain network and its constituents on various spatial and temporal scales. Network-based approaches further our understanding of how seizures emerge from the evolving epileptic brain network, and they provide both novel insights into pre-seizure dynamics and important clues for success or failure of measures for network-based seizure control and prevention. In this review, we summarize the current state of knowledge and address several important challenges that would need to be addressed to move network-based prediction and control of seizures closer to clinical translation.

The microbiota-gut-brain axis is associated with several behaviours, including those relevant to anxiety or sociability in rodents, however, no conceptual framework has yet been available. Summary of the effects of antibiotic-mediated gut microbiota depletion on anxiety and sociability is essential to both inform further preclinical investigations and to guide translational research into human studies. The main objective is to examine the role of gut microbiota depletion on anxiety and sociability in rodents, and to consider how the findings can be translated to inform the design of research in humans. We reviewed 13 research articles, indicating significant changes in gut microbiota composition and diversity have been found in animals treated with a mix or a single antibiotic. Nonetheless, there is no consensus regarding the impact of gut microbiota depletion on anxiety-like or social behaviour. Gut microbiota depletion may be a useful strategy to examine the role of gut microbes in anxiety and sociability, but the lack of data from rigorous animal investigations precludes any definitive interpretations for a translational impact on human health.

Recent studies have suggested an association between gut microbiomes (GMs) and epilepsy. However, the GM taxa identified in different studies are variable. In addition, observational studies cannot indicate causality. Therefore, our study aimed to explore the causal association of GMs with epilepsy and identify the most influential GM taxa.

We conducted a Mendelian randomization (MR) study using summary statistics from genome-wide association studies (GWAS) of 211 GM taxa and epilepsy. The GWAS summary statistics for 211 GM taxa (from phylum to genus level) were generated by the MiBioGen consortium, while the FinnGen consortium provided the GWAS summary statistics for epilepsy. The primary analytical method to assess causality was the inverse-variance weighted (IVW) approach. To complement the IVW method, we also applied four additional MR methods: MR-Egger, weighted median, simple mode, and weighted. In addition, we conducted sensitivity analyses using Cochrane's Q-test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis.

We evaluated the causal effect of 211 GM taxa (from phylum to genus level) on epilepsy, generalized epilepsy, and focal epilepsy. After using the Bonferroni method for multiple testing correction, Class Betaproteobacteria [odds ratio (OR) = 1.357, 95% confidence interval (CI): 1.126-1.635, p = 0.001] and Order Burkholderiales (OR = 1.336, 95% CI: 1.112-1.606, p = 0.002). In addition, 21 nominally significant causal relationships were also identified. Further, the MR-Egger intercept test and MR-PRESSO global test suggested that our MR analysis was unaffected by horizontal pleiotropy (p > 0.05). Finally, the leave-one-out analysis suggested the robustness of the results.

Through the MR study, we analyzed the causal relationship of 211 GM taxa with epilepsy and determined the specific intestinal flora associated with increased epilepsy risk. Our findings may provide helpful biomarkers for disease progression and potential candidate therapeutic targets for epilepsy. In addition, in-depth analysis of large-scale microbiome GWAS datasets based on metagenomics sequencing is necessary for future studies.

This review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.

It has been well established that traumatic brain injury (TBI) modifies the composition of gut microbiome. Epilepsy, which represents one of the common sequelae of TBI, has been associated with dysbiosis. Earlier study showed that the risk of post-traumatic epilepsy (PTE) after lateral fluid percussion injury (LFPI) in rats can be stratified based on pre-existing (i.e., pre-TBI) gut microbiome profile. In the present study, we examined whether fecal microbiota transfer (FMT) from naïve rats with different prospective histories of PTE would affect the trajectory of PTE in recipients. Fecal samples were collected from naïve adult male Sprague-Dawley rats, followed by LFPI. Seven months later, upon four weeks of vide-EEG monitoring (vEEG), the rats were categorized as those with and without PTE. Recipients were subjected to LFPI, followed by FMT from donors with and without impending PTE. Control groups included auto-FMT and no-FMT subjects. Seven month after LFPI, recipients underwent four-week vEEG to detect spontaneous seizures. After completing vEEG, rats of all groups underwent kindling of basolateral amygdala. Fecal microbiota transfer from donors with impending PTE exerted mild-to-moderate pro-epileptic effects in recipients, evident as marginal increase in multiple spontaneous seizure incidence, and facilitation of kindling. Analysis of fecal samples in selected recipients and their respective donors confirmed that FMT modified microbiota in recipients along the donors' lines, albeit without full microbiome conversion. The findings provide further evidence that gut microbiome may actively modulate the susceptibility to epilepsy.

We examined whether post-traumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome.

Adult Sprague-Dawley rats were subjected to Lateral Fluid Percussion Injury (LFPI). PTE was examined 7 months after LFPI, during a 4-week continuous video-EEG monitoring. 16S ribosomal ribonucleic acid gene sequencing was performed in fecal samples collected before LFPI/sham-LFPI and 1 week, 1 and 7 months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short-chain fatty acids (SCFA) were measured in fecal samples collected before LFPI by Liquid Chromatography with Tandem Mass Spectrometry.

Alpha diversity changed over time in both LFPI and sham-LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post-LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI-dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis-à-vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE with area under the curve (AUC) of 0.73. Global SCFA content was associated with the increased risk of PTE with AUC of 0.722, and with 2-Methylbutyric (depleted), valeric (depleted), isobutyric (enriched) and isovaleric (enriched) acids being most important factors (AUC of 0.717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to 0.78.

While LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content.