Is There a Link Between Epilepsy and Intestinal Microbiota: What is Your gut Feeling?

Abstract

Altered Gut Microbiome Profiles in Epileptic Children Are Associated With Spectrum of Anti-Seizure Medication Responsiveness

Yuwattana R, Suparan K, Kerdphoo S, Arunsak B, Sanguansermsri C, Katanyuwong K, Chattipakorn N, Wiwattanadittakul N, Chattipakorn SC. Brain Res. 2025;1849:149367. doi: 10.1016/j.brainres.2024.149367. Epub 2024 Dec 1. PMID: 39626831.

Gut microbiota plays a role in epilepsy. However, current knowledge of how gut dysbiosis is associated with a response to anti-seizure medications (ASMs) in epileptic children is still limited. We aimed to characterize the gut microbiota profiles in epileptic children based on response to ASMs. Eighty-six children aged 3–18 years old with a regular oral diet were enrolled onto the study and divided into three groups in accordance with ILAE definitions: 26 healthy controls, 31 drug-sensitive epilepsy (DSE) patients, and 29 drug-resistant epilepsy (DRE) patients. Based on ASM responsiveness, defined as a reduction in seizure frequency of at least 75% over one year, DRE individuals were subclassified into 13 drug responsive (DRE-DR) and 16 drug non-responsive (DRE-DNR) patients. Feces were collected at the time of enrollment for gut microbiota analysis using 16S rRNA sequencing. Epileptic patients exhibited distinctive gut dysbiotic profiles. Differential abundance investigation revealed that CAG-56 was significantly increased in epileptic patients compared to controls. Saccharimonadales and Peptoclostridium significantly increased in the DSE group, compared to the DRE group. Vibrionaceae, especially Grimontia, Rhodobacteraceae, and Enterobacter were significantly abundant in the DRE-DNR group, followed by abundance in the DRE-DR and DSE groups. Outcomes from PICRUSt2 analysis predicted that epileptic patients, especially those in the DRE group, had increased metabolic pathways responsible for vanillin and taurine degradation, compared to controls. These findings suggest that gut dysbiosis could play roles in epileptogenesis and ASM resistance. Notably, the identified gut microbes could serve as predictive biomarkers for the DRE condition.

Medication-Resistant Epilepsy is Associated With a Unique Gut Microbiota Signature

Riva A, Sahin E, Volpedo G, Catania NT, Venara I, Biagioli V, Balagura G, Amadori E, De Caro C, Cerulli Irelli E, Di Bonaventura C, Zara F, Sezerman OU, Russo E, Striano P. Epilepsia. 2025. doi: 10.1111/epi.18367. Epub ahead of print. PMID: 40119849.

Objective: Dysfunction of the microbiota-gut-brain axis is emerging as a new pathogenic mechanism in epilepsy, potentially impacting on medication response and disease outcome. We investigated the composition of the gut microbiota in a cohort of medication-resistant (MR) and medication-sensitive (MS) pediatric patients with epilepsy. Methods: Children with epilepsy of genetic and presumed genetic etiologies were evaluated clinically and subgrouped into MR and MS. Age-matched healthy controls (HCs) were also recruited. A food diary was used to evaluate nutritional habits, and the Rome IV questionnaire was used to record gastrointestinal symptoms. The microbiota composition was assessed in stool samples through 16S rRNA. α-Diversity (AD) and β-diversity (BD) were calculated, and differential abundance analysis was performed using linear multivariable models (significance: p.adj < .05). Results: Forty-one patients (MR:MS = 20:21) with a mean age of 7.2 years (±4.6 SD) and 27 age-matched HCs were recruited. No significant differences in AD were found when comparing patients and HCs. Significant positive correlation was found between AD and age (Chao1 p.adj = .0004, Shannon p.adj = .0004, Simpson p.adj = .0028). BD depicted a different bacterial profile in the epilepsy groups compared to HCs (MS vs HC: Bray-Curtis F = 1.783, p = .001; Jaccard F = 1.24, p = .001; MR vs HC: Bray-Curtis F = 2.24, p = .001; Jaccard F = 1.364, p = .001). At the genus level, the epilepsy groups were characterized by a significant increase in Hungatella (MS vs HC: + 4.95 log2 change; MR vs HC: + 6.72 log2 change); the [Eubacterium] siraeum group changed between the MR and MS subgroups. Significance: Epileptic patients display unique gut metagenomic signatures compared to HCs. Moreover, a different ratio of the butyrate-producing [Eubacterium] siraeum group suggests dissimilarities between patients based on the response to antiseizure medications.

Commentary

The gastrointestinal (GI) tract is colonized by trillions of microorganisms that form the gut microbiota. This is highly individual at the species level. The microbiota impacts immunity from directly solidifying gut integrity to indirectly regulating host immunity that incorporates the brain migroglia. ¹ Moreover, it plays a pivotal role in diverse metabolic pathways through secretion of neurotransmitters, neuromodulators, pro- and anti-inflammatory mediators, toxins, and vitamins. ²

Neglected for decades, the gut–brain axis has attracted scientific interest over the last years thanks to the progress in bioinformatics, high-throughput sequencing technology, and the advent of multiomics analysis. ³ Due to its abundant innervation with the enteric nervous system and its position as the main interface between the environment and the nervous system, ¹ the GI tract is now referred to as the “second brain.” Several studies have shown associations between a “leaky gut” and a multitude of neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Given the intimate link between epilepsy and neuroinflammation and the impact of ketogenic diet in its treatment, ⁴ it comes as no surprise that epilepsy has also emerged lately as the study focus of this interplay. The following 2 studies^5,6 constitute a testament to this trend.

The first study ⁵ is a case-control study of the gut microbiome in 60 children with epilepsy and 29 healthy controls (HCs). The patients were dichotomized into those with drug-sensitive epilepsy (DSE) and drug-resistant epilepsy (DRE) at baseline. The latter were further categorized in response to antiseizure medications (ASMs) versus not after 1 year of follow-up. Feces were collected at the time of enrollment for gut microbiome analysis, and blood was collected at the same time for measurement of inflammatory cytokines. DRE patients exhibited gut dysbiosis compared to DSE patients and HCs. However, no significant differences in the alpha-diversity (AD) indices were observed between persons with epilepsy (PWE) and HC, nor between those who responded to ASM down the road and those who did not. Yet, the genus CAG-56 was increased in PWE (DSE and DRE) compared to HC. Compared to the HC group, the DRE group demonstrated more pronounced microbial composition differences than the DSE group. Among PWE, specific taxa changed in parallel with the severity of ASM resistance (eg, increases were observed in Rhodobacteraceae and Vibrionacea at the family level, and Enterobacter and Grimontia at the genus level, while decreases were observed in Leuconostocaceae). DRE patients had elevated interleukin 6 (IL-6) plasma levels, suggesting that IL-6 can serve as one of the biomarkers in monitoring for the development of drug resistance. ⁵

The second study ⁶ is a cross-sectional study of the gut microbiota in 41 children with genetic or presumed genetic epilepsy and 27 age-matched HC. The former were further dichotomized in DSE and DRE. AD was positively correlated with age but did not vary significantly between PWE and HC. Beta-diversity (BD) depicted a different bacterial profile in PWE compared to HC (eg, increases were observed in Hungatella) and in the DRE compared to DSE groups (eg, decreases were observed in Eubacterium). ⁶ Cumulatively, these findings suggest that perturbation of the gut microbial microenvironment is associated with epilepsy and pharmacoresistance.^5,6

Both these studies^5,6 explore the impact of gut microbiota dysregulation in epilepsy. They follow a standard methodology of fecal sample collection in PWE and HC to avoid inclusion of potential confounders related to diet, GI, or systemic comorbidities, and medications used to tackle them. Patients are separated into DRE and DSE, and a control group is used for comparison. In the first study, ⁵ there is the additional benefit of follow-up of the initially categorized as DRE, although stool analysis is performed on baseline samples. Taxonomic richness and diversity within each sample (AD) and intersample species richness and evenness (BD) are assessed using a variety of indices. A detailed taxonomic analysis is provided, and correlations are investigated between PWE and HC and between DRE and DSE patients, at baseline and in follow-up. In the first study, ⁵ there is the additional benefit of comparison based on plasma interleukin measurements.

Yet, both studies^5,6 reflect single-center experiences derived exclusively from the pediatric population. While the underlying etiology of patients’ epilepsy and the gamut of antiepileptic treatment were diverse, the small sample size precluded stratification and subgroup analysis. Despite all good intentions, including the use of a dietary log and matching for age with HC in the second study, ⁶ factors associated with changes in the gut microbiota irrespective of epilepsy and ASM type could not be fully controlled. Additionally, medication and lifestyle changes related to seizure control were not accounted for when evaluating for pharmacoresistance down the road. Stool sample collection was performed cross-sectionally, preventing a longitudinal evaluation of the cohorts’ microbiota and limiting the ability to assess causation in the identified associations. No surrogate biomarkers, such as electroencephalography, were used to corroborate the correlations identified.

These limitations notwithstanding, both studies^5,6 offer new insights for clinical practice by highlighting the impact of ecological imbalance in the gut flora on the development of ASM resistance. These microorganisms may influence absorption, metabolism, and, hence, bioavailability of ASM. Moreover, some bacteria may produce or consume neurotransmitters and inflammatory mediators that can inevitably affect the equilibrium of inhibition–excitation in the brain. ⁷ A growing body of research has shown that different gut microbiota in the human intestine communicate bidirectionally with the central nervous system (CNS) via the gut–brain axis. Microbial metabolites have a direct impact on brain immune and neural activity, while microbial-derived systemic signals can affect these activities indirectly, thereby affecting CNS physiology and pathology. Conversely, the CNS can regulate the permeability of the intestinal barrier, gut peristalsis, secretory activity, and composition of the intestinal flora through the autonomic nervous system and endocrine responses. ⁸

A recent meta-analysis indicated that gut microbiota in PWE did not differ significantly in AD compared to HC. However, the relative abundance of specific flora, such as Verrucomicrobia and Ackermania, was significantly increased in PWE, while Lactobacillus was significantly decreased. ⁹ Yet, the available literature lacks consensus on specific species involved in the disease^10,11 since it is fraught with small sample sizes, heterogeneous populations, uncontrolled confounders, and cross-sectional design without neurophysiological support, limiting the value of any identified associations. Several questions still remain unanswered: What is the role of gut microbiota in epileptogenesis in different ethnic backgrounds and age groups, as well as in diverse epilepsy etiologies and syndromes? How does it affect not only pharmacotherapy but also response to other types of treatment, such as the ketogenic diet, neurostimulation, and destructive surgery? What is its impact on disease prognosis and its comorbidities? Answering these questions may not only improve our understanding of epilepsy, but it may also open the door to novel interventional pathways by means of changing the intestinal microbiota composition through ketogenic diet, probiotics, fecal microbiota transplants, and vagus nerve stimulation.

On the whole, the interaction between intestinal flora and epilepsy is dynamic, complex, and reciprocal, and it constitutes a promising, ever-growing research hotspot that could revolutionize our field. But there is a dire need to further transition from a suspected link based on a “gut feeling” to an evidence-based association founded on comprehensive and critical investigation, as well as systematic and scientifically rigorous intervention.