Gut Instincts: Unusual Suspects in Seizure Worsening

Abstract

Changes in Gut Microbiome Can Be Associated with Abrupt Seizure Exacerbation in Epilepsy Patients

Kwack DW, Lee S, Lee DH, Kim DW. Clin Neurol Neurosurg. 2024;246:108556. doi:10.1016/j.clineuro.2024.108556. Epub 2024 Sep 15. PMID: 39299008.

Objective: Seizures can be triggered by a variety of endogenous or exogenous factors. We hypothesized that alterations in the gut microbiome may be a seizure precipitant and analyzed the composition and characteristics of the gut microbiome in epilepsy patients who experienced an abrupt seizure exacerbation without a clear seizure precipitant. Methods: We prospectively enrolled 25 adult patients with epilepsy and collected fecal samples on the admission and after seizure recovery for next-generation sequencing analysis. We performed nonparametric paired t-test analysis to evaluate changes in the gut microbiota as seizures worsened and when it recovered and also estimated alpha and beta diversities in each category. Results: A total of 19 patients (13 males) aged between 19 and 78 years (mean: 45.2 years) were included in the study. The composition of the gut microbiota underwent a significant change following an abrupt seizure exacerbation. At the phylum level, the relative abundance of Fusobacteria and Synergistetes was decreased in the seizure recovery state compared to the acute seizure exacerbation. A similar trend was observed at the lower hierarchical levels, with a decrease in the relative abundance of Fusobacteria, Tissierellia, and Synergistia at the class level, and that of Synergistales, Tissierellales, and Fusobacteriales at the order level. At the family level, the relative abundance of Fusobacteriaceae and Staphylococcaceae was decreased, whereas that of Leuconostocaceae was increased. No statistical differences were observed in alpha and beta diversity between the pre- and post-acute seizure exacerbation periods. Significance: Our study suggests that the changes in Fusobacteriaceae and Lecuonostocaceae may be associated with acute seizure exacerbation in epilepsy patients. Given that Fusobacteriaceae are associated with various systemic diseases due to their invasive properties and that Leuconostocaceae are known to produce GABA, our results may suggest a gut microbiome-based treatment option for epilepsy patients.

Commentary

The gastrointestinal (GI) tract is home to a complex and dynamic bidirectional relationship between the host GI epithelium, host immune system, and the multitude of resident microbiota that can fluctuate based on host diet, disease, and pharmacological history. Intestinal microbial communities are an essential factor underlying many physiological processes including digestion, inflammation, protection against pathogens, and nervous system function. The GI microbiome is increasingly recognized to interact with host disease states. One important, non-pharmacological strategy to control drug-resistant epilepsy (DRE) is the ketogenic diet.^1,2 However, the mechanisms by which the ketogenic diet specifically mediates any anticonvulsant effect are still intensely investigated.^1-3 The ketogenic diet does, however, modulate the intestinal microbiome.^4,5 Patients with epilepsy can experience significant shifts in the composition and diversity of intestinal microorganisms with adherence to the ketogenic diet.^3,4 Thus, understanding how the gut microbiome dynamically shifts in epilepsy patients versus healthy individuals is important. More importantly, understanding how short-term fluctuations in an individual's GI microbiome composition can dynamically alter seizure risk is crucial to inform clinical epilepsy management.

Kwack et al prospectively assessed the changes in the composition and diversity of the GI microbiome of a small cohort of patients admitted to a single hospital in South Korea who experienced an episode of acute seizure exacerbation that could not be attributed to some other precipitating event. ⁶ Fecal samples were collected at initial admission and then at least 2 weeks later at outpatient clinic. The patients in this study reported consuming an Asian diet, had stable management of epilepsy with antiseizure medicines (ASMs), and had a history of epilepsy diagnosis lasting >2 years. No clearly discernable precipitants could explain the short-term seizure worsening in the patients, who had primarily focal onset seizures (13/19-68%). Because the patients were sampled at both admission and then again in the outpatient setting, the study provides an intriguing glimpse into how dynamic changes in the abundance of key bacterial species within the host's GI microbiome may influence an individual's seizure susceptibility over time in an otherwise well-controlled individual.

The relative abundance of bacterial species in the host microbiome can dramatically shift; yet most research has focused largely on changes in the alpha and beta diversity of samples under investigation. Alpha diversity provides a measure within a given sample to indicate both the richness (ie, the number of different taxa) and the evenness of distribution of the various taxa, with higher alpha diversity indicating greater richness and evenness. This study interestingly did not report any significant changes in alpha and beta diversity in the gut microbiome of these patients during the acute seizure worsening period compared with the post-admission period. As a result, this study highlights the importance of quantifying the differential abundance of intestinal microbiome species in context, rather than simply relying on global changes in alpha or beta diversity within a sample. Interestingly, the investigators uncovered greater alpha diversity in females. Additionally, there was markedly less species evenness (Shannon) and richness (Faith PD) in epilepsy patients admitted to the ICU versus individuals who did not require ICU care. Thus, further investigation is needed to ascertain the degree to which acute fluctuations in the intestinal microbiome change in discrete patient demographics over time.

It should be emphasized that the authors identified disruptions in the intestinal levels of several microbes previously undocumented to contribute to epilepsy or seizures. ⁶ These changes were largely within the Firmicutes phylum, which is notable because dynamic changes in the ratio of Bacteroides:Firmicutes closely correlate to DRE in humans.^7,8 Notably, there were significant reductions in the relative abundance of Fusobacteria and Synergistetes post-acute seizure exacerbation. These phyla have been previously unreported in the context of epilepsy or other neurological conditions; thus, little is known about their role in the gut-brain axis. Fusobacteriaceae is a family of Gram-negative, obligately anaerobic organisms known to produce butyrate. Other families that were significantly reduced during the acute seizure worsening period included Staphylococcaceae and Peptoniphilaceae. Staphylococcaceae is a family of Gram-positive, facultatively anaerobic organisms. We have previously reported a significant increase in Staphylococcaceae in the acute symptomatic seizure phase of the Theiler's virus mouse model of encephalitis-induced seizures relative to pre-infection levels, ⁹ but there are no clinical reports documenting short-term changes in the intestinal levels of Staphylococcaceae in people with epilepsy. Peptoniphilaceae is a family of Gram-positive, obligately anaerobic organisms. To our knowledge, no studies have assessed changes in intestinal Peptoniphilaceae levels in seizure models or clinical epilepsy cases. In this study, the authors found that only Leuconostocaceae levels were significantly elevated during the period following an acute seizure exacerbation. Leuconostocaceae is a family of Gram-positive, facultatively anaerobic organisms. Across nearly all these identified bacterial species reported to be affected during the period of acute seizure exacerbation, butyrate is the main metabolic endpoint. ² Considering that butyrate is known to be one of the main anticonvulsant byproducts of the ketogenic diet,^2,10 it is likely that the short-term changes in the relative abundance of these species may contribute to disruptions in butyrate concentrations. Altogether, few studies have assessed the interaction between these organisms in the context of epilepsy. Even fewer studies have tracked how short-term shifts in intestinal composition present during periods of seizure control and/or worsening, demonstrating a need for further clinical and mechanistic research.

The gut microbiome clearly influences individual seizure risk in the face of an epileptogenic- or seizure-precipitating insult. The larger question pressing epileptologists, neurologists, and basic scientists alike is: Why do some treatments work in some epilepsy cases, but not all? Preclinical studies illustrate that an individual's seizure risk can be dramatically altered by environmental factors, such as diet. ⁹ For example, we find that diet can modify the gut microbiome in as few as 3 days. ⁹ Kwack et al have now provided an important jumping-off point to further understand and harness the contributions of specific bacterial species to influence an individual's acute seizure risk across time. Discrete epilepsy patient demographics may exhibit time-related variability in microbiome composition and diversity both across patient groups and within subjects that warrant rigorous in-depth study with precisely timed fecal sampling alongside detailed medication history and documented lifestyle factors. Kwack and team identified interesting differences in the microbiota of individuals who were admitted into an ICU, as well as sex-related differences in alpha and beta diversity, uncovering microbiome variability even within a seemingly homogenous patient sample. This study also further supports the emerging precision medicine concept of pharmacomicrobiomics—ie, the complex interaction between the host's microbiome, gender, medication history, and individual drug disposition differences that can affect ASM pharmacodynamic response. While it is unclear whether the findings of Kwack et al would be generalizable to other dietary conditions or patient groups, the microbes identified need to be further assessed in a larger prospective, rather than somewhat retrospective, study across a heterogenous population with careful documentation of the many factors that go into a rigorous randomized clinical trial. Similarly to therapeutic drug monitoring to precisely tailor circulating drug concentrations for optimal seizure control in individual patients, intentionally harnessing discrete microbes would benefit from detailed information on gender, epilepsy classification, medication history, and lifestyle factors that address pharmacomicrobiomics in clinical trials. As an example, banking fecal samples from focal onset patients alongside large, prospective phase III clinical trials of investigational medicines could more rigorously define how specific ASMs and the host microbiome interact to affect an individual's seizure control long-term. Furthermore, microbiome sampling paired with classic therapeutic drug monitoring in epilepsy patients may provide greater information to understand an individual's seizure burden fluctuations, which would offer powerful insight into the under-recognized contributions of the gut microbiome in dynamically shaping epilepsy burden over a lifetime.