Gut Microbiome as a Mechanism of Drug Resistance in Epilepsy
An estimated 3.4 million Americans experience active epilepsy, with an annual cost of about $38 billion. Despite an exponential increase in approved medications to treat epilepsy, one third of patients remain refractory to medications, and mechanisms of drug resistance are not completely understood. The gut microbiome is altered in drug-resistant epilepsy.
Ketogenic diet studies suggest that the gut microbiome influences seizure control. In experimental epilepsy models, gut dysbiosis partially mediates the ketogenic diet’s efficacy on seizure control by modulating hippocampal GABA and glutamate ratios. After epilepsy patients initiate the ketogenic diet, the gut microbiota changes. Gut microbiome manipulation may therefore be an effective epilepsy therapy. To isolate cause and effect of the gut microbiome on seizure control in drug-resistant patients and devise effective therapies, key questions must be answered. The impact of seizures themselves on the gut microbiome remain unknown but need to be better understood to plan a disease-modifying intervention.
Neuroinflammation is a potential mechanism by which seizures may impact gut dysbiosis, and vice versa. Seizures are associated with neuro-inflammation, specifically IL1β and IL6 upregulation, both in animal models and human studies measuring cytokine levels after seizures. Inflammatory dysregulation, such as IL1β, can in turn lead to dysbiosis in animal models.
We hypothesize that seizures play independent and reciprocal roles with the gut microbiome, through upregulation of neuroinflammation. We are harnessing a unique opportunity for longitudinal biospecimen sampling in the epilepsy monitoring unit, where patients with epilepsy are electively admitted to the hospital for the purposes of provoking seizures on video electroencephalograph (EEG) monitoring to determine the best treatment options. In this setting, patients can provide biospecimens before seizures are captured, and then sequentially after seizures are captured, providing a unique opportunity for isolating the role of seizures themselves on dysbiosis, and for investigating the role of neuroinflammation as a mediating factor. We propose to advance our understanding through the following aims:
- In a prospective cohort study, we are exploring changes in microbiota before and immediately (4 to 24 hours) and subacutely (2 to 5 days) after a tonic–clonic seizure, by measuring gut microbiota on subjects undergoing seizure recordings in the epilepsy monitoring unit. We hypothesize that seizures will cause immediate and subacute changes in microbiota.
- Correlate gut microbiota alterations with serum IL1 β, IL6 and related cytokine levels. We hypothesize that gut microbiota alterations will predict elevation in IL1 β, IL6 and related cytokines, both at baseline and immediately and subacutely after a tonic–clonic seizure.
This project will improve the understanding of the independent role of seizures on the gut microbiome and explore neuro-inflammation as a potential mediator of the relationship between seizures and gut dysbiosis. These key potential mediators can inform the design of a rational targeted microbiome interventions.