The gut microbiome and drug‐resistant epilepsy: Microbiome–antiseizure medication interactions and implications for pharmacoresistance

Drug‐resistant epilepsy (DRE) affects approximately one‐third of patients with epilepsy and represents a major unmet clinical need. While traditional hypotheses of pharmacoresistance have focused on alterations in drug targets, efflux transporter overexpression, and intrinsic disease severity, the gut microbiome has recently emerged as a potentially modifiable factor that may function as a systems‐level modifier of these established mechanisms rather than a standalone pathway. The gut microbiome harbors a vast repertoire of drug‐metabolizing enzymes capable of directly biotransforming orally administered antiseizure medications (ASMs)—including valproic acid, lamotrigine, carbamazepine, and oxcarbazepine—thereby altering their pharmacokinetics, bioavailability, and therapeutic efficacy. Additionally, microbial metabolites modulate host cytochrome P450 enzymes, nuclear receptors, and efflux transporters such as P‐glycoprotein, while bacterial β‐glucuronidases influence the enterohepatic recirculation of glucuronidated ASMs. Conversely, chronic ASM exposure reshapes the gut microbial ecosystem, creating a self‐perpetuating cycle of dysbiosis and pharmacoresistance. This narrative review synthesizes current evidence on microbiome–ASM interactions in DRE, proposes a concrete experimental pipeline for characterizing ASM‐specific microbial biotransformation, and outlines a framework for integrating physiologically based pharmacokinetic modeling with microbiome data. We discuss clinical implications for epileptologists—including the role of therapeutic drug monitoring in detecting microbiome‐mediated pharmacokinetic variability, the concept of microbiome‐neutral ASM selection, and earlier deployment of the ketogenic diet as a microbiome‐targeted intervention. We highlight the translational potential of pharmacomicrobiomics—the study of how microbiome variation influences drug disposition and response—and identify critical knowledge gaps that warrant future investigation.

Plain Language Summary

About one in three people with epilepsy continue to have seizures despite treatment. This review summarizes growing evidence that the gut microbiome—the community of bacteria living in the intestines—can influence how seizure medications work by altering their absorption, metabolism, and clearance. The medications themselves can reshape the microbiome in return, creating a cycle that may sustain treatment failure. Understanding this gut–drug relationship may open new paths to personalized epilepsy care through diet, probiotics, and microbiome‐guided prescribing.