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

Abstract

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.

Key points.

• One‐third of epilepsy patients have drug‐resistant epilepsy (DRE); gut microbiota dysbiosis may contribute to pharmacoresistance.

• Gut bacteria harbor enzymes that can directly biotransform antiseizure medications (ASMs), altering their pharmacokinetics and efficacy.

• Chronic ASM exposure—especially carbamazepine—reshapes gut microbial composition and can enrich antibiotic resistance genes.

• Microbiota modulate host CYP enzymes, efflux transporters (P‐gp/ABCB1), and neuroinflammation—indirectly shaping ASM response.

• Ketogenic diet, probiotics, FMT, and pharmacomicrobiomics‐guided prescribing are emerging strategies to break the dysbiosis–DRE cycle.

1. INTRODUCTION

Epilepsy is one of the most common chronic neurological disorders, affecting over 70 million people worldwide, with approximately 2.4 million new cases diagnosed annually. ¹ , ² While antiseizure medications (ASMs) achieve adequate seizure control in the majority of patients, approximately one‐third develop drug‐resistant epilepsy (DRE), defined by the International League Against Epilepsy (ILAE) as the failure to achieve sustained seizure freedom after adequate trials of two appropriately chosen and tolerated ASM regimens, whether as monotherapies or in combination. ³ DRE imposes a substantial burden on patients and healthcare systems alike, with increased morbidity, mortality, cognitive impairment, psychiatric comorbidities, and diminished quality of life. ¹ , ⁴

The mechanisms underlying DRE remain incompletely understood. Several hypotheses have been proposed, including the pharmacokinetic hypothesis (overexpression of peripheral efflux transporters reducing plasma ASM concentrations reaching the brain), ⁵ the transporter hypothesis (overexpression of efflux transporters such as P‐glycoprotein at the blood–brain barrier), ⁵ , ⁶ the target hypothesis (altered drug targets reducing ASM sensitivity), ⁶ the intrinsic severity hypothesis, the neural network hypothesis, and the gene variant hypothesis. ⁵ , ⁶ , ⁷

More recently, the gut microbiota hypothesis has gained attention, ⁷ , ⁸ positing that intestinal dysbiosis may contribute to pharmacoresistance via several mechanisms: direct microbial biotransformation of ASMs, modulation of host drug‐metabolizing enzymes and efflux transporters, disruption of enterohepatic recirculation, and promotion of neuroinflammation. ⁹ Pharmacomicrobiomics—the study of how microbiome variation influences drug disposition, action, and toxicity—provides the conceptual framework for this emerging view. ¹⁰ , ¹¹ A paradigmatic example is the deconjugation of valproate‐glucuronide by bacterial β‐glucuronidases, which liberates free valproic acid for reabsorption and thereby prolongs systemic exposure—illustrating how microbial enzymatic capacity can meaningfully alter ASM pharmacokinetics in principle. ¹² , ¹³ Rather than an independent mechanism, the microbiota hypothesis may act as a unifying modifier of several established pathways—for example, by influencing P‐glycoprotein expression (the transporter hypothesis) or CYP (cytochrome P450)‐mediated drug metabolism. ⁷ , ⁸

The human gut microbiome—comprising trillions of microorganisms with a collective gene pool vastly exceeding that of the host genome—plays a fundamental role in maintaining metabolic homeostasis, immune regulation, and neurological function via the microbiota–gut–brain axis. ¹⁴ , ¹⁵ This bidirectional communication system encompasses the vagus nerve, neuroendocrine signaling through the hypothalamic–pituitary–adrenal axis, immune‐mediated pathways, and microbial metabolite signaling (notably short‐chain fatty acids and neurotransmitter precursors). ¹⁴ , ¹⁵ Accumulating evidence now indicates that the gut microbiome also influences the pharmacokinetics and pharmacodynamics of orally administered medications, including ASMs, through direct biotransformation, modulation of host drug‐metabolizing enzymes, and alteration of enterohepatic circulation. ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶

This narrative review aims to provide a comprehensive synthesis of the current literature on the interplay between the gut microbiome and ASM metabolism in the context of DRE. While previous reviews have addressed the broader relationship between the gut microbiome and epilepsy, ⁷ , ⁸ , ¹⁷ , ¹⁸ , ¹⁹ the present review focuses specifically on microbiome–antiseizure drug interactions as a mechanistic bridge between intestinal dysbiosis and pharmacoresistance—an angle that has not been comprehensively addressed. We examine how the microbiome may directly and indirectly alter ASM pharmacokinetics, how chronic ASM exposure reciprocally reshapes the microbial ecosystem, and the translational implications for precision epilepsy care.

We propose that microbiome‐mediated pharmacokinetic modulation of ASMs represents a previously underappreciated layer within established pharmacoresistance hypotheses—functioning as a systems‐level modifier rather than a standalone mechanism. By influencing drug biotransformation, host enzyme and transporter expression, and enterohepatic recirculation simultaneously, the gut microbiome may amplify or attenuate the effects of transporter overexpression, altered drug targets, and intrinsic disease severity, offering a unifying framework that integrates—rather than competes with—existing models of DRE.

2. METHODS

A literature search was conducted using PubMed, Scopus, and Web of Science databases from inception through September 2025, using combinations of the following terms: “gut microbiome,” “gut microbiota,” “dysbiosis,” “drug‐resistant epilepsy,” “refractory epilepsy,” “antiseizure medications,” “antiepileptic drugs,” “pharmacomicrobiomics,” “drug metabolism,” “ketogenic diet,” and “microbiota–gut–brain axis.” Reference lists of identified articles and relevant review articles were hand‐searched for additional citations.

Included studies were original research (clinical cohort studies, case–control studies, animal‐model experiments, and in vitro mechanistic investigations), systematic reviews, meta‐analyses, and narrative reviews reporting on microbiota–ASM pharmacology, microbiome composition in epilepsy cohorts, or microbiome‐targeted interventions in epilepsy. Studies were excluded if they did not report original data or substantive analysis relevant to microbiome–epilepsy interactions, were conference abstracts without full‐text availability, or were published in languages other than English. Priority was given to peer‐reviewed original research; strength of evidence for each mechanistic pathway is explicitly graded in Table 1.

TABLE 1.

Mechanistic pathways linking gut microbiome alterations to antiseizure medication (ASM) pharmacoresistance in drug‐resistant epilepsy (DRE).

Mechanism	Biological process	Supporting evidence	Strength of evidence	Potential clinical implication	Level of evidence
Direct microbial biotransformation of ASMs	Bacterial enzymes (reductases, hydrolases, β‐glucuronidases, demethylases) metabolize orally administered ASMs in the intestinal lumen	Xenobiotic metabolism studies (Zimmermann 2019; Javdan 2020) 10 , 16 ; theoretical relevance to VPA, CBZ, LTG	Indirect/extrapolated	Altered bioavailability; unpredictable serum levels; interindividual PK variability	Extrapolated
Microbiome‐mediated modulation of host CYP enzymes	Microbial metabolites (SCFAs, secondary bile acids) activate nuclear receptors (PXR, CAR, FXR) regulating CYP3A, CYP2B expression	Germ‐free mouse models; nuclear‐receptor studies, 12 , 36	Moderate (preclinical)	Altered hepatic ASM clearance; subtherapeutic or toxic levels	Animal model
Regulation of drug efflux transporters (P‐gp/ABCB1)	Microbial taxa or metabolites influence expression/activity of P‐glycoprotein in gut and BBB	In vitro Caco‐2 studies (Dai 2022) 35 ; transporter‐hypothesis literature	Limited (in vitro)	Enhanced ASM extrusion; reduced brain penetration	In vitro
Enterohepatic recirculation (EHR)	Bacterial β‐glucuronidases deconjugate glucuronidated ASMs → reabsorption	Established for VPA, LTG; theoretical modulation by dysbiosis, 12 , 13	Conceptual+pharmacologic	Variability in steady‐state concentrations	Extrapolated
Neuroinflammation via dysbiosis	LPS/TLR4 activation → cytokine release → seizure facilitation and reduced ASM efficacy	Human & animal epilepsy studies 29 , 30 , 31 , 32	Strong (inflammation–epilepsy link)	Reduced ASM responsiveness	Human clinical/Animal model
ASM‐induced microbiome remodeling	Chronic exposure reshapes microbial composition, resistome, metabolome	Dop 2024 34 longitudinal microcosm	Moderate (experimental)	Vicious cycle sustaining pharmacoresistance	Ex vivo microcosm

As this is a narrative rather than systematic review, formal risk‐of‐bias assessment and predefined inclusion/exclusion criteria were not applied. Narrative reviews are inherently subject to selection bias, and readers should interpret the evidence synthesized here with this limitation in mind.

3. GUT DYSBIOSIS IN DRUG‐RESISTANT EPILEPSY

Gut dysbiosis in DRE can be approached from two complementary angles: the biological mechanisms by which an altered microbiota may influence seizure susceptibility and drug response, and the clinical evidence documenting distinct microbial signatures in affected patients. We first outline these mechanisms to establish a functional framework, then review the clinical evidence in light of them.

3.1. Mechanisms of dysbiosis‐mediated epileptogenesis and ASM response

Pathways through which gut dysbiosis may promote seizure susceptibility and pharmacoresistance are multifaceted. ¹⁷ , ¹⁸ , ¹⁹ Intestinal barrier dysfunction (“leaky gut”) permits translocation of bacterial products such as lipopolysaccharide (LPS), triggering systemic and neuroinflammation through toll‐like receptor 4 (TLR4) activation and downstream cytokine cascades. ²⁸ This inflammatory state may both lower seizure thresholds ²⁹ , ³⁰ , ³¹ , ³² and reduce ASM responsiveness; in a mouse model, experimentally induced intestinal inflammation increased convulsant activity and reduced ASM efficacy ³⁰ —a finding that directly links dysbiosis to treatment failure rather than solely to seizure generation.

Microbial metabolites—SCFAs, GABA, serotonin, and tryptophan metabolites—can modulate neurotransmitter balance and neural excitability via the microbiota–gut–brain axis. ¹⁴ , ³³ Importantly, these metabolites may also modulate ASM response specifically, not only seizure biology: SCFAs enhance intestinal barrier integrity and blunt systemic inflammation that is known to impair ASM efficacy ³⁰ ; bacterial GABA and its precursors may additively or antagonistically interact with GABAergic ASMs (e.g., vigabatrin, tiagabine, benzodiazepines); and tryptophan‐kynurenine metabolites regulate neuroinflammatory pathways that influence blood–brain barrier permeability and, consequently, CNS ASM concentrations. Dysbiosis may therefore directly impair ASM handling—a possibility that is the central focus of this review. Against this mechanistic background, we next examine the clinical evidence that gut microbial composition is measurably altered in DRE, before turning to the specific microbiome–ASM interactions through which such alterations may translate into pharmacoresistance (Section 4).

3.2. Evidence from clinical studies

Clinical studies consistently show that gut microbial composition differs between patients with DRE, those with drug‐sensitive epilepsy, and healthy controls, although the particular taxa implicated vary across cohorts. Because genus‐level identity can obscure shared physiology, these signatures are most informative when interpreted by functional role—SCFA producers, mucin‐degrading taxa, β‐glucuronidase producers, and pro‐inflammatory taxa—the framework applied below.

A growing body of clinical evidence supports distinct gut microbial signatures in patients with DRE compared with drug‐sensitive epilepsy (DSE) and healthy controls. In a seminal study, Peng et al. ²⁰ analyzed the gut microbiota in 42 patients with DRE, 49 with DSE, and 65 healthy controls, finding that DRE patients harbored altered microbial composition characterized by enrichment of rare taxa—including Clostridium XVIII, Fusobacterium, Methanobrevibacter, Coprobacillus, Dorea, Akkermansia, and Roseburia. ²⁰ In contrast, DSE patients exhibited higher abundance of Bacteroidetes, Bacteroides, and Barnesiella—taxa associated with intestinal homeostasis. ²⁰

Subsequent studies have corroborated and extended these findings. ²¹ , ²² , ²³ Gong et al. ²⁴ reported that DRE patients showed enrichment of Verrucomicrobia, Nitrospirae, Blautia, Subdoligranulum, Bifidobacterium, and Dialister, and—importantly—that machine‐learning models built on microbiome data distinguished DRE from DSE with high accuracy (AUC = 0.97). Using 16S rRNA gene sequencing in an exploration cohort of 55 epilepsy patients and 46 spouse‐matched healthy controls, with validation in an independent cohort (13 patients, 10 controls), the investigators applied linear discriminant analysis effect size (LEfSe) for biomarker identification and random forest classification for disease prediction. ²⁴ Lee et al. ²⁵ further identified Enterococcus faecium, Bifidobacterium longum, and Eggerthella lenta as potential biomarkers of intractable epilepsy and suggested that ABC‐transporter‐associated microbiota may serve as functional biomarkers—directly implicating microbial modulation of drug efflux mechanisms. ²⁵ More recently, Riva et al. ²³ identified a distinct gut microbial signature associated with medication‐resistant epilepsy in a pediatric cohort, with Eubacterium depletion—a butyrate‐ and GABA‐producing genus—correlating with treatment resistance, further linking functional microbial output to ASM responsiveness.

A recent meta‐analysis pooling 16 case–control studies (438 cases, 369 controls) demonstrated that patients with intractable epilepsy had significantly reduced abundances of Bacteroidetes and Ruminococcaceae, with increased Proteobacteria and Verrucomicrobia. ²⁶ These compositional shifts are consistent with a pro‐inflammatory intestinal milieu and reduced short‐chain fatty acid production—both implicated in neuroinflammation and seizure facilitation. ²⁶

Viewed through this functional lens, several consistent patterns emerge across cohorts. SCFA producers (Faecalibacterium, Roseburia, Eubacterium, Subdoligranulum) are consistently depleted in DRE cohorts, ²³ , ²⁶ with potential consequences for intestinal barrier integrity, immune tone, and central neurotransmitter balance. Mucin‐degrading taxa such as Akkermansia muciniphila appear variably altered—depleted in some DRE cohorts but substantially enriched following ketogenic diet therapy (Section 6). ³⁸ β‐glucuronidase‐producing organisms (certain Bacteroides, Clostridium, and Escherichia strains) are especially relevant to enterohepatic recirculation of glucuronidated ASMs. ⁵⁴ Pro‐inflammatory Proteobacteria (including Escherichia) are often enriched in DRE, potentially contributing to LPS‐driven neuroinflammation. ²⁶ , ²⁸

Several important interpretive caveats apply to this body of evidence. First, these are associations, not demonstrations of causation; most studies are cross‐sectional and cannot establish directionality. The boundary between causative, correlative, and bidirectional effects—now a central concern across gut–brain research ²⁷ —remains particularly unresolved in epilepsy. Second, patients with DRE are almost universally on polytherapy and often receive microbiome‐modifying comedications (antibiotics, proton pump inhibitors, psychotropics), making it difficult to distinguish dysbiosis as a cause of drug resistance from a consequence of chronic multi‐ASM exposure (Section 4) or an epiphenomenon of disease severity, diet, comorbid gastrointestinal disease, or seizure frequency. ²⁷ Third, most existing studies rely on 16S rRNA gene sequencing, which offers taxonomic resolution but limited functional insight; metagenomic and metatranscriptomic approaches remain underused. Fourth, few studies control for sample timing relative to seizures (interictal versus peri‐ictal), which may independently influence microbial composition through stress‐mediated autonomic and neuroendocrine pathways. This “chicken‐or‐egg” problem, compounded by methodological heterogeneity, underscores the need for longitudinal multi‐omics studies tracking microbiome trajectories from epilepsy onset through treatment initiation and response assessment.

4. MICROBIOME–ANTISEIZURE MEDICATION INTERACTIONS

4.1. Direct microbial biotransformation of ASMs

Before considering specific biotransformation reactions, it is useful to clarify why this section concentrates on valproic acid (VPA), lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ). These agents are among the most frequently prescribed ASMs worldwide and remain mainstays of both monotherapy and combination regimens, including in DRE, where patients are almost invariably managed with polytherapy built upon these established drugs. ⁴ , ⁶ They were selected because, beyond this clinical prominence, they exemplify the two metabolic routes most susceptible to microbial influence: extensive hepatic glucuronidation with subsequent biliary excretion and enterohepatic recirculation (VPA, LTG, and the active oxcarbazepine metabolite, 10‐monohydroxy derivative [MHD]), and CYP‐mediated oxidation (CBZ). Because orally administered drugs that undergo glucuronidation and enterohepatic recycling are precisely those most exposed to bacterial β‐glucuronidase activity, and because CYP‐dependent drugs are sensitive to microbiome‐mediated modulation of host enzyme expression (Section 4.2), these four ASMs offer the clearest mechanistic windows onto microbiome–ASM interactions. By contrast, several widely used newer ASMs—most notably levetiracetam, together with gabapentin and pregabalin—are eliminated predominantly by renal excretion of unchanged drug, with little or no hepatic phase I/II metabolism or enterohepatic recirculation, and therefore offer comparatively few opportunities for microbiome‐mediated pharmacokinetic modulation; levetiracetam is included in Table 2 specifically as a comparatively microbiome‐neutral reference point. The drugs emphasized here are thus those in which microbial metabolism is both mechanistically plausible and clinically consequential, even though systematic, drug‐specific human data remain limited across the ASM class (Section 8).

TABLE 2.

Reported effects of commonly used antiseizure medications (ASMs) on gut microbial composition and function.

ASM	Reported microbiome effects	Evidence type	Notable findings	Clinical relevance
Carbamazepine (CBZ)	Depletion of Bacteroides, Flavonifractor; enrichment of Escherichia, Clostridium	Longitudinal microcosm (Dop 2024)	Increased antibiotic resistance genes; altered metabolome (↓ TCA intermediates)	Potential long‐term dysbiosis; resistome expansion
Valproic acid (VPA)	Altered microbial diversity; modulation of SCFA‐producing taxa	Observational human cohorts	Changes during 3‐month exposure (Gong 2022) 24	Possible influence on enterohepatic recirculation
Levetiracetam (LEV)	Minimal compositional shifts in in vitro models	Microcosm data	Less disruptive than CBZ	Potentially microbiome‐neutral profile
Polytherapy (DRE)	Poorly characterized	Unknown	High likelihood of cumulative microbial impact	Major knowledge gap

The gut microbiome possesses an extraordinary enzymatic repertoire, encoded by more than 300 000 bacterial genes, capable of diverse biotransformation reactions on xenobiotics and therapeutic drugs. ¹² , ¹³ , ¹⁶ These reactions include reduction, hydrolysis, deconjugation (of glucuronide and sulfate conjugates), demethylation, deamination, dehydroxylation, deacylation, decarboxylation, and oxidation. Because most ASMs are administered orally and encounter the gut microbiota before systemic absorption, this enzymatic capacity is of direct relevance. ¹³ Recent work conceptualizing microbiome‐active drug delivery further highlights that microbial enzymatic environments can be harnessed—or inadvertently disrupted—to modify drug release and absorption profiles. ⁹

Zimmermann et al. ¹⁰ demonstrated that 176 bacterial strains from the human gut could metabolize 271 orally administered drugs, with substantial interindividual variability attributable to microbiome composition. These biotransformations altered drug pharmacokinetics and in some cases generated metabolites with distinct pharmacological or toxicological profiles. Although specific ASMs were not the primary focus of that work, the enzymatic machinery identified—reductases, hydrolases, and β‐glucuronidases—is highly relevant to compounds such as carbamazepine, valproic acid, and other hepatically glucuronidated ASMs. However, direct bacterial metabolism of specific ASMs has not yet been systematically characterized in humans; the evidence here is largely extrapolated from general pharmacomicrobiomics data, and *in vitro* or preclinical models, and the clinical significance for ASM pharmacokinetics in epilepsy patients remains to be established.

Valproic acid (VPA) is extensively metabolized via glucuronidation by UDP‐glucuronosyltransferases (UGTs), producing valproate‐glucuronide that is excreted in bile and undergoes enterohepatic recirculation. Bacterial β‐glucuronidases can deconjugate these glucuronide metabolites, liberating free VPA for reabsorption and prolonging systemic exposure. ¹² , ¹³ Alterations in the abundance or activity of β‐glucuronidase‐producing bacteria could therefore influence VPA pharmacokinetics and steady‐state concentrations, with clinical implications for seizure control and dose‐related toxicity.

Lamotrigine (LTG) offers another illustrative example. LTG is primarily metabolized by UGT1A4 (with a minor UGT1A3 contribution) to lamotrigine‐2‐N‐glucuronide, which accounts for approximately 90% of the excreted dose and represents the major circulating metabolite. ⁵¹ Like VPA, lamotrigine‐glucuronide undergoes biliary excretion and is subject to bacterial β‐glucuronidase‐mediated deconjugation, potentially contributing to enterohepatic recirculation and variability in steady‐state concentrations. Oxcarbazepine (OXC) follows a different but equally microbiome‐relevant route: it is rapidly reduced by cytosolic arylketone reductases to its pharmacologically active 10‐monohydroxy derivative (MHD), the elimination of which proceeds predominantly through glucuronidation. ⁵² Because the resulting glucuronide is a candidate substrate for bacterial β‐glucuronidases, interindividual differences in gut β‐glucuronidase activity could in principle influence the enterohepatic handling of glucuronidated ASMs beyond VPA—with consequences for the steady‐state exposure that determines seizure control in DRE—although, as with VPA, direct clinical evidence in epilepsy patients remains to be generated.

Carbamazepine (CBZ), a widely used enzyme‐inducing ASM, undergoes hepatic oxidation primarily via CYP3A4 to its active metabolite carbamazepine‐10,11‐epoxide. ³⁴ While this primary metabolism is hepatic, the gut microbiome may indirectly influence CBZ disposition through modulation of CYP3A expression or direct interactions with CBZ or its metabolites in the intestinal lumen. CBZ also possesses intrinsic antimicrobial activity, raising the possibility of reciprocal microbiome–drug interactions whereby the drug reshapes the microbial community that, in turn, influences drug handling.

4.2. Indirect modulation of host drug metabolism

Beyond direct biotransformation, the gut microbiota exerts indirect but profound effects on host drug‐metabolizing capacity. Microbial metabolites—including secondary bile acids and short‐chain fatty acids—serve as ligands for nuclear receptors such as the pregnane X receptor (PXR), constitutive androstane receptor (CAR), and farnesoid X receptor (FXR). Activation of these receptors modulates expression of phase I (cytochrome P450) and phase II (conjugation) enzymes and drug efflux transporters in the liver and intestine. ¹²

Of particular relevance to DRE is the microbiome's influence on P‐glycoprotein (P‐gp, encoded by ABCB1/MDR1)—the efflux transporter implicated in the transporter hypothesis of pharmacoresistance. ⁵ , ⁶ P‐gp is expressed at the blood–brain barrier, intestinal epithelium, and liver, where it actively extrudes substrate ASMs from cells, thereby limiting their intestinal absorption and brain penetration; direct transport assays in MDR1‐transfected cells have confirmed phenytoin, phenobarbital, lamotrigine, levetiracetam, and topiramate as human P‐gp substrates, whereas carbamazepine transport has been more variable across systems. ⁵³ Preclinical evidence suggests that gut microbial metabolites can modulate P‐gp expression and activity, providing a plausible route by which dysbiosis could aggravate transporter‐mediated drug resistance. Dai et al. ³⁵ demonstrated that Bacillus subtilis inhibited ABCB1 transporter activity in Caco‐2 cell models, suggesting a direct link between specific microbial taxa and intestinal drug efflux. However, whether these *in vitro* findings translate to clinically meaningful modulation of intestinal or blood–brain barrier P‐gp function *in vivo* remains unknown; extrapolation from cell culture systems to the pharmacological environment of DRE patients warrants caution.

Studies in germ‐free and antibiotic‐treated mice have further demonstrated that absence of gut microbiota reduces hepatic expression of CYP3A and CYP2B enzymes, altering pharmacokinetics of substrates such as midazolam. ¹² , ³⁶ Extrapolating from these findings, dysbiosis‐induced changes in patients with epilepsy could alter ASM metabolic clearance in a clinically meaningful manner—contributing to subtherapeutic levels or, conversely, to accumulation and toxicity.

4.3. Microbiome‐mediated enterohepatic recirculation

Enterohepatic recirculation (EHR) is a pharmacokinetic process whereby drugs undergo hepatic phase II conjugation—predominantly glucuronidation by UDP‐glucuronosyltransferases (UGTs)—and biliary excretion as conjugates, which are then hydrolyzed by bacterial β‐glucuronidases in the gut lumen, liberating the parent drug for reabsorption into the portal circulation. This recycling prolongs systemic exposure, raises steady‐state concentrations, and lengthens apparent elimination half‐life. ¹² , ¹³ , ⁵⁴ The responsible bacterial β‐glucuronidases (the gut “GUSome”) are structurally diverse glycoside‐hydrolase enzymes encoded across all major gut phyla—including members of the Bacteroidetes (e.g., Bacteroides), Firmicutes (e.g., Clostridium, Faecalibacterium), and Proteobacteria (e.g., Escherichia coli)—and differ markedly in substrate preference, so the deconjugation capacity of a given microbiome reflects not merely overall bacterial load but the specific complement of GUS enzymes present. ⁵⁴ For ASMs whose disposition depends on glucuronidation—valproic acid, lamotrigine, and the oxcarbazepine metabolite MHD—the integrity and functional composition of this β‐glucuronidase repertoire is therefore a plausible determinant of EHR efficiency and of the steady‐state exposure on which seizure control in DRE depends.

The three glucuronidated ASMs differ instructively in how this mechanism might operate. Valproic acid is conjugated to valproate‐glucuronide by several UGT isoforms (notably UGT1A6, UGT1A9, and UGT2B7), excreted in bile, and is the ASM for which microbial deconjugation and reabsorption are best established mechanistically. ¹² , ¹³ Lamotrigine is conjugated chiefly by UGT1A4 to its 2‐N‐glucuronide, which constitutes roughly 90% of the excreted dose; this quaternary ammonium glucuronide is biliary‐excreted and, like other glucuronides, is a candidate substrate for luminal β‐glucuronidase‐mediated recycling. ⁵¹ Oxcarbazepine is first reduced to MHD, the principal active moiety, whose elimination proceeds mainly through glucuronidation; experimentally, the structurally related eslicarbazepine glucuronide is hydrolyzed by Escherichia coli β‐glucuronidase, providing direct enzymatic precedent that gut bacteria can deconjugate this drug class. ⁵² , ⁵⁴ Because UGT‐mediated glucuronidation is itself subject to genetic polymorphism and drug–drug induction (e.g., by enzyme‐inducing co‐ASMs), the microbial contribution to EHR is best understood as one variable within a multifactorial system rather than an isolated determinant.

Dysbiosis characterized by reduced abundance of β‐glucuronidase‐producing bacteria could impair deconjugation, diminishing EHR and lowering systemic drug exposure. Conversely, enrichment of these bacteria could enhance EHR, increasing drug concentrations. Importantly, direct evidence that gut bacterial β‐glucuronidase activity alters the pharmacokinetics of specific ASMs such as VPA or LTG in epilepsy patients is currently lacking; the mechanism described here is extrapolated from established pharmacokinetic principles and general pharmacomicrobiomics data. Given interindividual variability in gut microbiome composition among epilepsy patients, this mechanism may nonetheless contribute to the pharmacokinetic unpredictability and inconsistent therapeutic responses seen in clinical practice—particularly in DRE patients on polytherapy.

5. IMPACT OF CHRONIC ASM EXPOSURE ON THE GUT MICROBIOME

The relationship between ASMs and the gut microbiome is bidirectional: just as microbial communities influence drug metabolism, chronic drug exposure can profoundly reshape microbial ecology. Several complementary lines of evidence document this remodeling—controlled serial‐transfer microcosm experiments, ³⁴ targeted screens of ASM effects on the growth of individual gut bacterial species, ³⁶ and observational human cohorts sampled longitudinally during treatment ³⁷ —though the body of work remains modest and is dominated by a small number of drugs. This reciprocal interaction has significant implications for long‐term epilepsy management.

Dop et al. ³⁴ investigated repetitive exposure to three commonly prescribed ASMs—CBZ, VPA, and levetiracetam (LEV)—on gut‐derived microbial communities using a serial‐transfer microcosm model. Of the three, CBZ exerted the most pronounced impact on microbial composition and metabolic function: CBZ exposure depleted Bacteroides and Flavonifractor and enriched Escherichia and Clostridium, with concurrent increases in antibiotic resistance genes (ARGs), particularly those encoding efflux pumps and target‐alteration mechanisms. Notably, these microcosms were constructed from fecal samples of four healthy children (aged 11 months–5 years) without recent medication use or health conditions, rather than from epilepsy patients, and seizure outcomes were not assessed; translation to the DRE population therefore requires clinical validation. ³⁴

CBZ‐induced microbiome changes were mirrored by metabolome alterations, including reductions in citric‐acid‐cycle intermediates, glutamine, and spermidine, alongside elevated vitamin B6 levels. Microbiome composition showed only partial recovery during a drug‐free washout period, suggesting that CBZ may induce lasting perturbations with potential long‐term consequences for microbial and host health.

Beyond these compositional and metabolic shifts, the concurrent expansion of antibiotic resistance genes is particularly concerning, with clinical implications extending beyond the intended antiseizure action. ³⁴ Expansion of the gut resistome on chronic ASM therapy may (i) increase susceptibility to difficult‐to‐treat infections during hospitalization or immunosuppression, (ii) complicate empirical antibiotic selection in DRE patients—a population with higher rates of hospitalization and procedural interventions than the general population, and (iii) contribute to broader antimicrobial‐stewardship concerns if a substantial proportion of the chronic‐ASM‐exposed epilepsy population harbors expanded ARG reservoirs. Integrating targeted resistome surveillance—for example, screening for key efflux‐pump and target‐alteration genes via metagenomic methods—into long‐term monitoring of patients on enzyme‐inducing ASMs would provide an empirical basis for these considerations. VPA and LEV, by contrast, appeared less disruptive in this model, although in vivo human studies are needed to confirm differential profiles. ³⁴ , ³⁶ , ³⁷

These findings collectively suggest a vicious cycle in DRE: intestinal dysbiosis may impair ASM efficacy through altered drug metabolism, while chronic ASM exposure exacerbates dysbiosis, perpetuating pharmacoresistance (Figure 1). Breaking this cycle represents a compelling therapeutic target.

FIGURE 1.

Bidirectional interactions between the gut microbiome and antiseizure medications (ASMs) in drug‐resistant epilepsy (DRE). The schematic depicts a self‐perpetuating cycle in which gut dysbiosis alters ASM pharmacokinetics and efficacy to promote pharmacoresistance, while chronic ASM exposure in turn reshapes the microbiota. Arrow conventions: Solid arrows denote direct pathways; dashed arrows denote indirect pathways; the thick looping arrow denotes the reciprocal (drug‐to‐microbiome) effect; and green blunt‐ended connectors denote sites of therapeutic modulation. Direct pathways (solid arrows): (i) increased microbial β‐glucuronidase activity deconjugates glucuronidated ASMs (VPA, LTG, and the oxcarbazepine metabolite MHD), liberating free drug for enterohepatic reabsorption; and (ii) direct bacterial biotransformation of ASMs in the intestinal lumen via reductases, hydrolases, and related enzymes. Indirect pathways (dashed arrows): (iii) microbial‐metabolite signaling (short‐chain fatty acids [SCFAs], secondary bile acids) activates host nuclear receptors (PXR, CAR, FXR) that regulate CYP3A/CYP2B expression and phase II conjugation, altering hepatic ASM clearance; (iv) microbial modulation of P‐glycoprotein (P‐gp/ABCB1) at the intestinal epithelium and blood–brain barrier alters ASM efflux and CNS penetration; and (v) dysbiosis‐driven translocation of lipopolysaccharide (LPS) activates toll‐like receptor 4 (TLR4), triggering cytokine release and neuroinflammation that lower the seizure threshold and reduce ASM efficacy. These pathways converge on altered ASM pharmacokinetics and reduced efficacy, culminating in DRE. Reciprocal effect (thick looping arrow): Chronic ASM exposure—particularly to carbamazepine—depletes SCFA producers and enriches antibiotic‐resistance genes, perpetuating dysbiosis and closing the cycle. Therapeutic interventions (green blunt‐ended connectors): The ketogenic diet, probiotics/prebiotics, and fecal microbiota transplantation act on gut dysbiosis to restore a eubiotic community, whereas pharmacomicrobiomics‐guided prescribing acts on the pharmacokinetic node to individualize ASM selection; each represents a potential means of interrupting the cycle. ABCB1, ATP‐binding cassette subfamily B member 1; ASM, antiseizure medication; BBB, blood–brain barrier; CAR, constitutive androstane receptor; CBZ, carbamazepine; CYP, cytochrome P450; FMT, fecal microbiota transplantation; FXR, farnesoid X receptor; KD, ketogenic diet; LPS, lipopolysaccharide; LTG, lamotrigine; MHD, 10‐monohydroxy derivative (active oxcarbazepine metabolite); OXC, oxcarbazepine; P‐gp, P‐glycoprotein; PXR, pregnane X receptor; SCFA, short‐chain fatty acid; TLR4, toll‐like receptor 4; VPA, valproic acid.

6. THE KETOGENIC DIET AS A MICROBIOME‐MEDIATED ANTISEIZURE INTERVENTION

The ketogenic diet (KD)—a high‐fat, low‐carbohydrate regimen—has been used for more than a century as a non‐pharmacological treatment for DRE, yet its mechanisms of action have remained incompletely understood. Emerging evidence now strongly implicates the gut microbiome as a critical mediator of KD antiseizure effects.

In a landmark study, Olson et al. ³⁸ demonstrated that the gut microbiota is not merely associated with—but is required for—the seizure‐protective effects of the KD. Using two murine models of refractory epilepsy (6‐Hz psychomotor seizures and Kcna1 ⁻/⁻ spontaneous tonic–clonic seizures), the investigators showed that KD substantially altered gut microbial composition—notably increasing Akkermansia muciniphila (from ~3% to 36%) and Parabacteroides species. Critically, mice treated with broad‐spectrum antibiotics or reared under germ‐free conditions were resistant to KD‐mediated seizure protection, establishing a causal role for the microbiota. ³⁸ Gnotobiotic co‐colonization with Akkermansia and Parabacteroides was sufficient to restore seizure protection, even in mice fed a control diet. The mechanistic pathway involved microbiota‐mediated reductions in systemic γ‐glutamylated amino acids and consequent elevations in the hippocampal GABA‐to‐glutamate ratio—a measure of inhibitory versus excitatory neurotransmission. γ‐glutamyl transpeptidase inhibition mimicked the antiseizure effects of the KD‐associated microbiota, further corroborating the mechanism. ³⁸

The reproducibility of these findings across models merits careful consideration. The Olson et al. ³⁸ findings were demonstrated in two independent seizure models (acute electrical and genetic chronic) and recapitulated by defined bacterial consortia, supporting mechanistic generalizability. However, several dimensions of the response appear strain‐ or context‐specific rather than broadly reproducible: the specific bacterial taxa implicated in KD response (Akkermansia and Parabacteroides) vary across studies ³⁹ , ⁴⁰ , ⁴¹ , ⁴² ; effect magnitude differs by seizure etiology and baseline microbiome state; and the temporal kinetics of diet‐induced microbial and metabolic shifts have been variably described. These patterns suggest a model in which the functional pathway (γ‐glutamylation → hippocampal GABA/glutamate ratio) may be more generalizable than the specific taxa driving it.

Clinical studies in children with DRE have extended these findings. ³⁹ , ⁴⁰ , ⁴¹ , ⁴² Dahlin et al. ⁴³ reported that higher pretreatment levels of Bifidobacterium and tumor necrosis factor in children with DRE were associated with a favorable KD antiseizure response, suggesting baseline microbiome composition as a predictive biomarker for KD response and enabling a more personalized approach to dietary therapy. From a clinical monitoring perspective, microbiome‐derived metabolite signatures associated with KD efficacy—such as circulating γ‐glutamylated amino acid levels or fecal SCFA profiles—could potentially be tracked longitudinally to assess whether the KD is engaging its microbiome‐mediated mechanism in individual patients and to guide dietary adjustments. ⁴³ Recent pediatric microbiome research ⁴⁴ further supports the feasibility of such longitudinal approaches in children with DRE.

Framed against the mechanisms in Sections 4 and 5, the KD appears to act predominantly by bypassing—rather than reversing—microbiome‐mediated pharmacoresistance. Its antiseizure benefit is exerted through a metabolic and neurotransmitter pathway (microbiota‐dependent reductions in γ‐glutamylated amino acids and a raised hippocampal GABA‐to‐glutamate ratio) that is largely independent of how ASMs are absorbed, metabolized, or effluxed, which helps explain why dietary therapy can succeed where multiple pharmacologic agents have failed. ³⁸ At the same time, the diet may also modify the very mechanisms that drive pharmacoresistance: by enriching Akkermansia muciniphila and Parabacteroides and reshaping the broader community, the KD alters precisely the taxa relevant to β‐glucuronidase‐dependent enterohepatic recirculation and to the inflammatory tone that lowers ASM responsiveness, raising the untested possibility that diet could shift the pharmacokinetics or efficacy of co‐administered ASMs. ³⁸ , ⁴³ Whether the dominant clinical benefit derives from bypass, from modification of ASM handling, or from both has not been directly studied, and disentangling these is a tractable and high‐value question—for example, by pairing KD initiation with therapeutic drug monitoring and longitudinal metagenomics in patients continuing background ASM therapy.

7. EMERGING THERAPEUTIC STRATEGIES TARGETING THE MICROBIOME

7.1. Probiotics and prebiotics

Given the evidence for dysbiosis in DRE, probiotic supplementation represents a logical therapeutic strategy. The principal clinical signal to date comes from a single open‐label pilot study in patients with DRE, in which a multi‐strain formulation given as adjunctive therapy was associated with a clinically meaningful reduction in seizure frequency in a subset of participants over a four‐month period. ⁴⁵ The mechanistic rationale rests on preclinically demonstrated effects rather than on epilepsy‐specific clinical data: candidate strains can synthesize GABA, generate short‐chain fatty acids that reinforce barrier integrity and temper systemic inflammation, and engage vagal and immune signaling to the central nervous system. ⁵⁹ However, randomized controlled trials in epilepsy remain absent, and optimal bacterial strains, dosing regimens, and treatment durations are undetermined.

7.1.1. Strain specificity is likely to be critical

Effects attributed to a genus (e.g., Lactobacillus, Bifidobacterium) can differ markedly between species and between strains of the same species; GABA‐producing Lactobacillus brevis strains, for example, are not functionally interchangeable with Lactobacillus rhamnosus GG, which signals primarily through vagal and immune pathways. ⁵⁹ SCFA‐producing taxa such as Faecalibacterium prausnitzii and Roseburia spp. act via distinct metabolic routes from Akkermansia muciniphila, which exerts its effects largely through mucin turnover and barrier function. Any future trial design in DRE should therefore specify strains precisely, report colonization dynamics, and—ideally—match strain selection to the specific dysbiosis pattern observed in individual patients. Combination formulations targeting multiple functional niches (e.g., an SCFA producer paired with a mucin‐degrader) may prove more effective than single‐strain products. ⁴⁶

7.2. Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) offers a more comprehensive approach to microbiome reconstitution. The clinical evidence in epilepsy is, however, limited to isolated case reports rather than any controlled series—most prominently a single patient with comorbid Crohn's disease whose seizures remitted following FMT. ⁴⁷ Safety concerns—including transmission of drug‐resistant organisms (as highlighted by a fatal case of drug‐resistant Escherichia coli bacteremia reported by DeFilipp et al. ⁴⁸ )—necessitate rigorous donor screening and careful patient selection.

7.2.1. A fundamental limitation of FMT is engraftment variability

Donor microbiota do not colonize recipients uniformly; engraftment depth depends on donor–recipient microbiome compatibility, recipient baseline community resilience, pre‐FMT bowel preparation, route of administration (colonoscopic, capsule, nasogastric), and post‐FMT diet and antibiotic exposure. ⁵⁵ , ⁵⁶ Two recipients of the same donor product may show substantially different engraftment profiles, producing heterogeneous clinical outcomes that confound interpretation of small trials. ⁵⁶ Future FMT trials in DRE should therefore incorporate standardized engraftment assessment—including quantification of donor indicator features, chimeric community coalescence metrics, temporal stability analyses, and monitoring of donor and recipient ARG carriage—so that engraftment depth can be correlated with seizure outcomes and safety signals. ⁵⁵ Controlled clinical trials with these methodological safeguards are warranted to establish FMT efficacy, safety, and durability in DRE.

7.3. Pharmacomicrobiomics‐guided ASM selection

A further potential implication of microbiome–drug interaction research is pharmacomicrobiomics‐guided prescribing. In principle, profiling an individual patient's gut microbiome composition and metabolic capacity could help predict which ASMs are likely to be optimally absorbed, metabolized, and distributed, and which may be subject to unfavorable microbial biotransformation—a shift from empirical trial‐and‐error ASM selection toward microbiome‐informed precision medicine. It is important to be clear, however, that this remains an aspiration rather than a demonstrated capability: no clinical study has yet used microbiome profiling to guide ASM selection in epilepsy, and the supporting evidence is presently confined to proof‐of‐concept work in other drug classes showing that gut bacteria metabolize a large fraction of orally administered drugs with clinically relevant interindividual variability. ¹⁰ , ¹⁶

Computational tools for predicting microbiota‐mediated drug metabolism are emerging, incorporating metagenomic databases, biotransformation rule sets, and machine‐learning algorithms. ⁴⁹ While still in early development, these tools hold considerable promise for integrating microbiome data into pharmacokinetic modeling and clinical decision‐making.

An important consideration is the interaction between host pharmacogenomic variation and microbiome‐mediated drug handling. Many ASMs are substrates of polymorphic cytochrome P450 enzymes—phenytoin is primarily metabolized by CYP2C9, clobazam by CYP2C19—and interindividual differences in these enzymes are well‐established determinants of ASM pharmacokinetics, to the extent that CYP2C9 and CYP2C19 genotype‐based dosing recommendations now exist for phenytoin. ⁵⁷ , ⁵⁸ Because the gut microbiome also modulates CYP expression through nuclear‐receptor activation (Section 4.2), the net pharmacokinetic profile of a given ASM may reflect the combined influence of host genetic polymorphisms and microbial metabolic capacity. Integrating pharmacogenomic and pharmacomicrobiomic data into a unified predictive framework represents an important frontier, although the analytical and clinical tools required remain in their infancy.

7.3.1. Practical barriers to clinical implementation warrant explicit acknowledgment

Stool metagenomic sequencing currently requires several days to weeks of turnaround time—incompatible with acute decision‐making—and per‐sample costs (hundreds to low thousands of USD) preclude routine use in many healthcare systems. Results require specialized bioinformatic expertise to interpret, which is rarely available in neurology clinics. Sample collection, storage, and transport logistics add further operational complexity, and regulatory frameworks for microbiome‐based clinical decision tools remain nascent. These barriers are not insurmountable, but any realistic pathway to clinical deployment must address cost reduction, assay standardization, point‐of‐care or clinic‐integrated reporting, and training of neurologists to interpret microbiome data. Early implementation will likely target high‐value, narrowly defined clinical scenarios—such as unexplained pharmacokinetic variability on stable ASM regimens or selection between microbiome‐neutral and microbiome‐disruptive ASMs—before broader adoption becomes feasible.

7.4. Antibiotic modulation

Short‐course antibiotic therapy has been anecdotally reported to achieve temporary seizure freedom in patients with DRE—presumably through acute restructuring of the gut microbiome. Braakman and van Ingen ⁵⁰ reported a small series in which six patients with DRE experienced seizure cessation during a two‐week antibiotic course, with recurrence upon discontinuation. While this observation supports the gut microbiota hypothesis, the non‐selective nature of antibiotic effects, the risk of promoting antimicrobial resistance, and the transient benefit limit clinical applicability. Targeted antimicrobial strategies—narrow‐spectrum antibiotics or bacteriophage therapy directed against specific pathobiont taxa—may offer a more refined approach in the future.

8. KNOWLEDGE GAPS AND FUTURE DIRECTIONS

Despite the rapidly expanding evidence, several critical knowledge gaps remain.

First, most available studies on the gut microbiome in epilepsy are cross‐sectional, precluding causal inference. Confounding effects of chronic polytherapy, disease severity, diet, and comorbidities on observed dysbiosis patterns remain unresolved. Longitudinal studies tracking microbiome trajectories from epilepsy onset through treatment initiation and response assessment are urgently needed.

Second, specific ASM–microbiome interactions have been inadequately characterized at the molecular level. A concrete experimental pipeline is needed: metagenomics‐guided selection of candidate bacterial strains with relevant enzymatic capacity, followed by ex vivo incubation of patient‐derived microbiota with isotopically labeled ASMs to identify biotransformation products, and subsequent in vivo pharmacokinetic validation in gnotobiotic models and human subjects. High‐priority candidates include VPA, LTG, and CBZ, given their known glucuronidation pathways and the established relevance of bacterial β‐glucuronidases. The identification of specific bacterial enzymes responsible for metabolizing individual ASMs (analogous to Zimmermann et al. ¹⁰ for other drug classes) represents a major research priority that would inform targeted interventions to modulate unfavorable biotransformation.

Third, the clinical significance of microbiome‐mediated pharmacokinetic variability in epilepsy has not been quantified. Prospective studies pairing therapeutic drug monitoring with stool metagenomics and metatranscriptomics could explain currently unexplained pharmacokinetic variability in patients on stable ASM regimens. Development of physiologically based pharmacokinetic (PBPK) models incorporating microbiome enzyme priors—including β‐glucuronidase gene abundance and activity, CYP‐modulating metabolite concentrations, and transporter‐expression data—would provide a quantitative framework for predicting the net impact of microbiome variation on ASM disposition.

Fourth, microbiome‐based biomarkers for predicting treatment response (both to conventional ASMs and dietary interventions such as the KD) require validation in adequately powered multicenter trials.

Fifth, the interaction between host pharmacogenomic variation (e.g., CYP2C9, CYP2C19, UGT polymorphisms) and microbiome‐mediated drug handling remains unexplored in epilepsy.

Sixth, a comprehensive multi‐omics approach is essential to advance the field from association to mechanism. Integrating metagenomics (who is there?), metatranscriptomics (what are they doing?), metaproteomics (which enzymes are active?), and metabolomics (which products reach the host?)—paired with host pharmacogenomics, transcriptomics, and clinical phenotyping—offers the potential to resolve causal relationships and identify actionable intervention points. Benefits include the ability to identify functional microbiome states (beyond taxonomic signatures) that predict ASM response, to discover novel microbial biotransformation pathways, and to develop mechanistically anchored biomarkers. Current limitations include cost (multi‐omics datasets can run into tens of thousands of USD per patient), computational infrastructure and bioinformatic expertise requirements, lack of standardization across platforms, batch effects between cohorts, and—critically—the shortage of adequately powered DRE cohorts with banked longitudinal samples. Research consortia and shared biobanking frameworks will likely be required to overcome these limitations.

Finally, the safety and long‐term efficacy of microbiome‐targeted interventions (probiotics, FMT, targeted antimicrobials) in DRE need to be established through rigorous controlled trials before they can be recommended in clinical practice.

9. CLINICAL IMPLICATIONS FOR EPILEPTOLOGISTS

While pharmacomicrobiomics in epilepsy remains in its early stages, the evidence reviewed above carries several practical implications that warrant consideration by practicing epileptologists even as confirmatory trials are awaited.

First, therapeutic drug monitoring (TDM) may deserve a more prominent role in DRE management than is currently standard. If microbiome‐mediated pharmacokinetic variability contributes to inconsistent ASM serum concentrations—as the enterohepatic recirculation and microbial biotransformation data suggest—then unexplained fluctuations in drug levels, particularly without changes in dose, adherence, or concomitant medications, could reflect shifts in microbial metabolic capacity. Clinicians encountering such pharmacokinetic instability should consider the gut microbiome as a potential contributing factor, particularly in patients with concurrent gastrointestinal symptoms, recent antibiotic or proton pump inhibitor use, or significant dietary changes. In the future, a pharmacomicrobiomics‐guided workflow might integrate stool metagenomic profiling (to characterize bacterial drug‐metabolizing enzyme capacity and β‐glucuronidase gene abundance) with serial TDM and population PK modeling.

Second, differential ASM impact on gut microbial composition raises the question of whether “microbiome‐neutral” ASMs should be preferentially considered in treatment selection—particularly in patients at risk for or already experiencing DRE. The evidence that LEV exerts minimal effects on microbial homeostasis compared with the more disruptive profile of CBZ ³⁴ is preliminary but provocative; if confirmed in human cohorts, this could inform rational ASM selection beyond conventional efficacy and tolerability considerations. Given CBZ‐related enrichment of antibiotic resistance genes, integrating resistome surveillance—through targeted metagenomic screening of key efflux‐pump and target‐alteration genes—into long‐term monitoring of patients on chronic enzyme‐inducing ASM therapy deserves consideration.

Third, polytherapy—the rule rather than the exception in DRE—presents a particular challenge. Each additional ASM represents a potential perturbation to the gut microbial ecosystem, and the cumulative microbiome impact of multi‐drug regimens remains almost entirely uncharacterized. This gap should prompt caution and heightened pharmacovigilance and reinforces the importance of minimizing unnecessary polytherapy where clinically feasible.

Fourth, the demonstration that the KD exerts its antiseizure effects, at least in part, through microbiome‐mediated mechanisms ³⁸ suggests that earlier consideration of dietary therapy in the DRE treatment algorithm may be warranted—not merely as a last resort after multiple ASM failures, but as a targeted intervention addressing the microbial dimension of pharmacoresistance. The identification of baseline microbiome predictors of KD response ⁴³ further supports a more personalized dietary‐intervention approach in selected patients.

Finally, while routine gut microbiome profiling cannot yet be recommended in clinical epilepsy practice, the trajectory of the field suggests this may become feasible in the foreseeable future. Epileptologists should be aware of emerging evidence linking the gut microbiome to drug resistance and should consider this axis when evaluating patients with unexplained treatment failure or pharmacokinetic variability.

10. CONCLUSIONS

The gut microbiome has emerged as a compelling and potentially modifiable factor in the pathophysiology of DRE. The evidence reviewed herein supports a model in which dysbiosis contributes to pharmacoresistance through multiple interconnected mechanisms: direct microbial biotransformation of ASMs altering pharmacokinetics and bioavailability; indirect modulation of host drug‐metabolizing enzymes, nuclear receptors, and efflux transporters; disruption of enterohepatic recirculation of glucuronidated ASMs; and chronic ASM‐induced perturbation of microbial composition creating a self‐perpetuating cycle of dysbiosis and treatment failure.

The landmark demonstration by Olson et al. ³⁸ that specific gut bacteria (Akkermansia muciniphila and Parabacteroides) mediate the antiseizure effects of the KD provides powerful proof of concept that the microbiome can be leveraged therapeutically in DRE. However, translating these findings from bench to bedside requires substantial further investigation—including mechanistic studies of specific ASM–microbiome interactions, prospective pharmacokinetic–microbiome correlation studies, and controlled clinical trials of microbiome‐targeted interventions.

The emerging field of pharmacomicrobiomics holds transformative potential for epilepsy care. Integrating gut microbiome profiling into the clinical evaluation of patients with DRE could enable more rational ASM selection, identify patients likely to benefit from dietary or probiotic interventions, and ultimately shift the paradigm from empirical polypharmacy toward microbiome‐informed precision medicine. As our understanding of the intricate crosstalk between the gut microbiome, ASM pharmacology, and seizure susceptibility continues to deepen, the prospect of harnessing this knowledge to improve outcomes for the millions of patients living with DRE becomes increasingly tangible.

AUTHOR CONTRIBUTIONS

The following contributions are described using the CRediT (Contributor Roles Taxonomy): Khaled Zammar: Conceptualization; methodology; investigation; writing—original draft; visualization; project administration. Majd A. AbuAlrob: Investigation; writing—review and editing. Musab Ali: Investigation; writing—review and editing. Simona Lattanzi: Validation; writing—review and editing; supervision. Boulenouar Mesraoua: Conceptualization; supervision; writing—review and editing. All authors read, critically revised, and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflicts of interest to disclose.

ETHICS STATEMENT

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article, as no new data were created or analyzed in this study. All data discussed are available in the cited published literature.