Epilepsy is a complex, chronic neurological disorder with diverse underlying etiologies characterized by the spontaneous occurrence of seizures. Epilepsy affects all ages from neonates to elderly adults, with the most recent CDC estimates stating that ~3 million adults and over 400,000 children are currently suffering from active epilepsy in the U.S. alone. In adults, the leading cause of epilepsy worldwide in central nervous system (CNS) infection, while in neonates the most common cause of seizures is hypoxic/ischemic encephalopathy (HIE). However, in both adults and neonates, current antiepileptic drugs (AEDs) are ineffective in 30-50% of patients, despite the availability of over 20 FDA approved AEDs with diverse molecular targets. This disparity highlights a critical need for novel therapeutics in seizure-susceptibility and epilepsy. The microbes that inhabit gut mucosal surfaces, termed the gut microbiota, have been increasingly implicated in the pathology of neurological diseases including epilepsy. This gut-brain axis is an intriguing therapeutic target in epilepsy as gut microbes can affect the CNS through multiple mechanisms including vagus nerve signaling, immune-gut interactions, and through production of microbial-metabolites including neurotransmitters, short chain fatty acids (SCFAs), lactate, vitamins, and S-equol. Furthermore, the gut microbiota is crucial for neurodevelopment, indicating that the gut-brain axis may be involved in pediatric seizure-susceptibility. This dissertation reviews current evidence on the role of gut metabolites in seizure-susceptibility in epilepsy, highlighting the microbial-derived metabolite S-equol as a potential novel AED. We then evaluate gut microbiome alterations in the Theiler's murine encephalomyelitis virus (TMEV) adult mouse model of CNS infection-induced seizures and find decreases in S-equol-producing bacteria in the gut microbiomes of TMEV-infected mice with seizure phenotypes. We characterize the effect of exogenous S-equol on neuronal function in vitro, demonstrating a reduction in neuronal excitation following S-equol exposure. We additionally characterize entorhinal cortex (ECTX) pyramidal neuronal hyperexcitability, and demonstrate the ability of exogenous S-equol to ameliorate CNS-infection-induced ECTX neuronal hyperexcitability ex vivo. Finally, we demonstrate that perinatal and postnatal exposure to antibiotics alters the gut microbiome and increases seizure-susceptibility following HIE exposure in p9/p10 mice, potentially via sex-specific alterations in neuronal function. Together, this dissertation evaluates the gut-brain axis in pediatric and adult mouse models of seizure-susceptibility and identifies the gut metabolite S-equol as a potential target for the treatment of seizures. / Doctor of Philosophy / Epilepsy, a disease defined by the occurrence of two or more spontaneous seizures, affects over 50 million people worldwide. This makes epilepsy one of the most common chronic neurological disorders across the globe. People with epilepsy suffer increased mortality, lower quality of life, and increased social stigma. There is currently a crisis in the treatment and management of epilepsy, because although over 20 different anti-epileptic drugs (AEDs) are available to patients, these drugs only work in ~70% of individuals with epilepsy, leaving 30% of patients with uncontrolled seizures. Currently available AEDs are designed to target classical central nervous system (CNS) components. However, a growing body of evidence suggests that epilepsy is related to complex systems throughout the body. Therefore, in this manuscript we explore novel therapeutic targets outside of the CNS for the management of seizures. Over 1000 species of bacteria live in the in the human gut, and are termed the gut microbiota. Gut microbes produce a variety of chemicals that circulate through the body and can even reach the brain. Interaction of chemicals produced by the gut microbiota and brain chemistry have been shown to affect disease outcomes in Autism Spectrum Disorder, Parkinson Disease, and other brain disorders. However, very few studies have examined the possibility of a role for the gut microbiota in epilepsy. In this dissertation, we review chemicals produced by the gut microbiota that may alter epilepsy biology. We additionally examine gut microbiota alterations in a rodent model of epilepsy, and identify a novel chemical, S-equol, that is produced by the gut microbiota and impacts epilepsy biology in our rodent model. Lastly, we explore how altering the maternal gut microbiota in rodents can influence seizure-susceptibility in infants.