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The intestinal myobiota is conditioned from birth and is composed of more than 100 trillion microbes including bacteria, fungi, protozoa and viruses. It is now known that we are what we eat and this microbiota can be affected over the years, today it explains many neurological diseases or at least a relationship has been proposed that requires further study. One third of patients with epilepsy have drug-resistant epilepsy (DRE) with recurrent seizures despite trials of two or more appropriate anti-seizure medications (ASM) at optimal doses used in treatment. Patients with DRE are unlikely to achieve seizure control with additional MAPE1 trials and face high rates of multiple drug toxicity; physical injuries; social, educational, and occupational limitations; progressive cognitive deficits; and even epilepsy-related mortality. Resection of the epileptogenic focus is currently done, but not all patients benefit or are candidates; some have significant adverse effects, and there is a low referral rate for epilepsy surgery. Alternative dietary (e.g., ketogenic/very low carbohydrate diets) and medical (e.g., neuromodulation devices) therapies are used as well as poorly studied nonmedical (e.g., probiotics or vitamins) therapies. Advances in understanding the microbiome and gut-brain axis could shed light on the pathogenesis of epilepsy and resistance to MAPE, and suggest targets for intervention.