A novel ketogenic diet that reduces seizures and prevents liver steatosis leads to related gut microbiome changes and restores cecal short-chain fatty acid levels in the rapid kindling rat model of epileptogenesis.

We recently introduced an innovative ketogenic diet (KD) demonstrating superior antiseizure efficacy in a rat kindling model of epileptogenesis without inducing hepatic steatosis compared to a classic KD. This new diet features reduced fat content, lower plasma ketosis levels, and incorporates new ingredients, including a novel fermentable fiber blend, omega-3 polyunsaturated fatty acids (PUFAs) that partially replace omega-6 PUFAs, and medium-chain fatty acids that partially substitute for stearic acid. In the present study, we conducted gut microbiota analyses on cecum samples to elucidate its contribution to these effects. The analysis revealed distinctive features compared to the classic KD and control diet: higher weighted alpha diversity, distinct beta diversity, increased Bifidobacterium and Clostridium sensu stricto 1 abundances, and altered genera abundances correlated with seizure scores and liver triglyceride content. Furthermore, these genera abundances were linked to stearic acid and omega-3 PUFA plasma levels. Notably, the novel KD restored short-chain fatty acid levels and the butyrate-to-propionate ratio in the cecum, possibly driving lipid oxidation and ketone production while preventing liver steatosis. These findings suggest the involvement of the gut microbiome in mediating the antiseizure efficacy and reducing the adverse metabolic effects of a KD, thereby enhancing its utility for epilepsy treatment.