Dietary Fibers in Clinical Ketogenic Diets Promotes Seizure Resistance in Mice Through Modulation of Gut Microbiome

Objectives: Gut microbiome has been shown to play a pivotal role for the anti-seizure effects of the classical ketogenic diet (KD). However, how different variations of KD differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. Methods: We tested three different clinically prescribed KD infant formulas for their effects on resistance to 6-Hz psychomotor seizures in mice and identified microbial metagenomic signatures for each dietary treatment that correlate with seizure outcome. We designed a defined bacterial consortium that represents the human infant gut microbiome and screened the effects of specific dietary variables in KD on microbial community structure and function in order to identify the dietary components that elicit the most striking alterations in the microbiome. Finally, we tested the top dietary candidates for their ability to modify seizure resistance in mice. Results: We found that clinically prescribed KD infant formulas that vary in macronutrient ratio, fat source, and fiber content also vary in their ability to promote seizure resistance in mice. Low-fiber KD formula conferred increased susceptibility to seizures. This was associated with reduced representation of pathways for L-glutamate and L-glutamine biosynthesis and increased representation of pathways related to amide, amidine, amine, and polyamine degradation, fatty acid and lipid biosynthesis, carboxylic acid degradation, and fermentation in the gut microbiome metagenome. By screening specific dietary variables, we observed that dietary fiber drove the most substantial metagenomic shifts on a model human gut microbiome. Addition of dietary fiber to the low-fiber KD formula restored seizure resistance, and supplementing protective KD with excess dietary fiber further potentiates seizure resistance. Conclusions: This study reveals that different formulations of clinical KDs, and dietary fiber content in particular, differentially impact seizure outcome in mice, likely through modification of the gut microbiome. Insights gained from interactions between KD components, the gut microbiome, and host's susceptibility to seizures could lead development of novel strategies targeting microbiome for more effective treatment of refractory epilepsy.