Varied Clinical Ketogenic Diets Elicit Both Shared and Unique Functional and Taxonomic Responses on the Human Gut Microbiome in Refractory Epilepsy

Abstract

ObjectivesThe high fat low carbohydrate ketogenic diet (KD) has been used to treat refractory epilepsy wherein 1 in 3 do not respond to anti-epileptic drugs. KD-induced alterations in the gut microbiome are necessary to mediate anti-seizure effects in mice. However, the efficacy of KDs have been inconsistent across human cohorts likely due to KD composition heterogeneity and microbiome variability. Thus, we aim to uncover how varied KDs shape composition and function of gut microbiome to influence host physiology. We hypothesize that clinical KDs will elicit common and unique microbial functional signatures.MethodsWe designed a defined bacterial consortium that represents the human infant gut microbiome and evaluated effects of clinical KD infant formulas on microbial community structure and function in vitro. We identified specific KD components that drive shifts in microbial taxa and functions via qPCR and metagenomic analysis. Furthermore, we characterized effects of clinical KDs on the composition and function of fecal microbiota collected from infants with refractory epilepsy. Finally, we tested various clinical KDs for their ability to treat seizures in a mouse model of refractory epilepsy, which identified dietary factors and microbial alterations that correlate with seizure protection.ResultsKD formulas increase the abundance of E. faecalis and B. breve in the model infant gut microbiota. In addition, KD at 3:1 macronutrient ratio but not other KDs promotes B. vulgatus. Our metagenomic analysis showed amino acid and fatty acid biosynthesis are differentially decreased in KDs where linoleic acid, palm oil, and medium chain triglycerides are the main components. Cross comparison of functional response to KD revealed that particular pathways are shared between model microbiome and pediatric epilepsy cohort. The KD ratio and specific KD components correlate with anti-seizure response in the 6-Hz mouse model for epilepsy.ConclusionsOverall, this study suggests that clinical KDs elicit common microbial responses and unique microbial features based on dietary composition. Understanding interactions between KD components, gut microbiota, and host susceptibility to seizures could lead to precision nutritional approaches to treat epileptic seizures.Funding SourcesNINDS, NYSCF.