The impact of Scn1a deficiency and ketogenic diet on the intestinal microbiome: A study in a genetic Dravet mouse model.

PURPOSE

The gut-brain axis has been discussed as a possible factor contributing to ictogenesis and epilepsy. While recent preclinical studies have proposed a link between the antiseizure effect of a ketogenic diet (KD) and alterations to the gut microbiota, there is a knowledge gap about microbial composition as a result of Scn1a genetic deficiency and how this is affected by KD in Dravet syndrome.

METHODS

A large-scale microbiome analysis using 16S rRNA gene sequencing was performed in fecal samples collected from wildtype and Dravet mice fed either control diet (CD) or KD. Microbial alterations associated with the Dravet phenotype or triggered by KD exposure were identified.

RESULTS

The comprehensive microbial analysis revealed pronounced alterations in gut microbiota between wildtype and Dravet mice. The regulation of Chao index indicated a reduced species richness in Dravet mice when compared to wildtype controls. The ratio between Firmicutes and Bacteroidetes phyla was increased in mice with the Dravet genotype, therefore implying a microbial dysbiosis in these animals. Following the switch to CD or KD, several bacteria phyla and genera were regulated in Dravet mice. Interestingly, an increased abundance of the Clostridium genus and a decreased abundance of the Romboutsia genus showed a significant correlation with the severity of the phenotype in Dravet mice. KD increased the abundance of Firmicutes and reduced the abundance of Bacteroidetes phyla in Dravet mice. The degree of these microbial alterations correlated with the reduction in the frequency and duration of motor seizures in these animals.

CONCLUSION

In conclusion, the comprehensive microbial analysis demonstrated pronounced alterations in the gut microbiota with evidence of a gut dysbiosis as a consequence of the Scn1a genetic deficiency. Exposure to KD affected the gut microbiome in Dravet mice. Interestingly, abundance of selected genera correlated with the seizure phenotype of Dravet mice. Future studies investigating the functional relevance of disease-associated and KD-triggered changes would be essential to confirm the relevance of these findings.