The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet

Abstract

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

Exercise with food withdrawal at thermoneutrality impacts fuel use, the microbiome, AMPK phosphorylation, muscle fibers, and thyroid hormone levels in rats

“…Of the downregulated genera, Lachnospiraceae are the most prominent. These changes, like those we observed in ketone body profiles, are reminiscent to those induced by ketogenic diets, and are associated with the reduction of epileptic seizures (Olson et al, ).…”

Stress co‐opts the gut to affect epileptogenesis. Commentary on “Facilitation of kindling epileptogenesis by chronic stress may be mediated by intestinal microbiome”

“…This study, as admitted by the authors, is preliminary and lacks mechanistic insight. However, it complements a study that appeared almost concurrently showing that the effects of the ketogenic diet on seizures in mice were mediated by changes in the gut microbiome . It is interesting that the current study did not reveal any alteration in brain excitability (revealed by after‐discharge threshold) as a function of the transplantation of the “stress” microbiota.…”

The immune system and psychiatric disease: a basic science perspective

“…The human commensal Bacteriodes is protective against behavioral deficits seen in the MIA model [124]. Finally, bacterial species that reduce gamma-glutamyl amino acids may be responsible for some of the benefits of the ketogenic diet, widely used in intractable epilepsy and, despite weaker evidence, recommended by some for treatment of autism [126]. While much remains to be determined about direct versus indirect effects of the microbiome on the brain, defining the underlying mechanisms represents an exciting area for further study with many potential therapeutic implications.…”