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

Christine A. Olson, Helen E. Vuong, Jessica M. Yano, Qingxing Y. Liang, David J. Nusbaum, Elaine Y. Hsiao

Research output: Contribution to journalArticlepeer-review

578 Scopus citations

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. The beneficial effects of a ketogenic diet on epileptic seizures are mediated by the gut microbiome through their modulation of hippocampal GABA/glutamate ratios.

Original languageEnglish (US)
Pages (from-to)1728-1741.e13
JournalCell
Volume173
Issue number7
DOIs
StatePublished - Jun 14 2018

Bibliographical note

Funding Information:
The authors acknowledge Julianne McGinn and Tomiko Rendon for generating and caring for the germ-free animals; Kristie Yu, Sandy Wong, and Gauri Shastri for assistance with initial experiments and data analysis; Thomas Fung, Geoffrey Pronovost, Gregory Donaldson, Xia Yang, Carlos Cepeda, and Kim McDowell for helpful advice; and Bruce Tempel and Marie Francoise-Chesselet for sharing mice and reagents. This work was supported by funds from UCLA Department of Integrative Biology & Physiology and Division of Life Sciences (to E.Y.H.), Alfred P. Sloan Foundation Fellowship ( FG-201606433 to E.Y.H.), Army Research Office Multidisciplinary University Research Initiative ( W911NF-17-1-0402 to E.Y.H.), Mallinckrodt Foundation ( 20181433 to E.Y.H.), NIH Ruth L. Kirschstein Award ( T32GM065823 to C.A.O.), and UPLIFT: UCLA Postdoctoral Longitudinal Investment in Faculty Award ( K12GM106996 to H.E.V.).

Funding Information:
The authors acknowledge Julianne McGinn and Tomiko Rendon for generating and caring for the germ-free animals; Kristie Yu, Sandy Wong, and Gauri Shastri for assistance with initial experiments and data analysis; Thomas Fung, Geoffrey Pronovost, Gregory Donaldson, Xia Yang, Carlos Cepeda, and Kim McDowell for helpful advice; and Bruce Tempel and Marie Francoise-Chesselet for sharing mice and reagents. This work was supported by funds from UCLA Department of Integrative Biology & Physiology and Division of Life Sciences (to E.Y.H.), Alfred P. Sloan Foundation Fellowship (FG-201606433 to E.Y.H.), Army Research Office Multidisciplinary University Research Initiative (W911NF-17-1-0402 to E.Y.H.), Mallinckrodt Foundation (20181433 to E.Y.H.), NIH Ruth L. Kirschstein Award (T32GM065823 to C.A.O.), and UPLIFT: UCLA Postdoctoral Longitudinal Investment in Faculty Award (K12GM106996 to H.E.V.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • 6-Hz seizures
  • Akkermansia
  • GGsTop
  • Kcna1
  • Parabacteroides
  • epilepsy
  • gamma-glutamyl transpeptidase
  • ketogenic diet
  • microbiome
  • microbiota

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