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, Christine A Olson, Helen E Vuong, Jessica M Yano, Qingxing Y Liang, David J Nusbaum, Elaine Y Hsiao
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.
Keywords: 6-Hz seizures; Akkermansia; GGsTop; Kcna1; Parabacteroides; epilepsy; gamma-glutamyl transpeptidase; ketogenic diet; microbiome; microbiota.
Conflict of interest statement
DECLARATION OF INTERESTS
The authors declare no competing interests. Findings reported in the manuscript are the subject of UCLA provisional patent application US 2017/67548.
Copyright © 2018 Elsevier Inc. All rights reserved.
Figures
![Figure 1. The Ketogenic Diet Alters the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f1.jpg)
Figure 2. The Microbiota is Required for…
Figure 2. The Microbiota is Required for the Anti-Seizure Effects of the Ketogenic Diet
(A)…
Figure 3. KD-Associated Bacteria Sufficiently Mediate the…
Figure 3. KD-Associated Bacteria Sufficiently Mediate the Anti-Seizure Effects of the Ketogenic Diet
(A) Fluorescence…
Figure 4. KD-Associated Bacteria Sufficiently Confer Seizure…
Figure 4. KD-Associated Bacteria Sufficiently Confer Seizure Protection in Mice Fed the Control Diet
(A)…
Figure 5. KD-Associated Bacteria Mediate Protection Against…
Figure 5. KD-Associated Bacteria Mediate Protection Against Tonic-Clonic Seizures in Response to the Ketogenic Diet
Figure 6. Reductions in Peripheral Gamma-Glutamyl Amino…
Figure 6. Reductions in Peripheral Gamma-Glutamyl Amino Acids and Increases in Hippocampal GABA/Glutamate Ratios are…
Figure 7. The Ketogenic Diet and Bacterial…
Figure 7. The Ketogenic Diet and Bacterial Cross-Feeding Reduces Gamma Glutamyltranspeptidase (GGT) Activity, and GGT…
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- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Animals
- Anti-Bacterial Agents / pharmacology
- Bacteroides / drug effects
- Bacteroides / genetics
- Bacteroides / isolation & purification
- Diet, Ketogenic*
- Disease Models, Animal
- Feces / microbiology
- Gastrointestinal Microbiome* / drug effects
- Glutamic Acid / metabolism
- Hippocampus / metabolism
- Intestinal Mucosa / metabolism
- Kv1.1 Potassium Channel / deficiency
- Kv1.1 Potassium Channel / genetics
- Metabolome / drug effects
- Mice
- Mice, Inbred C3H
- Mice, Knockout
- Principal Component Analysis
- RNA, Ribosomal, 16S / genetics
- RNA, Ribosomal, 16S / metabolism
- Seizures / diet therapy*
- Seizures / pathology
- gamma-Aminobutyric Acid / metabolism
- gamma-Glutamyltransferase / metabolism
- Anti-Bacterial Agents
- Kcna1 protein, mouse
- RNA, Ribosomal, 16S
- Kv1.1 Potassium Channel
- Glutamic Acid
- gamma-Aminobutyric Acid
- gamma-Glutamyltransferase
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
![Figure 2. The Microbiota is Required for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f2.jpg)
Figure 3. KD-Associated Bacteria Sufficiently Mediate the…
Figure 3. KD-Associated Bacteria Sufficiently Mediate the Anti-Seizure Effects of the Ketogenic Diet
(A) Fluorescence…
Figure 4. KD-Associated Bacteria Sufficiently Confer Seizure…
Figure 4. KD-Associated Bacteria Sufficiently Confer Seizure Protection in Mice Fed the Control Diet
(A)…
Figure 5. KD-Associated Bacteria Mediate Protection Against…
Figure 5. KD-Associated Bacteria Mediate Protection Against Tonic-Clonic Seizures in Response to the Ketogenic Diet
Figure 6. Reductions in Peripheral Gamma-Glutamyl Amino…
Figure 6. Reductions in Peripheral Gamma-Glutamyl Amino Acids and Increases in Hippocampal GABA/Glutamate Ratios are…
Figure 7. The Ketogenic Diet and Bacterial…
Figure 7. The Ketogenic Diet and Bacterial Cross-Feeding Reduces Gamma Glutamyltranspeptidase (GGT) Activity, and GGT…
![Figure 3. KD-Associated Bacteria Sufficiently Mediate the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f3.jpg)
![Figure 4. KD-Associated Bacteria Sufficiently Confer Seizure…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f4.jpg)
![Figure 5. KD-Associated Bacteria Mediate Protection Against…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f5.jpg)
![Figure 6. Reductions in Peripheral Gamma-Glutamyl Amino…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f6.jpg)
![Figure 7. The Ketogenic Diet and Bacterial…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6003870/bin/nihms962831f7.jpg)
Source: PubMed