The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet
Open accessAbstract
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.
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Restriction of peripheral ketogenic amino acids is necessary for mediating microbiota- and ketogenic diet-dependent increases in seizure resistance.
“Specifically, it was demonstrated that the restriction of peripheral ketogenic amino acids is necessary for mediating microbiota-and ketogenic diet-dependent increases in seizure resistance (Olson et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Olson et al., 2018
Alterations in colonic luminal, serum, and hippocampal metabolomic profiles correlate with seizure protection.
“They also reported alterations in colonic luminal, serum, and hippocampal metabolomic profiles that also correlate with seizure protection (Olson et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Olson et al., 2018
The ketogenic diet increases the relative abundance of Akkermansia, Parabacteroides, Sutterella and Erysipelotrichaceae levels in the gut microbiota in mice compared to a control group.
“One study showed the ketogenic diet increasing the relative abundance of Akkermansia, Parabacteroides, Sutterella and Erysipelotrichaceae levels in the gut microbiota in mice compared to a control group, and that the gut microbiota is required for ketogenic diet-mediated protection against acute epileptogenic seizures (Olson et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Olson et al., 2018
The gut microbiota is required for ketogenic diet-mediated protection against acute epileptogenic seizures.
“and that the gut microbiota is required for ketogenic diet-mediated protection against acute epileptogenic seizures (Olson et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Olson et al., 2018
Colonization of GF mice with ketogenic diet-associated strains, Akkermansia and Parabacteroides, restores seizure protection.
“Furthermore, colonization of GF mice with ketogenic diet-associated strains, Akkermansia and Parabacteroides, restored seizure protection.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Olson et al., 2018
Animal evidence suggests that the neuroprotective effects of a ketogenic diet are mediated by specific gut bacteria that raise hippocampal GABA and glutamate levels.
“Animal data suggest that the neuroprotective effects are mediated through modulation of specific gut bacteria that enhance hippocampal γ-aminobutyric acid/glutamate levels (58)”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [58]
Protection from seizure correlated with hippocampal GABA/glutamate ratios.
“Furthermore, protection from seizure correlated with hippocampal GABA/glutamate ratios [363].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [363]
The anti-seizure effect of ketogenic diet was mediated by microbiota in the 6-Hz induced seizure model and in the Kcna1-/- genetic model of temporal lobe epilepsy.
“The anti-seizure effect of ketogenic diet was mediated by microbiota in the 6-Hz induced seizure model and in Kcna1 -/-genetic model of temporal lobe epilepsy.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [363]
Transplantation of ketogenic diet-gut microbiota and treatment with Akkermansia and Parabacteroides each conferred seizure protection to mice fed a control diet.
“Moreover, transplantation of the ketogenic diet-gut microbiota and treatment with Akkermansia and Parabacteroides each conferred seizure protection to mice fed with a control diet.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [363]
Mice treated with antibiotics or germ-free mice were resistant to ketogenic diet-mediated protection from seizures.
“Mice treated with antibiotics or GF mice were resistant to ketogenic diet-mediated protection from seizures.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [363]
The ketogenic diet increased abundance of Akkermansia muciniphila and Parabacteroides.
“The ketogenic diet increased the abundance of Akkermansia muciniphila and Parabacteroides.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [363]
Enrichment of, and gnotobiotic cocolonization with Akkermansia and Parabacteroides restored seizure protection.
“Enrichment of, and gnotobiotic cocolonization with Akkermansia and Parabacteroides restored seizure protection.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [363]
A landmark study in mouse models of epilepsy showed that a ketogenic diet protected against refractory epileptic seizures only in mice that were colonized with certain gut microbiota compared to mice treated with antibiotics.
“A landmark study in mouse models of epilepsy showed that a ketogenic diet protected against refractory epileptic seizures only in mice that were colonized with certain gut microbiota compared to mice treated with antibiotics [125].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [125]
The microbiota is required for the antiseizure effect of the ketogenic diet.
“In a recent study, it was revealed that the microbiota is required for the antiseizure effect of the ketogenic diet (341).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [341]
In mice, transplantation of ketogenic-diet microbiota confers an antiseizure effect in the absence of the ketogenic diet.
“Transplantation of KD | microbiota confers | antiseizure effect in absence | of KD”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [341]
In mice, a ketogenic diet increased seizure threshold.
“↑ Seizure threshold after KD”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [341]
In mice, germ-free status and antibiotic treatment abolish the antiseizure effect of a ketogenic diet.
“Germ-free status and antibiotic | treatment abolish antiseizure | effect of KD”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [341]
GF status or antibiotic treatment abolished the antiseizure effect of the ketogenic diet, and fecal transplant of a microbiota induced by the ketogenic diet elicited seizure protection.
“The authors not only showed that GF status or antibiotic treatment abolished the antiseizure effect of the ketogenic diet, but fecal transplant of a microbiota induced by the ketogenic diet also elicited seizure protection.”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [341]
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- Authors
- Olson, C. A., Vuong, H. E., Yano, J. M., Liang, Q. Y., Nusbaum, D. J., & Hsiao, E. Y.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Hsiao, Elaine Y.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 173
- Issue
- 7
- Pages
- 1728-1741.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6062008
- OpenAlex
- W2804460705
- Cited by
- 1,057
- References
- 54
- Citations by year
- 2026: 95 · 2025: 131 · 2024: 145 · 2023: 133 · 2022: 188 · 2021: 168 · 2020: 108 · 2019: 65 · 2018: 23 · 2014: 1
- FWCI
- 32.55
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-07-12)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- UCLA Department of Integrative Biology & Physiology and Division of Life Sciences
- Alfred P. Sloan Foundation Fellowship (FG-201606433)
- Army Research Office Multidisciplinary University Research Initiative (W911NF-17-1-0402)
- Mallinckrodt Foundation (20181433)
- NIH Ruth L. Kirschstein Award (T32GM065823)
- UPLIFT: UCLA Postdoctoral Longitudinal Investment in Faculty Award (K12GM106996)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- ketogenic diet, gut microbiota, epilepsy, seizure susceptibility, Akkermansia, Parabacteroides, germ-free mice, antibiotic therapy, microbiota transplantation, gamma-glutamyltranspeptidase, GABA/glutamate ratio, neuroprotection
- MeSH terms
- Gastrointestinal Microbiome, Animals, Anti-Bacterial Agents, Bacteroides, Disease Models, Animal, Feces, gamma-Aminobutyric Acid, gamma-Glutamyltransferase, Hippocampus, Intestinal Mucosa, Mice, Inbred C3H, RNA, Ribosomal, 16S, Seizures, Mice, Knockout, Glutamic Acid, Principal Component Analysis, Mice, Kv1.1 Potassium Channel, Diet, Ketogenic, Metabolome
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