Ketogenic Diets Alter the Gut Microbiome, Resulting in Decreased Susceptibility to and Cognitive Impairment in Rats with Pilocarpine-Induced Status Epilepticus

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study design

laboratory experiment

Citation

PMID PubMed identifier for scientific articles.

38935224

DOI Digital object identifier for electronic documents.

10.1007/s11064-024-04168-y

URI

Authors

Li B, Ma Y, Wang X, Zhao D, Wang Z, Wang G, Li C, Yang L, Ji H, Liu K, Chen Q, Yang Y, Ma W, Du J, Ma L, Zhang L, Qiang Y

Journal

Neurochemical research

Year

2024

Keywords:

Cognitive function, Gut microbiota, Ketogenic diet, Lithium-pilocarpine, Status epilepticus, Temporal lobe epilepsy

A ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that exerts antiepileptic effects by attenuating spontaneous recurrent seizures, ameliorating learning and memory impairments, and modulating the gut microbiota composition. However, the role of the gut microbiome in the antiepileptic effects of a KD on temporal lobe epilepsy (TLE) induced by lithium-pilocarpine in adult rats is still unknown. Our study provides evidence demonstrating that a KD effectively mitigates seizure behavior and reduces acute-phase epileptic brain activity and that KD treatment alleviates hippocampal neuronal damage and improves cognitive impairment induced by TLE. We also observed that the beneficial effects of a KD are compromised when the gut microbiota is disrupted through antibiotic administration. Analysis of gut microbiota components via 16S rRNA gene sequencing in fecal samples collected from TLE rats fed either a KD or a normal diet. The Chao1 and ACE indices showed decreased species variety in KD-fed rats compared to TLE rats fed a normal diet. A KD increased the levels of Actinobacteriota, Verrucomicrobiota and Proteobacteria and decreased the level of Bacteroidetes. Interestingly, the abundances of Actinobacteriota and Verrucomicrobiota were positively correlated with learning and memory ability, and the abundance of Proteobacteria was positively correlated with seizure susceptibility. In conclusion, our study revealed the significant antiepileptic and neuroprotective effects of a KD on pilocarpine-induced epilepsy in rats, primarily mediated through the modulation of the gut microbiota. However, whether the gut microbiota mediates the antiseizure effects of a KD still needs to be better elucidated.

Experiment 1

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Curated date: 2024/12/17

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Subjects

Location of subjects

China

Host species Species from which microbiome was sampled. Contact us to have more species added.

Rattus norvegicus

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology

Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology

Group 0 name Corresponds to the control (unexposed) group for case-control studies

normal diet status epilepticus model (SE group)

Group 1 name Corresponds to the case (exposed) group for case-control studies

ketogenic diet (SE + KD group)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

male rats fed ketogenic diet for three weeks before undergoing pilocarpine-induced status epilepticus

Group 0 sample size Number of subjects in the control (unexposed) group

6

Group 1 sample size Number of subjects in the case (exposed) group

6

Lab analysis

Sequencing type

16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene

V3-V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance

Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).

relative abundances

Statistical test

ANOVA

Significance threshold p-value or FDR threshold used for differential abundance testing (if any)

0.05

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness

decreased

Chao1 Abundance-based estimator of species richness

decreased

Simpson Estimator of species richness and species evenness: more weight on species evenness

decreased

Signature 1

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Curated date: 2024/12/17

Curator: Kavyaayala

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Source: Figure 7B

Description: Fecal microbiome of SE + KD group compared to SE group

Abundance in Group 1: increased abundance in

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Actinomycetota
Pseudomonadota

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Signature 2

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Source: Figure 7B

Description: Fecal microbiome of SE + KD group compared to SE group

Abundance in Group 1: decreased abundance in

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Bacteroidota

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Experiment 2

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Curated date: 2024/12/31

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Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies

normal diet healthy controls (NC group)

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness

decreased

Chao1 Abundance-based estimator of species richness

decreased

Simpson Estimator of species richness and species evenness: more weight on species evenness

decreased

Signature 1

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Curated date: 2025/01/03

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Source: Figure 7B

Description: Fecal microbiome of SE + KD group compared to NC group

Abundance in Group 1: increased abundance in

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Actinomycetota
Pseudomonadota

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Signature 2

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Source: Figure 7B

Description: Fecal microbiome of SE + KD group compared to NC group

Abundance in Group 1: decreased abundance in

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Bacteroidota

Revision editor(s): Kavyaayala, WikiWorks

Experiment 3

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Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology

Group 1 name Corresponds to the case (exposed) group for case-control studies

ketogenic diet and antibiotics (SE + KD + Ab group)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

male rats receiving antibiotic treatment and fed ketogenic diet for three weeks before undergoing pilocarpine-induced status epilepticus

Lab analysis

Statistical Analysis

Signature 1

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Source: Figure 7B

Description: Fecal microbiome of SE + KD + Ab group compared to NC group

Abundance in Group 1: increased abundance in ketogenic diet and antibiotics (SE + KD + Ab group)

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Pseudomonadota

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Signature 2

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Source: Figure 7B

Description: Fecal microbiome of SE + KD + Ab group compared to NC group

Abundance in Group 1: decreased abundance in ketogenic diet and antibiotics (SE + KD + Ab group)

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Bacteroidota

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Experiment 4

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Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology

Group 0 name Corresponds to the control (unexposed) group for case-control studies

ketogenic diet (SE + KD group)

Lab analysis

Statistical Analysis

Signature 1

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Source: Figure 7B

Description: Fecal microbiome of SE + KD + Ab group compared to SE + KD group

Abundance in Group 1: increased abundance in

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Pseudomonadota

Revision editor(s): Kavyaayala, WikiWorks

Signature 2

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Source: Figure 7B

Description: Fecal microbiome of SE + KD + Ab group compared to SE + KD group

Abundance in Group 1: decreased abundance in

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Actinomycetota

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Experiment 5

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Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology

Group 0 name Corresponds to the control (unexposed) group for case-control studies

normal diet status epilepticus model (SE group)

Lab analysis

Statistical Analysis

Signature 1

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Source: Figure 7B

Description: Fecal microbiome of SE + KD + Ab group compared to SE group

Abundance in Group 1: increased abundance in

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Pseudomonadota

Revision editor(s): Kavyaayala, WikiWorks

Signature 2

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Source: Figure 7B

Description: Fecal microbiome of SE + KD + Ab group compared to SE group

Abundance in Group 1: increased abundance in

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Bacteroidota

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Experiment 6

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Curated date: 2025/01/04

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Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology

Group 0 name Corresponds to the control (unexposed) group for case-control studies

(SE + KD + Ab), SE, and NC groups

Group 1 name Corresponds to the case (exposed) group for case-control studies

ketogenic diet (SE + KD group)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

male rats fed ketogenic diet for three weeks before undergoing pilocarpine-induced status epilepticus

Group 0 sample size Number of subjects in the control (unexposed) group

18

Lab analysis

Statistical Analysis

Statistical test

LEfSe

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool

4

Signature 1

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Source: Figure 7C

Description: Fecal microbiome of SE + KD group compared to (SE + KD + Ab), SE, and NC groups

Abundance in Group 1: increased abundance in ketogenic diet (SE + KD group)

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Actinomycetota
Atopobiaceae
Blautia
Coriobacteriales
Coriobacteriia
Peptococcaceae
unclassified Blautia
unclassified Peptococcaceae
uncultured Allobaculum sp.
unclassified Coriobacteriaceae UCG-002unclassified Coriobacteriaceae UCG-002
Coriobacteriaceae UCG-002Coriobacteriaceae UCG-002
Peptostreptococcales-TissierellalesPeptostreptococcales-Tissierellales
PeptococcalesPeptococcales

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Experiment 7

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Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies

(SE + KD + Ab), (SE + KD), and NC groups

Group 1 name Corresponds to the case (exposed) group for case-control studies

normal diet status epilepticus model (SE group)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

male rats fed normal diet and having pilocarpine-induced status epilepticus

Lab analysis

Statistical Analysis

Signature 1

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Curated date: 2025/01/05

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Source: Figure 7C

Description: Fecal microbiome of SE group compared to (SE + KD + Ab), (SE + KD), and NC groups

Abundance in Group 1: increased abundance in

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Bacteroidaceae
Bacteroides
Christensenellaceae
Christensenellales
Lactobacillaceae
Lactobacillales
Lactobacillus
Ligilactobacillus
Phocaeicola sartorii
Trichinella pseudospiralis
unclassified Lactobacillus
unclassified Ligilactobacillus
Christensenellaceae R-7 groupChristensenellaceae R-7 group
UCG-005UCG-005
unclassified UCG-005unclassified UCG-005

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Experiment 8

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Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies

(SE + KD), SE, and NC groups

Group 1 name Corresponds to the case (exposed) group for case-control studies

ketogenic diet and antibiotics (SE + KD + Ab group)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

male rats fed ketogenic diet for three weeks and receiving antibiotic treatment before undergoing pilocarpine-induced status epilepticus

Lab analysis

Statistical Analysis

Signature 1

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Curated date: 2025/01/05

Curator: Kavyaayala

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Source: Figure 7C

Description: Fecal microbiome of SE + KD + Ab group compared to (SE + KD), SE, and NC groups

Abundance in Group 1: increased abundance in

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Coprobacillaceae
Enterobacterales
Enterobacteriaceae
Erysipelotrichaceae
Erysipelotrichales
Flavonifractor
Gammaproteobacteria
Lachnoclostridium
Oscillospiraceae
Pseudomonadota
Thomasclavelia
unclassified Erysipelotrichaceae
unclassified Flavonifractor
unclassified Lachnoclostridium
unclassified Thomasclavelia
Escherichia ShigellaEscherichia Shigella
unclassified Escherichia Shigellaunclassified Escherichia Shigella
unclassified Clostridium innocuum groupunclassified Clostridium innocuum group
Clostridium innocuum groupClostridium innocuum group
unclassified Eubacterium nodatum groupunclassified Eubacterium nodatum group
Eubacterium nodatum groupEubacterium nodatum group

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Experiment 9

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Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies

(SE + KD + Ab), (SE + KD), and SE groups

Group 1 name Corresponds to the case (exposed) group for case-control studies

normal diet controls (NC group)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

healthy male rats fed normal diet

Lab analysis

Statistical Analysis

Signature 1

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Source: Figure 7C

Description: Fecal microbiome of NC group compared to (SE + KD + Ab), (SE + KD), and SE groups

Abundance in Group 1: increased abundance in

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Bacteroidales
Bacteroidia
Bacteroidota
Lachnospiraceae bacterium NK4A136
Muribaculaceae
Ruminococcus
rumen bacterium NK4A214
unclassified Muribaculaceae
unclassified Oscillospiraceae
unclassified Ruminococcus
OscillospiralesOscillospirales
Clostridia UCG-014Clostridia UCG-014
unclassified Clostridia UCG-014unclassified Clostridia UCG-014

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