Higher levels of Bifidobacteria and tumor necrosis factor in children with drug-resistant epilepsy are associated with anti-seizure response to the ketogenic diet

Study information

Needs review

study design

prospective cohort

Citation

PMID PubMed identifier for scientific articles.

35598439

DOI Digital object identifier for electronic documents.

10.1016/j.ebiom.2022.104061

URI

Authors

Dahlin M, Singleton SS, David JA, Basuchoudhary A, Wickström R, Mazumder R, Prast-Nielsen S

Journal

EBioMedicine

Year

2022

Keywords:

Bifidobacterium, Bioinformatics, Epilepsy, Gut microbiota, Inflammation, Ketogenic diet, Machine learning, Omics, TNF

BACKGROUND: Recently, studies have suggested a role for the gut microbiota in epilepsy. Gut microbial changes during ketogenic diet (KD) treatment of drug-resistant epilepsy have been described. Inflammation is associated with certain types of epilepsy and specific inflammation markers decrease during KD. The gut microbiota plays an important role in the regulation of the immune system and inflammation. METHODS: 28 children with drug-resistant epilepsy treated with the ketogenic diet were followed in this observational study. Fecal and serum samples were collected at baseline and three months after dietary intervention. FINDINGS: We identified both gut microbial and inflammatory changes during treatment. KD had a general anti-inflammatory effect. Novel bioinformatics and machine learning approaches identified signatures of specific Bifidobacteria and TNF (tumor necrosis factor) associated with responders before starting KD. During KD, taxonomic and inflammatory profiles between responders and non-responders were more similar than at baseline. INTERPRETATION: Our results suggest that children with drug-resistant epilepsy are more likely to benefit from KD treatment when specific Bifidobacteria and TNF are elevated. We here present a novel signature of interaction of the gut microbiota and the immune system associated with anti-epileptic response to KD treatment. This signature could be used as a prognostic biomarker to identify potential responders to KD before starting treatment. Our findings may also contribute to the development of new anti-seizure therapies by targeting specific components of the gut microbiota. FUNDING: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Stiftelsen Sunnerdahls Handikappfond, Linnea & Josef Carlssons Foundation, and The McCormick Genomic & Proteomic Center.

Experiment 1

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Curated date: 2024/12/09

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Subjects

Location of subjects: Sweden

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

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: Response to ketogenic diet Response to ketogenic diet,response to ketogenic diet

Group 0 name Corresponds to the control (unexposed) group for case-control studies: responders pre ketogenic diet

Group 1 name Corresponds to the case (exposed) group for case-control studies: responders post ketogenic diet

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: "Responders" are children with drug resistant epilepsy having been identified as having greater than or equal to 50% reduction in seizures post ketogenic diet treatment. Of the identified responders, this group refers to children over eight years of age at the time when samples were taken after three months ketogenic diet implementation.

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): 3 months

Lab analysis

Sequencing type: PCR

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

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: Welch's T-Test

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

Signature 1

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Curated date: 2024/12/17

Curator: Kavyaayala

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Source: Figure 4C

Description: Fecal microbiome of responders post ketogenic diet compared to responders pre ketogenic diet

Abundance in Group 1: decreased abundance in responders post ketogenic diet

NCBI	Quality Control	Links
Bifidobacterium breve JCM 7019
Bifidobacterium longum subsp. infantis
Bifidobacterium longum subsp. infantis ATCC 15697 = JCM 1222 = DSM 20088
Bifidobacterium longum subsp. longum JDM301

Revision editor(s): Kavyaayala

Experiment 2

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Curated date: 2025/01/15

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Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies: non-responders pre ketogenic diet

Group 1 name Corresponds to the case (exposed) group for case-control studies: non-responders post ketogenic diet

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: "Non-responders" are children with drug resistant epilepsy having been identified as having less than 50% reduction in seizures post ketogenic diet treatment. Of the identified responders, this group refers to children over eight years of age at the time when samples were taken after three months ketogenic diet implementation.

Lab analysis

Statistical Analysis

Signature 1

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Curated date: 2025/01/15

Curator: Kavyaayala

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Source: Figure 4C

Description: Fecal microbiome of non-responders post ketogenic diet compared to non-responders pre ketogenic diet

Abundance in Group 1: decreased abundance in non-responders post ketogenic diet

NCBI	Quality Control	Links
Bifidobacterium longum subsp. longum JDM301
Bifidobacterium breve JCM 7019

Revision editor(s): Kavyaayala

Experiment 3

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incomplete

Curated date: 2025/01/15

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies: non-responders post ketogenic diet

Group 1 name Corresponds to the case (exposed) group for case-control studies: responders post ketogenic diet

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: "Responders" are children with drug resistant epilepsy having been identified as having greater than or equal to 50% reduction in seizures post ketogenic diet treatment. Of the identified responders, this group refers to children over eight years of age at the time when samples were taken after three months ketogenic diet implementation.

Lab analysis

Statistical Analysis

Experiment 4

Edit History Delete Duplicate this Experiment Add a new Signature

incomplete

Curated date: 2025/01/15

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies: non-responders pre ketogenic diet

Group 1 name Corresponds to the case (exposed) group for case-control studies: responders pre ketogenic diet

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: "Responders" are children with drug resistant epilepsy having been identified as having greater than or equal to 50% reduction in seizures post ketogenic diet treatment. Of the identified responders, this group refers to children over eight years of age at the time when samples were taken before ketogenic diet implementation.

Lab analysis

Statistical Analysis

Signature 1

Edit History Delete

Mark reviewed

Your review change was submitted

Needs review

Curated date: 2025/01/15

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Source: Figure 4C

Description: Fecal microbiome of responders pre ketogenic diet compared to non-responders pre ketogenic diet

Abundance in Group 1: increased abundance in responders pre ketogenic diet

NCBI	Quality Control	Links
Bifidobacterium breve JCM 7019
Bifidobacterium longum DJO10A
Bifidobacterium longum subsp. infantis
Bifidobacterium longum subsp. infantis ATCC 15697 = JCM 1222 = DSM 20088

Revision editor(s): Kavyaayala