Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice

Study information

Needs review

study design

randomized controlled trial

Citation

PMID PubMed identifier for scientific articles.

39131354

DOI Digital object identifier for electronic documents.

10.1101/2024.07.31.606041

URI

Authors

Özcan E, Yu KB, Dinh L, Lum GR, Lau K, Hsu J, Arino M, Paramo J, Lopez-Romero A, Hsiao EY

Journal

bioRxiv : the preprint server for biology

Year

2024

The gut microbiome is emerging as an important modulator of the anti-seizure effects of the classic ketogenic diet. However, many variations of the ketogenic diet are used clinically to treat refractory epilepsy, and how different dietary formulations differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. We find that clinically prescribed ketogenic infant formulas vary in macronutrient ratio, fat source, and fiber content and also in their ability to promote resistance to 6-Hz psychomotor seizures in mice. By screening specific dietary variables for their effects on a model human infant microbial community, we observe that dietary fiber, rather than fat ratio or source, drives substantial metagenomic shifts. Addition of dietary fiber to a fiber-deficient ketogenic formula restores seizure resistance, and supplementing protective ketogenic formulas with excess dietary fiber further potentiates seizure resistance. By screening 13 fiber sources and types, we identify distinct subsets of metagenomic responses in the model human infant microbial community that correspond with increased seizure resistance in mice. In particular, supplementation with seizure-protective fibers enriches microbial representation of genes related to queuosine biosynthesis and preQ0 biosynthesis and decreases representation of microbial genes related to sucrose degradation, which is also seen in seizure-protected mice that are fed fiber-containing ketogenic infant formulas. Overall, this study reveals that different formulations of clinical ketogenic diets, and dietary fiber content in particular, differentially impact seizure outcome in mice, likely through modification of the gut microbiome. Understanding interactions between dietary components of the ketogenic diet, the gut microbiome, and host susceptibility to seizures could inform novel microbiome-guided approaches to treat refractory epilepsy.

Experiment 1

Edit History Delete

Mark reviewed

Your review change was submittedDuplicate this Experiment Add a new Signature

Needs review

Curated date: 2024/12/17

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Subjects

Location of subjects: United States of America

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

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: control diet group

Group 1 name Corresponds to the case (exposed) group for case-control studies: KD4:1 group

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice fed a ketogenic diet of 4:1 fat to protein ratio

Group 0 sample size Number of subjects in the control (unexposed) group: 4

Group 1 sample size Number of subjects in the case (exposed) group: 4

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: Kruskall-Wallis

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

Alpha Diversity

Pielou Quantifies how equal the community is numerically: unchanged

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

Richness Number of species: increased

Signature 1

Edit History Delete

Mark reviewed

Your review change was submitted

Needs review

Curated date: 2024/12/17

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Source: Figure 2a

Description: Comparing difference in fecal microbiome of rats undergoing KD4:1 diet vs rats with a control diet

Abundance in Group 1: increased abundance in KD4:1 group

NCBI	Quality Control	Links
Bacteroidia
Coriobacteriia
Deferribacteres
Streptococcaceae
unclassified Bacteria

Revision editor(s): Kavyaayala

Signature 2

Edit History Delete

Mark reviewed

Your review change was submitted

Needs review

Curated date: 2024/12/17

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Source: Figure 2a

Description: Comparing difference in fecal microbiome of rats undergoing KD4:1 diet vs rats with a control diet

Abundance in Group 1: decreased abundance in KD4:1 group

NCBI	Quality Control	Links
Erysipelotrichia

Revision editor(s): Kavyaayala

Experiment 2

Edit History Delete

Mark reviewed

Your review change was submittedDuplicate this Experiment Add a new Signature

Needs review

Curated date: 2024/12/17

Curator: Kavyaayala

Revision editor(s): Kavyaayala

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies: KD3:1 group

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice fed a ketogenic diet of 3:1 fat to protein ratio

Lab analysis

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: Not specified