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Cited by 272Gut microbiota and healthAutism Spectrum Disorder ResearchDiet and metabolism studies

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Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder

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Newell, Christopher, Bomhof, Marc R., Reimer, Raylene A., Hittel, Dustin S., Rho, Jong M., Shearer, Jane·2016·Molecular Autism
DOI 10.1186/s13229-016-0099-3PMC PMC5009541
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Abstract

BACKGROUND: Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBR(T + tf/j) (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile. FINDINGS: Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10-14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals. CONCLUSIONS: Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.

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Fig. 1 Assessment of total microbial content, partial least squares discriminant analysis (PLS-DA), and variable importance of projection (VIP) scores for relative bacterial abundance. Descriptive comparisons of total microbial content, score plots of PLS-DA, and VIP scores for both cecal and fecal matter are presented. a Total bacterial species composition measured from cecal matter. b Total bacterial species composition measured from fecal matter. c PLS-DA score plot for cecal matter showing model discrimination between each genotype. d PLS-DA score plot for fecal matter showing model discrimination between each genotype. e Cecal VIP plot indicating the most discriminating bacteria in descending order of importance. f Fecal VIP plot indicating the most discriminating bacteria in descending order of importance. Statistical comparisons between genotype and diet were determined by ANOVA, followed by Tukey’s post hoc test. PLS-DA and VIP scores were assessed using MetaboAnalyst 3.0. Ellipses represent 95 % confidence intervals for each individual group on PLS-DA plots with Q 2 and R 2 values being used to assess the robustness of the model and the amount of variation represented by the principal components, respectively. VIP scores reflect the degree of importance of a bacteria, with values >1.0 seen as driving the calculated discrimination. All data were collected using qRT-PCR and are presented as mean 16S rRNA gene copies/mg of corresponding tissue ± SEM (CC, B6-chow; CK, B6-ketogenic; BC, BTBR-chow; and BK, BTBR-ketogenic; n = 11, 10, 15, and 10, respectively). p < 0.01 if values do not share a superscript letter. An adapted version of this table has been previously published. Reprinted with permission of the American Chemical Society, Copyright 2016
Fig. 1 Assessment of total microbial content, partial least squares discriminant analysis (PLS-DA), and variable importance of projection (VIP) scores for relative bacterial abundance. Descriptive comparisons of total microbial content, score plots of PLS-DA, and VIP scores for both cecal and fecal matter are presented. a Total bacterial species composition measured from cecal matter. b Total bacterial species composition measured from fecal matter. c PLS-DA score plot for cecal matter showing model discrimination between each genotype. d PLS-DA score plot for fecal matter showing model discrimination between each genotype. e Cecal VIP plot indicating the most discriminating bacteria in descending order of importance. f Fecal VIP plot indicating the most discriminating bacteria in descending order of importance. Statistical comparisons between genotype and diet were determined by ANOVA, followed by Tukey’s post hoc test. PLS-DA and VIP scores were assessed using MetaboAnalyst 3.0. Ellipses represent 95 % confidence intervals for each individual group on PLS-DA plots with Q 2 and R 2 values being used to assess the robustness of the model and the amount of variation represented by the principal components, respectively. VIP scores reflect the degree of importance of a bacteria, with values >1.0 seen as driving the calculated discrimination. All data were collected using qRT-PCR and are presented as mean 16S rRNA gene copies/mg of corresponding tissue ± SEM (CC, B6-chow; CK, B6-ketogenic; BC, BTBR-chow; and BK, BTBR-ketogenic; n = 11, 10, 15, and 10, respectively). p < 0.01 if values do not share a superscript letter. An adapted version of this table has been previously published. Reprinted with permission of the American Chemical Society, Copyright 2016CC BY · PubMed Central

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Metadata

Authors
Newell, C., Bomhof, M. R., Reimer, R. A., Hittel, D. S., Rho, J. M., & Shearer, J.
Affiliations
University of Calgary (CA)
Corresponding author
Newell, Christopher
ORCID
Venue
Molecular Autism
Publisher
Springer Science and Business Media LLC
Published
2016-09-01
Volume
7
Issue
1
Pages
37-37
ISSN
2040-2392 (ISSN-L)
DOI
10.1186/s13229-016-0099-3
PMC
PMC5009541
OpenAlex
W2509638174
Cited by
272
References
30
Citations by year
2026: 13 · 2025: 30 · 2024: 23 · 2023: 31 · 2022: 41 · 2021: 33 · 2020: 40 · 2019: 29 · 2018: 20 · 2017: 10 · 2016: 2
FWCI
10.56
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Autism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Alberta Children's Hospital Foundation
  • Canadian Institutes of Health Research
  • MitoCanada
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
Keywords
ketogenic diet, autism spectrum disorder, gut microbiota, gut-brain axis, Akkermansia muciniphila, Firmicutes/Bacteroidetes ratio, cecal microbiota, fecal microbiota, dietary fat, gastrointestinal dysfunction
MeSH terms
Autism Spectrum Disorder, Gastrointestinal Microbiome, Animals, Bacteria, Behavior, Animal, Cecum, Disease Models, Animal, Feces, Male, Mice, Inbred C57BL, Social Behavior, Mice, Diet, Ketogenic

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