Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder

Authors:
Allan, N.P., Yamamoto, B.Y., Kunihiro, B.P., Nunokawa, C.K., Rubas, N.C., Wells, R.K., Umeda, L., Phankitnirundorn, K., Torres, A., Peres, R. and Takahashi, E.

Summary of the Article

The article, titled "Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder" by Allan et al., published in Nutrients (2024), details an interventional pilot study examining the effects of a modified ketogenic diet (KD) on seven children with autism spectrum disorder (ASD) over four months. The study aimed to explore how this diet influences the gut microbiome, inflammation, and brain-related microRNAs (miRNAs), building on prior observations of improved behavioral symptoms in the same cohort. Blood and stool samples were collected before and after the diet to assess biological changes. The findings suggest that the KD may reduce inflammation, enhance gut microbial health, and affect brain activity through the brain-derived neurotrophic factor (BDNF) pathway, potentially improving sociability in children with ASD. However, the study’s small sample size and lack of a control group call for cautious interpretation and further research.

Key Findings

• Gut Microbiome Changes:

  • Increased microbial diversity (measured by Shannon and Simpson indices) at family, genus, and species levels.

  • Notable shifts included increased Lactobacillales and decreased Bacteroidaceae, Oscillospiraceae, Bacteroides, Ruminococcus, Clostridium cocleatum, and Ruminococcus gnavus.

  • Elevated levels and expression of the butyrate kinase (BUK) gene, indicating enhanced butyrate production capacity, which supports gut and brain health.

• Inflammatory Markers:

  • Significant reductions in proinflammatory cytokines: IL-1b (p = 0.04) and IL-12p70 (p = 0.02).

  • A non-significant trend toward increased anti-inflammatory cytokine IL-10.

  • Decreased plasma BDNF levels (p = 0.02), an unexpected finding given BDNF’s role in brain function.

• Brain-Related Markers:

  • Altered BDNF-associated miRNAs: decreased miR-134 (p = 0.008) and miR-132 (p = 0.027), increased miR-375 (p = 0.044), with no change in miR-125b.

  • These changes suggest a potential impact on brain activity and inflammation regulation.

• Ketone Bodies:

  • Increased plasma levels of acetoacetic acid (p = 0.021) and hydroxybutyric acid (p = 0.028), confirming ketosis.

Details of the Diet

• Type of Diet: A modified ketogenic diet (KD):

  • Low in carbohydrates (20-25 grams of net carbs daily).

  • Moderate in protein (up to twice the Recommended Dietary Allowance based on age and weight).

  • High in fat, with 20% of energy from medium-chain triglyceride (MCT) oil (sourced from coconut or pure MCT oil).

  • Gluten-free, excluding wheat, barley, and rye products.

• Duration: The diet was followed for 4 months.

Symptoms That Improved

• The current study focuses on biological changes rather than direct symptom assessment. However, it references a previous study on the same cohort where behavioral symptoms improved, as measured by the Autism Diagnostic Observation Schedule (ADOS-2).

• The authors suggest that the observed reductions in inflammation and improvements in gut health may positively influence sociability in children with ASD, though specific symptoms are not detailed in this report.

Percentage of Participants Who Improved

• The article does not specify a percentage of participants who showed symptom improvement in this study. It focuses on biological markers across all seven participants rather than individual behavioral outcomes. The prior study indicated behavioral improvements, but no percentage is provided here.

Time Taken for Symptoms to Improve

• Biological changes were assessed after 4 months on the diet. The study does not specify when symptom improvements occurred, but it is implied that any behavioral changes from the previous study were evaluated at the end of this period.

Considerations (Pros and Cons)

• Pros:

  • May reduce inflammation, potentially benefiting ASD symptoms.

  • Enhances gut microbial diversity and butyrate production, supporting gut-brain health.

  • Could improve sociability via the BDNF pathway.

• Cons:

  • Small sample size (only seven children), limiting generalizability.

  • Restrictive nature of the diet may be challenging for children with ASD to maintain.

  • Lack of a control group makes it hard to attribute changes solely to the diet.

  • Long-term effects and safety remain unclear.

Conclusion

This pilot study provides preliminary evidence that a modified ketogenic diet may positively affect children with ASD by reducing inflammation, improving gut microbiome diversity, and altering brain-related markers. While these changes hint at potential benefits for sociability, the small sample size and absence of a control group underscore the need for larger, controlled studies to validate these findings and assess the diet’s long-term efficacy and safety.

https://pubmed.ncbi.nlm.nih.gov/38794639/

doi: 10.3390/nu16101401