Ketogenic Diet and the Microbiome
CONTEXT
The ketogenic diet is an established treatment for patients with uncontrolled epilepsy. Potential mechanisms to explain the anti-seizure effect of the include changes in energy metabolism and neurotransmitter production. But previous studies have never explored whether alterations in the gut microbiome might also mediate the ketogenic diet’s anti-seizure effect.
Explorations of the microbiota-gut-brain axis show that the gut microbiome can affect brain physiology. Also, gut dysbiosis is associated with a range of neurological disorders. And in patients with epilepsy, it’s been observed that treatment with antibiotics—which affects the gut microbiome—increases seizure risk.
Human studies suggest that the animal-based ketogenic diet alters the composition of the gut microbiome by increasing the abundance of bile-tolerant microorganisms and decreasing the abundance of organisms that metabolize dietary plant polysaccharides. There’s no doubt that diet has a profound ability to alter the composition of the intestinal microbiome.
OBJECTIVE
This study explored whether the anti-seizure effect of the might be mediated by alterations in the gut microbiome.
STUDY DESIGN
Experimental animal study
KEY FINDINGS
Two seizure mouse models were utilized to investigate the effects of the ketogenic diet on the gut microbiome, amino acid metabolism, brain neurotransmitters, and seizure risk.
The researchers first found that mice fed ahad a lower risk of seizures (a higher seizure threshold) than mice fed a control diet. This finding was not surprising and merely confirmed the anti-seizure effect of the ketogenic diet.
The scientists also discovered that the ketogenic diet altered the composition of the gut microbiota within four days of treatment. The diet decreased alpha-diversity and increased the relative abundance of Akkermansia muciniphila, Parabacteroides, Sutterella, and Erysipelotrichaceae.
Next, the researchers found that germ-free mice and antibiotic-treated mice were resistant to the seizure protection of the ketogenic diet. This key finding showed that the gut microbiota is required for the anti-seizure effect of the ketogenic diet.
The scientists then enriched germ-free mice and antibiotic-treated mice with two of the microbial species that were enhanced by the ketogenic diet: A. muciniphila and Parabacteroides. Co-administration with both of these microbial species (but not with each alone) restored the anti-seizure effect of the ketogenic diet.
Surprisingly, the administration of A. muciniphila and Parabacteroides offered seizure protection even in mice fed the control diet. Persistent exposure to A. muciniphila and Parabacteroides was required to maintain protection, as the anti-seizure effect was lost after treatment had ceased for 21 days.
After establishing that the microbiome was essential for the anti-seizure effect of the ketogenic diet in mice, the scientists then explored the metabolic changes that occurred simultaneously. They found a decreased activity of gamma-glutamyl transpeptidase (GGT) in the intestinal lumen, decreased gamma-glutamyl amino acids in the blood, and an increased ratio of gamma-aminobutyric acid (GABA):glutamate in the brain.
CLINICAL RELEVANCE
This study demonstrates that alterations in the gut microbiome are essential for the anti-seizure effect of the ketogenic diet in mice. Many questions remain as to how this information translates to humans.
Different animal species exhibit varying microbiota profiles that nevertheless exert similar functions. A. muciniphila and Parabacteroides conferred protection in mice, but we don’t know whether they would confer protection in humans. They might, as one study of caloric restriction in humans also found that A. muciniphila was enhanced.
One intriguing finding from this study was that the administration of protective microorganisms offered anti-seizure protection even when mice were fed a control diet. This raises the question of whether the introduction of specific probiotics might help to manage seizures in humans—without the restrictions of the ketogenic diet.
Another unanswered question is whether the other known benefits of the ketogenic diet are also mediated by changes in the gut microbiome.
Despite the many unanswered questions, this study tells us that the gut microbiome likely plays a role in some of the health benefits of the ketogenic diet. This can inform future research and help clinicians better understand the complex mechanisms of the ketogenic diet.