What is the gut and the gut microbiome?

The gut is a term used to describe the entire digestive system. The digestive system begins at the mouth and ends at the anus. The gut microbiome is the entire population of microorganisms that live within the gut. These microorganisms, or the microbiota, are responsible for helping us not only digest our food but are also responsible for playing a role in our immune health and are key players in the gut-brain axis, which is the bi-directional communication between the gut and the central nervous system.

How the ketogenic diet affects the microbiome

Two recent studies looked at the gut microbiome in relation to epilepsy and its treatment with a ketogenic diet. Even if you are not one of the 65 million people in the world who have epilepsy, a condition that affects the brain and causes seizures, these studies are important because they tell us how a ketogenic diet can possibly affect our microbiome.

The first study I will mention here was published in Cell and is titled “The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.” In this study, researchers used an animal model to study the effects of the ketogenic diet and how it might alter the microbiome. They found that within four days of being on the diet, mice experienced significant gut bacterial changes. Two species of bacteria were found in high amounts, among others, in the gut microbiomes of the mice that were fed ketogenic diets: Akkermansia and Parabacteroides.

In order to perform neurotransmitter synthesis, the brain relies on the active import of essential amino acids. These amino acids are moved across the blood-brain barrier and serve as substrates for the synthesis of GABA, a neurotransmitter that can silence neurons, and glutamate, which activates neurons and causes them to fire.

The researchers found that in seizure-protected mice fed ketogenic diets, an increase in the gut bacteria Akkermansia and Parabacteroides led to a lowered production of gamma-glutamyl transpeptidase by the gut microbiome. This enzyme helps transfer gamma-glutamyl, a moiety of the antioxidant glutathione, from glutathione to an acceptor such as an amino acid. This process leads to the formation of glutamate. The researchers also observed a decrease in amino acids tagged with the gamma-glutamyl moiety in these mice, and a decrease in the amount of gamma-glutamyl amino acids in the gut and in the blood. This, in turn, had the effect of increasing the ratio of GABA to glutamate in the brain of mice. By increasing this ratio in the brain, seizure frequency was reduced.

The researchers confirmed their findings by selectively inhibiting gamma-glutamyl in-vivo in the non-ketogenic diet fed control mice; they observed that they were able to confer seizure protection. This confirmed a previous theory that high levels of GABA contribute to reduced seizure frequency.

What is most fascinating about this study is that researchers took antibiotic-treated, germ-free mice and found that they did not have protection against seizures even when fed a ketogenic diet. When transplanted with Akkermansia and Parabacteroides bacteria however, these previously germ-free mice fed a ketogenic diet were protected from seizures. When mice were transplanted with just one of the two bacterial species, seizure protection was not conferred. This shows that the two bacteria work together to provide seizure protection. Overall, this study was able to show that when combined with a ketogenic diet, these two gut bacteria were able to alter host metabolism, alter levels of brain chemistry and protect mice from seizures.

A look at the microbiome of children fed a therapeutic Ketogenic Diet

Another recent study titled “Altered gut microbiome composition in children with refractory epilepsy after a ketogenic diet” was published in Elsevier’s Epilepsy Research. Researchers investigated differences in the microbiota of pediatric epilepsy patients fed a ketogenic diet. They looked at the differences between responders, patients whose seizure frequency was reduced or stopped completely, and non-responders, patients whose seizure frequency did not change. They found that Bacteroides species were increased in the microbiomes of responders, while Firmicutes and Actinobacteria were lowered. Rikenellaceae and Alistipes, members of the Bacteroides phylum, were also significantly increased as in the responders. In non-responders, the opposite was true: Clostridia, Ruminococcus, and Lachnospiraceae, all members of the Firmicutes phylum, were significantly increased.

With this study, researchers were able to conclude that the ketogenic diet alters the gut microbiome of individuals, and that the microbiome should be considered as a biomarker of efficacy of anti-seizure treatment. These bacteria could also be used as a potential therapeutic target for epileptic patients.

How do the changes in the microbiome triggered by a ketogenic diet affect you?

It is clear that the ketogenic diet can cause changes to the microbiome, which in turn can influence the chemistry of the brain and confer seizure protection. When restricting carbohydrates or any food, it is possible to get rid of certain bacterial species in the gut while enriching others. What’s most interesting is that the bacteria that were found to be enriched by a ketogenic diet in the studies above have been shown to have positive effects when present in high amounts. For example, studies have shown that Akkermansia are beneficial microbes that positively affect glucose metabolism, lipid metabolism and intestinal immunity. Parabacteroides can have anti-inflammatory effects. All of these bacteria can interact with our brain through our gut.

Editor’s note: Akkermansia and Parabacteroides are both enriched by dietary interventions involving resistant starches (plant fibers) and polyphenols such as those contained in berries. These and other beneficial bacteria may be selected for in the gut by ketogenic diets that incorporate lots of plants and plant-based fats, as opposed to animal fats.

There is still much more to learn about how diet affects our overall health, but these studies show how certain gut bacteria may be used to target epilepsy or other ailments. It also shows us the importance of being mindful about what we eat, or what we don’t eat. The ketogenic diet appears to increases the amount of certain gut bacteria that can benefit us in more than one way, but more research needs to be done. The complexity of the human microbiome makes “one-size-fits-all” treatments based on gut microbes very unlikely.

Sources:

Olson, C. A., Vuong, H. E., Yano, J. M., Liang, Q. Y., Nusbaum, D. J., & Hsiao, E. Y. (2018). The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell.

Zhang Y, Zhou S, Zhou Y, Yu L, Zhang L, Wang Y. (2018) Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet. Epilepsy Res.