Ketogenic Diet Alters Gut Microbiome and Improves Brain Functions

By Lucille M. Yanckello

Ketogenic diet (KD), a high fat and low carbohydrate diet, has been an effective therapeutic for a wide range of neurological disorders. Clinically, KD has been used to treat epilepsy, Parkinson’s disease, and autism. Recent research shows surprising findings that KD may protect brain functions through altering gut microbiome.

Our gut microbiome, which is often referred to as “the forgotten organ”, has been a hot topic of scientific literature as of late.  Although it seems counter-intuitive, the microbes in our gut have been found to have an effect on our brains. A gut microbiome in dysbiosis (more bad bacteria than good) has been implicated in many neurodegenerative and neurological disorders.

It has become evident that using dietary or nutritional interventions to positively change the gut microbiome’s composition can mediate the effects of these neurological and neurodegenerative disorders. A recent study in the journal Cell found that gut microbiota altered by KD mediates the anti-seizure effects. In particular, there is a positive shift in the microbial community to an increase of two types of bacteria- Akkermansia muciniphila and the genus Parabacteroides– even though the overall microbial diversity was decreased.

The authors concluded that an increase in both types of bacteria is required for the KD to exhibit anti-seizure effects. Akkermansia muciniphila stimulates the growth of Parabacteroides, which leads changes in neurotransmission (elevation in the GABA/glutamate ratio) in the hippocampus, and thus further prevent seizure. These results reveal that KD alters the microbiota in such a way positively modulate this ratio and result in seizure protection.

Very similar findings were seen when KD was applied to an autism spectrum disorder (ASD) mouse model. Just as in the epilepsy mouse model, an overall decrease in bacterial content was seen. Interestingly, Akkermansia muciniphila levels were much higher in ASD, and the KD diet decreased the levels of this microbe. These findings indicate that the KD normalizes the level of Akkermansia muciniphila depending on the level of the microbe prior to dietary intervention.

Although KD has proven effective in disease states, our lab recently sought to find out if the impact of this diet would be beneficial in young healthy mice as well.

The results related to microbial diversity and composition were strikingly similar to the other two studies. Overall diversity decreased, but an increase in Akkermansia muciniphila and Lactobacillus was seen. A decrease in members of the genus Desulfovibrio was also seen.

Desulfovibrio bacteria are capable of producing hydrogen sulfide which is known to induce gut barrier impairment. Because the gut and the brain can talk to each other, a leaky gut can have negative effects on blood brain barrier (BBB) and neurovascular functions. A decrease in Desulfovibrio is thought to facilitate an increase in these functions.

The ketogenic diet did increase neurovascular functions in young healthy mice. Blood brain barrier function was improved through an increase in the transporter P-glycoprotein as well as its activity, which transports amyloid-beta (Aβ) across the BBB. P-gp activity decreases in neurodegenerative diseases such as Alzheimer’s disease leading to an increased incidence of Aβ plaques in the brain.

The changes that are exhibited in healthy mice could point to a protective mechanism of the ketogenic diet. Starting KD during the early stages of disease progression may lead to positive neuroprotective effects via not only neurovascular functions, but also through modulation of the gut microbiota.

Overall, KD is able to modulate the level of Akkermansia muciniphila, Lactobacillus, and Desulfovibrio, which may play a critical role in protecting functions in healthy and disease states.

*Lucy is a 2nd year PhD student in the Lin Brain Lab

Citations:

1. Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. (2018). The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell doi: 10.1016/j.cell.2018.04.027. Epub 2018 May 24.
2. Ma D, Wang A, Parikh I, Hoffman JD, Green SJ, Chlipala G, Murphy MP, Sokola BS, Bauer B, Hartz AMS, Lin AL. (2018). Ketogenic Diet Enhances Neurovascular Function with Altered gut Microbiome in Young Healthy Mice. Scientific Reports 8: 6670.
3. Newell C, Bomhof MR, Reimer RA, Hittel DS, Rho JM, Shearer J. (2016).  Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol Autism 7:37.