When we think of ourselves, our health and our behavior, most of us don’t often think of the trillions of bacteria, fungi and other microorganisms living inside of us. But researchers like Dr. Elaine Hsiao are showing us that we should. Our bodies have 10 times as many microorganism cells as human cells, and we are just beginning to understand the complexities of these microbial communities, collectively known as the microbiome, and to appreciate the profound effects they have on our bodies, brains and behavior, in health and disease. Research in Dr. Elaine Hsiao’s laboratory at the University of California Los Angeles is unraveling the effects and mechanisms of the microbiome-gut-brain axis and exploring how this knowledge can be used in the treatment of neurological diseases.

Given the great genetic and functional complexities of the microbiome, determining exactly how changes in the microbiome affect host development, physiology, and behavior and how we can use this knowledge to improve health is not a simple task. One approach that Dr. Hsiao and her team are taking to delineate the role of the gut microbiota in the treatment of neurological disease can be seen in the lab’s recent publication in Cell, led by Dr. Hsiao’s graduate student Christine Olson, “The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet” (Olson et. al. 2018). In this paper, the authors manipulate the gut microbiome to establish that changes in gut microbiota composition are necessary and sufficient mediators of a dietary treatment in mouse models of refractory epilepsy. They then use metabolomics to guide the discovery of a molecular target sufficient to confer seizure protection, independent of diet.

A ketogenic diet, a diet that is high in fat and low in carbohydrates, is an effective treatment for refractory epilepsy (epilepsy that does not respond to current anticonvulsant medications), but it often fails because it is difficult for patients to maintain. The authors of this paper offer compelling evidence that the gut microbiome and its effects on host metabolism are important mediators of the seizure reducing effects of a ketogenic diet. They also show how this knowledge can be used to develop pharmacological alternatives. To do this, they first show that a ketogenic diet both reduces seizure susceptibility and changes the composition of the microbiome in two mouse models of refractory epilepsy. However, in germ free mice that lack a microbiome or in mice whose microbiome had been depleted by antibiotics, ketogenic diet did not reduce seizure susceptibility, suggesting that the microbiome is a necessary mediator of the effect. Furthermore, transferring either the fecal microbiota from mice on a ketogenic diet or only the species most greatly increased by the ketogenic diet (A. muciniphila, P. merdae, and P. distasonis) to germ-free mice, antibiotic treated mice, and  mice on control diet with intact microbiota reduced seizure susceptibility similarly to the ketogenetic diet, establishing sufficiency of changes in the microbiota composition to protect against seizure. The authors then used colonic, plasma and brain metabolomics to identify candidate mediators of the effect of the microbiome. Among their findings was a decrease in gamma-glutamylated amino acids in the colon and plasma in groups with reduced seizure susceptibility, suggesting that microbial communities that confer seizure resistance had reduced Gamma-Glutamyltranspeptidase (GGT) activity. To establish a link between this aspect of bacterial metabolism and seizure protection and to provide evidence that GGT activity may be an important pharmacological target for epilepsy treatment, they then treated mice with a GGT inhibitor. They indeed found that GTT inhibition was sufficient to confer seizure protection.

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Schematic of the findings in Olson et. al. 2018. Taken from Olson et. al. 2018.

Beyond advancing the understanding of a current epilepsy treatment and proposing a new pharmacological target for this devastating disease, this paper provides an excellent example of how Dr. Hsiao and her team are translating understanding the microbiome and its metabolism to meaningful insights about neurological development, disease and treatment.

To hear more about the work being done in Dr. Elaine Hsiao’s lab, please join us at 4:00pm, Tuesday 03/03/2020 in the Marilyn G. Farquhar Seminar Room at the Center for Neural Circuits and Behavior.


Written by Jennifer Jensen, a 1st year in the Neurosciences Graduate Program at UCSD currently working in Amir Zarrinpar’s Lab studying how engineered native bacteria can be used to manipulate the microbiome-gut-brain axis.

References

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 173, 1728–1741.

 

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