UCLA researchers in the Department of Integrative Biology and Physiology have successfully mapped the functional gut microbiota and specific metabolic molecules that promote relief from epilepsy through the ketogenic diet.

BACKGROUND: Research supported by the National Institutes of Health has shown that the gut microbiome has tremendous impact on human health. Perturbations to its composition and function have been implicated in numerous chronic diseases and neural activity. Consequently, physicians and scientists have been researching the use of dietary therapies to modify the gut microbiome and prevent or treat disease. Introduced in the 1920s, the ketogenic diet (KD), which is a non-invasive high-fat and low-carbohydrate diet, has been used to help control seizures in patients with refractory epilepsy, a condition characterized by failure to respond to anti-epileptic drugs. According to the World Health Organization, approximately 50 million people worldwide have epilepsy, making it one of the most common neurological diseases; amongst those, more than one third eventually develop refractory epilepsy. Despite its use over the last century, the mechanism by which the diet controls seizures is poorly understood. Thus, better understanding of the gut microbiome’s role in controlling seizures could reveal more potent diet and medical interventions in treating refractory epilepsy and other chronic diseases associated with the gut microbiome.

INNOVATION: Researchers at UCLA led by Dr. Elaine Hsiao in the Department of Integrative Biology and Physiology have identified the causal roles for the clinical ketogenic diet-associated human gut microbiota for promoting seizure protection. Initially, the researchers examined the gut microbiota of pediatric epilepsy patients before and after treatment with the clinical ketogenic diet. After treatment, patient stool samples were transplanted into mice. This experiment showed that human microbiota after KD was effective in protecting mice against seizures. This innovative finding has successfully mapped specific microbiome compositions and metabolite output that will lead to more robust clinical treatments for epilepsy.

POTENTIAL APPLICATIONS:

• Enhancement of seizure protection by the ketogenic diet
• Novel microbe-based neuroprotective treatment for neurological disorders, including refractory epilepsy

ADVANTAGES:

• Ketogenic diet has been used clinically to treat refractory epilepsy since the 1920s
• This novel discovery used pediatric epilepsy microbiome samples
• Metagenomic profiling combined with causal assessment in gnotobiotic mice shows functional genomic features of the human gut microbiome that promote seizure protection
• Metabolomic profiling combined with causal assessment in gnotobiotic mice shows functional features of the human gut microbiome that promote seizure protection

DEVELOPMENT-TO-DATE: Researchers have used human patient samples before and after KD to show that there is a shift in the metagenomic and metabolomic profile and effectively linked it to protection against seizures.

Related Papers (from the inventors only): Olson, C.A.; Vuong, H.E.; Yano, J.M.; Liang, Q.Y.; Nusbaum, D.J.; Hsiao, E.Y. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018, 173, 1728-1741.

KEYWORDS: Epilepsy, Ketogenic diet, gut microbiome, bacteria, refractory epilepsy