Gut bacteria mechanism behind the anti-seizure effects of ketogenic diet uncovered
The ketogenic diet was originally developed a century ago to treat children with severe epilepsy, but how it actually worked was always unclear. Now an exciting and rigorous study from researchers at UCLA suggests the diet can elevate levels of specific gut bacteria that subsequently affect certain neurotransmitters to reduce the risk of seizures.
The ketogenic diet was first developed in 1921, after researchers initially set out to understand how fasting was reducing the frequency of seizures in patients with epilepsy. Since indefinite fasting was not a pragmatic treatment option, it was discovered that similar effects could be generated through a high-fat/low-carbohydrate diet, and so the now infamous ketogenic diet was born.
At the time, Dr Russel Wilder, from the Mayo Clinic and first to coin the term "ketogenic diet," wrote, "If this is the mechanism responsible for the beneficial effect of fasting, it may be possible to substitute for that rather brutal procedure a dietary therapy which the patient can follow with little inconvenience and continue at home as long as seems necessary."
With the development of modern anticonvulsant drugs in the mid-20th century, the ketogenic diet as a treatment for epilepsy slipped into the annals of outdated medical treatments and was rarely utilized unless a particularly severe case arose. The diet remerged as a weight-loss fad in the later parts of the century, in part due to the popularity of the famous Atkins Diet, an eating plan somewhat modeled on a ketogenic framework.
Over recent years, scientists have rekindled an interest in the clinical applications of ketogenic diets for a variety of metabolic and psychiatric disorders. And now, new research from UCLA has for the first time uncovered a clear causal link explaining how a ketogenic diet could be reducing the number of seizures in epileptics, with the answer lying in the enormous population of bacteria that lives in our gut.
The study, using a mouse model, first identified that the ketogenic diet both reduces the amount of seizures and significantly alters gut microbiota in fewer than four days. To establish the connection between gut bacteria and seizure reduction, the researchers examined the effects of a ketogenic diet on two different groups of mice with compromised microbiomes. One group was treated with antibiotics to destroy its microbiome, while the other was reared in a sterile, germ-free environment.
"In both cases, we found the ketogenic diet was no longer effective in protecting against seizures," says lead author Christine Olson. "This suggests that the gut microbiota is required for the diet to effectively reduce seizures."
The next step was to try and isolate which specific species of bacteria could be generating the protective, seizure-reducing effects. Levels of two types in particular were found to be elevated by a ketogenic diet: Akkermansia muciniphila and Parabacteroides. The germ-free mice were then administered these two bacteria and the seizure-protecting benefits suddenly reappeared.
"We found we could restore seizure protection if we gave these particular types of bacteria together," says Olson. "If we gave either species alone, the bacteria did not protect against seizures; this suggests that these different bacteria perform a unique function when they are together."
Finally, the researchers investigated by what mechanism these bacteria could be working to generate the remarkable seizure-reducing effects. They focused their sights on the hippocampus – a part of the brain known to be responsible for generating many epileptic seizures – asking, what compounds in the gut and blood could be directly affecting hippocampal neurotransmitter activity, and how was this possibly modulated by gut bacteria?
It was revealed that these two types of bacteria work together to reduce gut and blood levels of gamma-glutamylated amino acids. This subsequently elevated hippocampal GABA/glutamate levels, which reduced the amount of spontaneous seizures in the mouse models.
"The bacteria increased brain levels of GABA – a neurotransmitter that silences neurons – relative to brain levels of glutamate, a neurotransmitter that activates neurons to fire," says co-author Helen Vuong.
This excitingly comprehensive study offers a complete description of exactly how a ketogenic diet alters the levels of gut bacteria to result in a direct action in the brain. While the study so far has only been proven in mouse models, the implications are profoundly exciting for future human applications. The immediate goal of the research is to verify the mechanism in humans and then find a drug treatment that can better mimic the diet's action so an effective seizure prevention medication can be developed.
The research was published in the journal Cell.