For nearly a century, doctors have found that a strict high-fat, low-carbohydrate diet can limit seizures in children with epilepsy when medications fail. But exactly how this ketogenic diet works has remained largely a mystery.

Now, researchers at the University of California, Los Angeles have uncovered one explanation deep within the gut. Working in two mouse models of epilepsy, the team found that two species of gut bacteria flourish under the ketogenic diet and protect the mice from seizures. Their work, recently published in Cell, could suggest ways to deliver seizure relief without diet changes.

“The translational possibilities are very clear,” says neurologist and pharmacologist Michael Rogawski of the University of California, Davis School of Medicine, who was not involved in the study. “It could completely turn this field on its head and change the direction of research.”

The team began by feeding one group of mice a ketogenic diet and another a control diet. Within eight days, mice fed the ketogenic diet were significantly less susceptible to seizures. The ketogenic diet also reduced the diversity of gut microbes, while raising the relative abundance of particular bacterial species.

The researchers then tested whether this altered microbiome affected seizure susceptibility. They fed the ketogenic diet to mice that lacked microbes, either because they received antibiotics or because they were reared in a microbe-free environment. In both cases, the protective effect of the ketogenic diet disappeared. When they colonized the guts of the microbe-free mice with microbes from other mice, the diet once again worked.

The team then tested whether the protective effects stemmed from particular bacterial species. Akkermansia muciniphila and Parabacteroides merdae, two species that proliferated most under the ketogenic diet, together restored the effect in mice lacking microbes.

In a final series of studies, the team began exploring exactly how these microbes reduce susceptibility to seizures. In one experiment, they found that the hippocampus of the microbe-protected mice had increased levels of the neurotransmitter GABA, which silences neurons, relative to glutamate, which activates them.

“It is not at all shocking that such a radical change in diet would affect major change in the microbiome,” says Marc Yudkoff, a professor of pediatrics at the University of Pennsylvania Perelman School of Medicine, who was not involved in the study. “What is exciting, though, is the possibility that that change might be of some therapeutic benefit,” adds Yudkoff, whose work has explored the ketogenic diet’s effect on how the brain metabolizes amino acids.

Alternatives are desirable, as the ketogenic diet is extremely challenging to maintain. “It is an imposition on a family,” says Yudkoff. “It provides at least 80 to 90 percent of total calories as fat.” There are also health concerns associated with the diet, including risks of kidney stones, constipation, and elevated cholesterol.

The findings provide “an excellent platform to begin to try to understand how one might create a ketogenic diet in a pill,” says Rogawski. “It might be as simple as strategies to alter the gut microbiome that don’t rely on the diet.”

But Yudkoff and Rogawski agree that it’s still unclear how exactly the microbes limit seizures, and whether the same results would hold in humans. “We are really interested in learning more about how exactly select gut microbes impact the brain in ways that modulate seizure outcomes,” says biologist and senior author Elaine Hsiao, a professor of integrative biology and physiology at UCLA. “We hope to identify specific molecules, cells and mechanisms that are involved.”

The UCLA Technology Development Group licensed a patent, based on the team’s findings, to a startup that Hsiao helped launch. The company is now examining potential clinical applications for a “live biotherapeutic product” that mimics the ketogenic diet.