Daniel Lowenstein, MDDaniel Lowenstein, MD
Connecting the dots between the gut microbiome and brain activity has increasingly become a central focus of research in neurological disorders, including Parkinson disease, multiple sclerosis, and now epilepsy. The role of microbes in the immune system, and in turn the brain, has presented a new category of treatment targets, especially for patients with disorders that don’t respond well to current first-line therapies.

Following a symposium on the topic, Daniel Lowenstein, MD shared his insight with NeurologyLive at the 73rd annual meeting of the American Epilepsy Society (AES), which took place December 6-10, 2019, in Baltimore, Maryland. Lowenstein, who is a professor of neurology and executive vice chancellor and provost at the University at the University of California, San Francisco, where he previously served as director of the UCSF epilepsy center and epilepsy research laboratory, spoke about the various research efforts in epilepsy and the potential of therapy targeting the gut environment.

In part 1 of this interview, Lowenstein shares how the gut microbiome can play a pivotal role in learning more about brain activity and how it is impacted by the immune system.

NeurologyLive: How does the gut microbiome interplay with brain activity?

Daniel Lowenstein, MD: Over the last decade or so there's been a growth in research in the potential relationship between the microbes in our gut and how the brain works. At this point, it's fair to say that it's quite clear that the local environment of the gut affects the immune system, which we've known for a long time has effects on the brain. There's also probably a direct connection in terms of the vagus nerve and the way it actually interacts with the gut, affects the gut, and also brings back information to the nervous system. So the connection, whether it's the immune system and other factors that are released into the bloodstream that make their way to the brain, or these direct neural connections, there's now absolutely no doubt whatsoever that there are some major interactions between the gut and the brain. =It's known that the gut influences the production of neurotrophic factors in the brain, and it also changes the release of various kinds of cytokines that circulate in the blood making their way into the brain and can affect the function of the brain itself.

What can we learn about epilepsy knowing the connection between the gut microbiome and other neurological diseases like Parkinson disease?

That's just beginning, which is one of the reasons why it was exciting to bring this body of work to the epilepsy meeting. In fact, one of the speakers at the session, Andrey Mazarati, MD, PhD, from UCLA, recently published a commentary on the potential influence of the gut on epilepsy, the microbiome and epilepsy, and he showed a graph of the publications that have been done in the field of all of microbiome versus the brain versus autism versus epilepsy, and it's quite extraordinary to know how much work has been done in the microbiome, and how very little has been done in epilepsy, per say. Even autism, for example, if you look on PubMed, you'll find well over 400 articles that investigate the connection between the microbiome and autism. But if you look in epilepsy, it's still less than 25 or so. This is just the beginning. How much it's going to translate into epilepsy is unknown, because it's kind of like this vast, unexplored universe for us.

What do we already know about the gut microbiome and epilepsy that is motivating the community to conduct further research?

I think it's fair to say that one of the big catalysts for the excitement in the field was a very important paper that Elaine Chow, also from UCLA, published in the journal cell in June of 2018. Elaine is a microbiome person, she's not an epilepsy person. But she asked a series of really interesting questions beginning with “how does the ketogenic diet work, since it's an exposure to a diet that interacts with our microbiome and then has been shown to be effective in the treatment of at least a subset of patients with epilepsy?” And without going into all the detail, what she was eventually able to learn, was that the ketogenic diet requires the existence of the microbiome in order to work. That was interesting, and maybe not too surprising that you need to have the right microbes in there to metabolize the food that you're taking in, but potentially groundbreaking was that she discovered that, in fact, elements of the microbiome itself are capable of reproducing the effect of the ketogenic diet without having the diet itself. She went a step further, and she was able to identify 2 specific bacteria of the gazillions that exist in our microbiome, that those 2 alone were sufficient for producing the effects of the ketogenic diet. And then she took it yet one step further and came up with some potential mechanisms of the interaction between those bacteria and ultimately the GABA neuroinhibitory neurotransmitter that is so important for brain function. She was able to show that 1 potential mechanism of action was the influence of these bacteria in the gut on the ultimate production of GABA in the brain. When I first saw that paper, it just really opened my eyes to what I think many of us now believe to be an extraordinarily interesting area that has essentially remained unexplored in the field of epilepsy until recently.