The Brain–Gut Axis and Neuropsychiatric Disease: A Paradigm Shift

In the past decade, scientists have learned that the microbiome, or the diverse population of microbes housed in the human gut, influences far more than our gastro-intestinal health. In fact, scientists have discovered that the brain and the gut are in almost constant communication, sending various neurocrine and endocrine signals back and forth. Our emerging understanding of the microbiome and its influence on the brain, according to Emeran Mayer, director of the Center for the Neurobiology of Stress at the University of California Los Angeles (UCLA), means that neuroscience will have to make a profound paradigm shift—and start looking beyond the central nervous system when studying brain development and disease.

“As our understanding of the microbiome grows, we see a new opportunity for new questions and new understanding of brain disorders ranging from autism and depression,” Mayer says. “It’s a paradigm shift—and it’s opening up whole new avenues of study to look at diseases of the central nervous system, redefining those diseases and, then, it’s our hope, new avenues in treating them.”

Mayer and colleagues presented some of this research at a special symposium entitled “Gut Microbes and the Brain:  Paradigm Shift in Neuroscience” at this year’s Society for Neuroscience (SfN) Meeting in Washington, DC.

The gut-brain axis and stress

The gut-brain axis is the bi-directional communication that goes on between the gastro-intestinal tract and the brain. John Cryan, a neuroscientist at Ireland’s University College Cork, likens this communication to the upstairs/downstairs communication between the well-to-do house dwellers and the working class house staff seen in a show like Downton Abbey.

“The upstairs and the downstairs need each other to survive. From a distance, it looks like they are living completely separate and they don’t have much to do with one another,” he says. “But when things start going wrong downstairs that filters on upstairs. It’s the same with the gut and the brain. If there is something wrong with your microbiome, it’s going to filter on upstairs in the brain, too.”

At the SfN symposium, Cryan discussed work from his own lab and others’ concerning how the gut-brain axis may mediate stress and anxiety.

“Some of our earliest work showed that if you stress a rat early in life, lo and behold, you’ll see that microbiome diversity in the gut is greatly reduced. So early life stress can impact your microbiome—and we know that early life stress also impacts the brain,” he says. “The question remained whether the microbiome could affect stress. And labs that work with germ-free animals found that these animals with no real bacteria in their guts had a much greater stress response than normal animals. But when you introduced specific bacteria to those animals, the researchers were able to reverse that increased stress response. From there, we started to understand that how you deal with stress is mediated by your microbiome, and we wanted to learn more.”

From animals to humans

News on the importance of gut-brain communication is not just limited to animal models. Paul O’Toole, a microbial genomicist from University College Cork learned that a lack of diversity in the microbiome was also linked to obesity, inflammatory diseases, and cognitive decline in elderly populations. O’Toole and colleagues followed 178 people, comparing their health status with their gut make-up. In a paper published in the January 10, 2012, issue of Nature, they demonstrated that a less-diverse microbiome was linked to increased frailty, and that diversity appeared to be mediated by diet. The work suggests that specific dietary interventions might help improve health both in the elderly and in younger people.  

“It appears that a more diverse diet governs the diversity of the ecosystem in your intestines,” he says. “We hadn’t expected to find such a straight-line correlation but there it was.”

Other human research was also presented at the SfN symposium, showing links between microbiome contents and disorders like autism, depression, and chronic pain. It’s long been known that many neuropsychiatric disorders are accompanied by gastro-intestinal symptoms. Taking anecdotal and correlational data together, the idea that some of these disorders could be prevented or better controlled with diet or some kind of probiotic supplement is a fascinating possibility.

“There is a lot of compelling research out there. And, in our own studies, we’re focusing on to what degree the animal findings are translatable to humans,” says Mayer. “With autism, we see a lot of bizarre eating behaviors and food avoidance, so the idea that the gut may play a role, especially at some point in development, makes sense. But we have to get past correlational studies and do the longitudinal studies so we can get some idea about causality.”

Looking towards the future

Cryan is very enthusiastic about the possibilities of using information we’ve learned from the gut to treat psychiatric disorders one day—and thinks that if we can better understand the molecular mechanisms that underlie their communication, we can get there.

“We’re right at the dawn of a whole new way of thinking about brain development and brain heath,” he says. “And the neuroscientific evidence for the role of the microbiome is just getting stronger and stronger at the basic level.”

Still, he cautions that microbiome won’t be the be-all-end-all when it comes to understanding neuropsychiatric disorders, and that there is still much work to be done before we get to specific treatments. O’Toole agrees.

“There is a paradigm shift going on, to be sure. But people need to be patient and realize that we’re in the very early stages of a new interface between human physiology and microbiology,” says O’Toole. “It’s a very exciting place to be—and we have some excellent pioneering scientists working on these problems. But pioneers are people with arrows in their back. We need to do the work and see how it all works out in five or ten years time. Then we’ll know.”