Although serotonin is well known as a brain neurotransmitter, it is estimated that 90 percent of the body's serotonin is made in the digestive tract. In fact, altered levels of this peripheral serotonin have been linked to diseases such as irritable bowel syndrome, cardiovascular disease, and osteoporosis. New research at Caltech, published in the April 9 issue of the journal Cell, shows that certain bacteria in the gut are important for the production of peripheral serotonin.
"More and more studies are showing that mice or other model organisms with changes in their gut microbes exhibit altered behaviors," explains Elaine Hsiao, research assistant professor of biology and biological engineering and senior author of the study. "We are interested in how microbes communicate with the nervous system. To start, we explored the idea that normal gut microbes could influence levels of neurotransmitters in their hosts."
Peripheral serotonin is produced in the digestive tract by enterochromaffin (EC) cells and also by particular types of immune cells and neurons. Hsiao and her colleagues first wanted to know if gut microbes have any effect on serotonin production in the gut and, if so, in which types of cells. They began by measuring peripheral serotonin levels in mice with normal populations of gut bacteria and also in germ-free mice that lack these resident microbes. The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ-free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.
"EC cells are rich sources of serotonin in the gut. What we saw in this experiment is that they appear to depend on microbes to make serotonin—or at least a large portion of it," says Jessica Yano, first author on the paper and a research technician working with Hsiao. The researchers next wanted to find out whether specific species of bacteria, out of the diverse pool of microbes that inhabit the gut, are interacting with EC cells to make serotonin. After testing several different single species and groups of known gut microbes, Yano, Hsiao, and colleagues observed that one condition—the presence of a group of approximately 20 species of spore-forming bacteria—elevated serotonin levels in germ-free mice. The mice treated with this group also showed an increase in gastrointestinal motility compared to their germ-free counterparts, and changes in the activation of blood platelets, which are known to use serotonin to promote clotting. Wanting to home in on mechanisms that could be involved in this interesting collaboration between microbe and host, the researchers began looking for molecules that might be key. They identified several particular metabolites—products of the microbes' metabolism—that were regulated by spore-forming bacteria and that elevated serotonin from EC cells in culture. Furthermore, increasing these metabolites in germ-free mice increased their serotonin levels.
Previous work in the field indicated that some bacteria can make serotonin all by themselves. However, this new study suggests that much of the body's serotonin relies on particular bacteria that interact with the host to produce serotonin, says Yano. "Our work demonstrates that microbes normally present in the gut stimulate host intestinal cells to produce serotonin," she explains.
"While the connections between the microbiome and the immune and metabolic systems are well appreciated, research into the role gut microbes play in shaping the nervous system is an exciting frontier in the biological sciences," says Sarkis K. Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and a coauthor on the study. "This work elegantly extends previous seminal research from Caltech in this emerging field".
Additional coauthor Rustem Ismagilov, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering, adds, "This work illustrates both the richness of chemical interactions between the hosts and their microbial communities, and Dr. Hsiao's scientific breadth and acumen in leading this work." Serotonin is important for many aspects of human health, but Hsiao cautions that much more research is needed before any of these findings can be translated to the clinic.
"We identified a group of bacteria that, aside from increasing serotonin, likely has other effects yet to be explored," she says. "Also, there are conditions where an excess of peripheral serotonin appears to be detrimental."
Although this study was limited to serotonin in the gut, Hsiao and her team are now investigating how this mechanism might also be important for the developing brain. "Serotonin is an important neurotransmitter and hormone that is involved in a variety of biological processes. The finding that gut microbes modulate serotonin levels raises the interesting prospect of using them to drive changes in biology," says Hsiao.
Think Twice: How the Gut's "Second Brain" Influences Mood and Well-Being
As Olympians go for the gold in Vancouver, even the steeliest are likely to experience that familiar feeling of "butterflies" in the stomach. Underlying this sensation is an often-overlooked network of neurons lining our guts that is so extensive some scientists have nicknamed it our "second brain".
A deeper understanding of this mass of neural tissue, filled with important neurotransmitters, is revealing that it does much more than merely handle digestion or inflict the occasional nervous pang. The little brain in our innards, in connection with the big one in our skulls, partly determines our mental state and plays key roles in certain diseases throughout the body. Although its influence is far-reaching, the second brain is not the seat of any conscious thoughts or decision-making.
"The second brain doesn't help with the great thought processes…religion, philosophy and poetry is left to the brain in the head," says Michael Gershon, chairman of the Department of Anatomy and Cell Biology at New York–Presbyterian Hospital/Columbia University Medical Center, an expert in the nascent field of neurogastroenterology and author of the 1998 book The Second Brain (HarperCollins). Technically known as the enteric nervous system, the second brain consists of sheaths of neurons embedded in the walls of the long tube of our gut, or alimentary canal, which measures about nine meters end to end from the esophagus to the anus. The second brain contains some 100 million neurons, more than in either the spinal cord or the peripheral nervous system, Gershon says.
This multitude of neurons in the enteric nervous system enables us to "feel" the inner world of our gut and its contents. Much of this neural firepower comes to bear in the elaborate daily grind of digestion. Breaking down food, absorbing nutrients, and expelling of waste requires chemical processing, mechanical mixing and rhythmic muscle contractions that move everything on down the line. Thus equipped with its own reflexes and senses, the second brain can control gut behavior independently of the brain, Gershon says. We likely evolved this intricate web of nerves to perform digestion and excretion "on site," rather than remotely from our brains through the middleman of the spinal cord. "The brain in the head doesn't need to get its hands dirty with the messy business of digestion, which is delegated to the brain in the gut," Gershon says. He and other researchers explain, however, that the second brain's complexity likely cannot be interpreted through this process alone.
"The system is way too complicated to have evolved only to make sure things move out of your colon," says Emeran Mayer, professor of physiology, psychiatry and biobehavioral sciences at the David Geffen School of Medicine at the University of California, Los Angeles (U.C.L.A.). For example, scientists were shocked to learn that about 90 percent of the fibers in the primary visceral nerve, the vagus, carry information from the gut to the brain and not the other way around. "Some of that info is decidedly unpleasant," Gershon says.
The second brain informs our state of mind in other more obscure ways, as well. "A big part of our emotions are probably influenced by the nerves in our gut," Mayer says. Butterflies in the stomach—signaling in the gut as part of our physiological stress response, Gershon says—is but one example. Although gastrointestinal (GI) turmoil can sour one's moods, everyday emotional well-being may rely on messages from the brain below to the brain above. For example, electrical stimulation of the vagus nerve—a useful treatment for depression—may mimic these signals, Gershon says.
Given the two brains' commonalities, other depression treatments that target the mind can unintentionally impact the gut. The enteric nervous system uses more than 30 neurotransmitters, just like the brain, and in fact 95 percent of the body's serotonin is found in the bowels. Because antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels, it's little wonder that meds meant to cause chemical changes in the mind often provoke GI issues as a side effect. Irritable bowel syndrome—which afflicts more than two million Americans—also arises in part from too much serotonin in our entrails, and could perhaps be regarded as a "mental illness" of the second brain.
Scientists are learning that the serotonin made by the enteric nervous system might also play a role in more surprising diseases: In a new Nature Medicine study published online February 7, a drug that inhibited the release of serotonin from the gut counteracted the bone-deteriorating disease osteoporosis in postmenopausal rodents. (Scientific American is part of Nature Publishing Group.) "It was totally unexpected that the gut would regulate bone mass to the extent that one could use this regulation to cure—at least in rodents—osteoporosis," says Gerard Karsenty, lead author of the study and chair of the Department of Genetics and Development at Columbia University Medical Center.
Serotonin seeping from the second brain might even play some part in autism, the developmental disorder often first noticed in early childhood. Gershon has discovered that the same genes involved in synapse formation between neurons in the brain are involved in the alimentary synapse formation. "If these genes are affected in autism," he says, "it could explain why so many kids with autism have GI motor abnormalities" in addition to elevated levels of gut-produced serotonin in their blood.
Down the road, the blossoming field of neurogastroenterology will likely offer some new insight into the workings of the second brain—and its impact on the body and mind. "We have never systematically looked at