It is estimated that 90 percent of the body's
serotonin is made in the digestive tract: altered
levels of this peripheral serotonin have been linked
to diseases such as irritable bowel syndrome,
cardiovascular disease, and osteoporosis.
Gut microbes play an important role in modulating
metabolites that impact health and disease. Credit:
New research at Caltech shows that certain bacteria
in the gut are important for the production of
Elaine Hsiao, research assistant professor of
biology and biological engineering and senior author
of the study explains: "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
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.
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
"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
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
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".
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
"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.
The serotonin system in women’s brains is damaged
more readily by alcohol than that in men’s brains
For more information
Indigenous Bacteria from the Gut Microbiota Regulate
Host Serotonin Biosynthesis
California Institute of Technology