Michael Gershon studies brain-gut connections.
The Other Brain Also Deals With Many Woes
NEW YORK TIMES:
August 23, 2005: Harriet Brown
For Dr. Michael D. Gershon, the author of "The Second
Brain" and the chairman of the department of anatomy and cell biology at
Columbia, the connection between the two can be unpleasantly clear. "Every
time I call the National Institutes of Health to check on a grant proposal,"
Dr. Gershon said, "I become painfully aware of the influence the brain has
on the gut."
In fact, anyone who has ever felt butterflies in the stomach before giving a
speech, a gut feeling that flies in the face of fact or a bout of intestinal
urgency the night before an examination has experienced the actions of the
dual nervous systems.
The connection between the brains lies at the heart of many woes, physical
and psychiatric. Ailments like anxiety, depression, irritable bowel
diseases such as ulcerative colitis and Crohn's, ulcers and Parkinson's disease manifest symptoms at the brain and
the gut level.
"The majority of patients with anxiety and depression will also have
alterations of their GI function," said Dr. Emeran Mayer, professor of
medicine, physiology and psychiatry at the University of California, Los
A study in 1902 showed changes in the movement of food through the
gastrointestinal tract in cats confronted by growling dogs.
One system's symptoms - and cures - may affect the other. Antidepressants,
for example, cause gastric distress in up to a quarter of the people who
take them. Butterflies in the stomach are caused by a surge of stress
hormones released by the body in a "fight or flight" situation. Stress can
also over-stimulate nerves in the esophagus, causing a feeling of choking.
Dr. Gershon, who coined the term "second brain" in 1996, is one of a number
of researchers who are studying brain-gut connections in the relatively new
field of neurogastroenterology. New understandings of the way the second
brain works, and the interactions between the two, are helping to treat
disorders like constipation, ulcers and Hirschprung's disease.
The role of the enteric nervous system is to manage every aspect of
digestion, from the esophagus to the stomach, small intestine and colon. The
second brain, or little brain, accomplishes all that with the same tools as
the big brain, a sophisticated nearly self-contained network of neural
circuitry, neurotransmitters and proteins.
The independence is a function of the enteric nervous system's complexity.
"Rather than Mother Nature's trying to pack 100 million neurons someplace in
the brain or spinal cord and then sending long connections to the GI tract,
the circuitry is right next to the systems that require control," said
Jackie D. Wood, professor of physiology, cell biology and internal medicine
at Ohio State.
Two brains may seem like the stuff of science fiction, but they make literal
and evolutionary sense.
"What brains do is control behavior," Dr. Wood said. "The brain in your gut
has stored within its neural networks a variety of behavioral programs, like
a library. The digestive state determines which program your gut calls up
from its library and runs."
When someone skips lunch, the gut is more or less silent. Eat a pastrami
sandwich, and contractions all along the small intestines mix the food with
enzymes and move it toward the lining for absorption to begin. If the
pastrami is rotten, reverse contractions will force it - and everything else
in the gut - into the stomach and back out through the esophagus at high
In each situation, the gut must assess conditions, decide on a course of
action and initiate a reflex.
"The gut monitors pressure," Dr. Gershon said. "It monitors the progress of
digestion. It detects nutrients, and it measures acid and salts. It's a
little chemical lab."
The enteric system does all this on its own, with little help from the
central nervous system.
The enteric nervous system was first described in 1921 by Dr. J. N. Langley,
a British physician who believed that it was one of three parts - along with
the parasympathetic and sympathetic nervous systems - of the autonomic
nervous system, which controls involuntary behaviors like breathing and
circulation. In this triad, the enteric nervous system was seen as something
of a tag-along to the other two.
After Langley died, scientists more or less forgot about the enteric nervous
system. Years later, when Dr. Gershon reintroduced the concept and suggested
that the gut might use some of the same neurotransmitters as the brain, his
theory was widely ridiculed.
"It was like saying that New York taxi drivers never
miss a showing of 'Tosca' at the Met," he recalled.
By the early 80's, scientists had accepted the idea of the enteric nervous
system and the role of neurotransmitters like serotonin in the gut.
It is no surprise that there is a direct relationship between emotional
stress and physical distress. "Clinicians are finally acknowledging that a
lot of dysfunction in GI disorders involves changes in the central nervous
system," said Gary M. Mawe, a professor of anatomy and neurobiology at the
University of Vermont.
The big question is which comes first, physiology or psychology?
The enteric and central nervous systems use the same hardware, as it were,
to run two very different programs. Serotonin, for instance, is crucial to
feelings of well-being. Hence the success of the antidepressants known as
S.S.R.I.'s that raise the level of serotonin available to the brain.
But 95 percent of the body's serotonin is housed in the gut, where it acts
as a neurotransmitter and a signaling mechanism. The digestive process
begins when a specialized cell, an enterochromaffin, squirts serotonin into
the wall of the gut, which has at least seven types of serotonin receptors.
The receptors, in turn, communicate with nerve cells to start digestive
enzymes flowing or to start things moving through the intestines.
Serotonin also acts as a go-between, keeping the brain in the skull up to
date with what is happening in the brain below. Such communication is mostly
one way, with 90 percent traveling from the gut to the head.
Many of those messages are unpleasant, and serotonin is involved in sending
them. Chemotherapy drugs like doxorubicin, which is used to treat breast
cancer, cause serotonin to be released in the gut, leading to nausea and
vomiting. "The gut is not an organ from which you wish to receive frequent
progress reports," Dr. Gershon said.
Serotonin is also implicated in one of the most debilitating gut disorders,
ulcerative colitis and Crohn's diseases which areis classified as IBD (irritable bowl disease),
and which causes abdominal pain and cramping, bloating and, in some patients,
alternating diarrhea and constipation.
"You can run any test you want on people with IBD, and their GI tracts look
essentially normal," Dr. Mawe said. The default assumption has been that the
syndrome is a psychosomatic disease.
But it turns out that IBD, like depression, is at least in part a function
of changes in the serotonin system. In this case, it is too much serotonin
rather than too little.
In a healthy person, after serotonin is released into the gut and initiates
an intestinal reflex, it is whisked out of the bowel by a molecule known as
the serotonin transporter, or SERT, found in the cells that line the gut
People with IBD do not have enough SERT, so they wind
up with too much serotonin floating around, causing diarrhea.
The excess serotonin then overwhelms the receptors in the gut, shutting them
down and causing constipation.
When Dr. Gershon, whose work has been supported by Novartis, studied mice
without SERT, he found that they developed a condition very much like IBD in
Several new serotonin-based drugs - intestinal antidepressants, in a way -
have brought hope for those with chronic gut disorders.
Another mechanism that lends credence to physiology as the source of
intestinal dysfunctions is the system of mast cells in the gut that have an
important role in immune response.
"During stress, trauma or 'fight or flight' reactions, the barrier between
the lumen, the interior of the gut where food is digested, and the rest of
the bowel could be broken, and bad stuff could get across," Dr. Wood said.
"So the big brain calls in more immune surveillance at the gut wall by
activating mast cells."
These mast cells release histamines and other inflammatory agents,
mobilizing the enteric nervous system to expel the perceived intruders, and
Inflammation induced by mast cells may turn out to be crucial in
understanding and treating GI disorders. Inflamed tissue becomes tender. A
gut under stress, with chronic mast cell production and consequent
inflammation, may become tender, as well.
In animals, Dr. Mawe said, inflammation makes the
sensory neurons in the gut fire more often, causing a kind of sensory
hyperactivity. "I have a theory that some chronic disorders may be caused by
something like attention deficit disorder in the gut," he said.
Dr. Gershon, too, theorizes that physiology is the original culprit in
brain-gut dysfunctions. "We have identified molecular defects in the gut of
everyone who has irritable bowel syndrome," he said. "If you were chained by
bloody diarrhea to a toilet seat, you, too, might be depressed."
Still, psychology clearly plays a role. Recent studies suggest that stress,
especially early in life, can cause chronic GI diseases, at least in
animals. "If you put a rat on top of a little platform surrounded by water,
which is very stressful for a rat, it develops the equivalent of diarrhea,"
Dr. Mayer said.
Another experiment showed that when young rats were separated from their
mothers, the layer of cells that line the gut, the same barrier that is
strengthened by mast cells during stress, weakened and became more
permeable, allowing bacteria from the intestine to pass through the bowel
walls and stimulate immune cells.
"In rats, it's an adaptive response," Dr. Mayer said. "If they're born into
a stressful, hostile environment, nature programs them to be more vigilant
and stress responsive in their future life."
He said up to 70 percent of the patients he treats for chronic gut disorders
had experienced early childhood traumas like parents' divorces, chronic
illnesses or parents' deaths. "I think that what happens in early life,
along with an individual's genetic background, programs how a person will
respond to stress for the rest of his or her life," he said.
Either way, what is good for one brain is often good for the other, too. A
team of researchers from Penn State University recently discovered a
possible new direction in treating intestinal disorders, biofeedback for the
brain in the gut.
In an experiment published in a recent issue of Neurogastroenterology and
Motility, Robert M. Stern, a professor of psychology at Penn State, found
that biofeedback helped people consciously increase and enhance their
gastrointestinal activity. They used the brains in their heads, in other
words, to help the brains in their guts, proving that at least some of the
time two brains really are better than one.