Abstract

Though few know about it, humans have a second brain that handles most of the body's digestive functions. Study of the enteric nervous system is a rapidly growing specialty, offering insight into malfunctions of the "gut brain" as well as the more complex cranial brain.

Digestion is such a prosaic function that most people prefer not to think about it. Fortunately, they don't have to - at least not with the brain in their heads. Though few know about it, humans (and other animals) have a second brain that handles most digestive functions.

Deep in your gut lies a complex self-contained nervous system containing more nerve cells than the spinal cord, and indeed more neurons than all the rest of the peripheral nervous system. There are over 100 million nerve cells in the human small intestine alone.

Malfunctions of this "gut brain" may be involved in irritable bowel syndrome (IBS), a condition that affects an estimated 20 percent of the U.S. population and is believed to be responsible for $8 billion in health care costs alone in the United States each year, according to the International Foundation for Functional Gastrointestinal Disorders. Patients with IBS suffer bouts of chronic diarrhea, constipation, or sometimes both alternately. IBS is the most common diagnosis made by gastroenterologists.

The study of the enteric nervous system is a rapidly growing specialty known as neurogastroenterology.

"What the gut has to do is extremely complicated," says Michael Gershon, chair of the department of anatomy and cell biology at the Columbia University College of Physicians and Surgeons and author of The Second Brain (Harper Perennial, 1999). "If the brain had to control that, it would have to run huge cables and have a huge number of cells devoted solely to that purpose. It makes great evolutionary sense to [separate these functions] and essentially use a microcomputer that is independent rather than a central processing unit."

In fact, researchers believe that the gut brain evolved first - because digestion came before locomotion in multicellular creatures. In mammals, the two systems originate near each other in the outer layer of the early embryo.

Like many poorly understood organs, the gut brain was discovered by classical anatomists in the 19th century and then ignored. "No one knew what it did," says David Wingate, emeritus professor of gastrointestinal science at Queen Mary, University of London. "When you'd ask what it was for in medical school, they'd say, 'Let's move on.'"

In 1899, physiologists studying dogs found that unlike any other reflex, the continuous push of material through the digestive system (now called the peristaltic reflex) continued when nerves linking the brain to the intestines were cut.

By the 1970s, a society for the study of gastrointestinal motility had been set up - but how this motility was controlled remained unclear. The vagus nerve, for example, sends some fibers from the brain to the gut; however, it connects directly with only a tiny minority of cells there.

In 1965, Gershon published a paper in Science suggesting that serotonin might act as a neurotransmitter in the gut. At the time, acetylcholine and norepinephrine were accepted as transmitters in the peripheral nervous system, but serotonin was seen as a centrally acting transmitter used by some nerves to modulate the action of others.

The peripheral nervous system wasn't supposed to use such controls - only the brain and spinal cord were believed to process information through "interneurons" such as those containing serotonin.

At a meeting of the Society for Neuroscience in 1981, however, Gershon and others marshaled enough data to finally convince skeptics that serotonin was indeed a key transmitter in the gut.

In fact, it is now known that 95% of the body's serotonin is used by the gut - and the enteric nervous system contains every neurotransmitter and neuromodulator found so far in the brain.

"We now know quite a lot about the library of programs run by the [gut brain]," says Jackie Wood, professor of physiology and cell biology and of internal medicine at Ohio State University. "For example, when the bowel is empty, one particular program runs." Called the migrating motor complex (MMC), this involves a series of movements running from the stomach to the end of the small intestine, which is believed to function in keeping the potentially dangerous bacteria stored in the colon from moving upwards rather than out.

At least 500 different species of deadly bacteria have been found to inhabit a person's colon at any given time; "traveler's diarrhea" often results when this mix is changed through exposure to new pathogens. If this happens, the gut runs a program designed to expel as much of its contents as quickly as possible - unpleasant for the vacationer, but much better than a fatal infection.

"Another program involves a flood of serotonin throughout the entire circuit, which produces the digestive pattern that mixes and stirs the contents," says Wood.

Because the gut brain is smaller and more accessible than the brain itself, understanding it could offer insights about how to parse the more complex organ. "[That idea] was what lead me to begin my research when I was a fledgling neuroscientist," says Gershon. "I looked at the brain and found it daunting, and I still do, so I looked for a simpler nervous system to study." He adds, "'Simple nervous system,' of course, turned out to be an oxymoron."

Unlike the cranial brain, however, the gut brain doesn't seem to be conscious - or at least, in health, it doesn't impinge much on consciousness. "The gut is not an organ from which you like to receive frequent progress reports," says Gershon. For most digestive processes, no news is good news.

The problem in IBS, in fact, may be that the enteric nervous system becomes overly sensitive to normal functioning and reports to the brain when it shouldn't. Or, the brain may overreact to normal bowel signals.

Normally, the brain may avoid conscious awareness of most gut activity. But in IBS, says Wingate, one theory is that "the barrier to information being projected into consciousness is lowered."

As in many heterogeneous conditions defined by symptoms rather than specific pathology, different subgroups of patients may have different causes or varying levels of contributions by different factors.

In some cases, IBS may be an autoimmune problem - something like multiple sclerosis of the gut, where immune cells attack nervous tissue. "If you catch it early enough," says Wood, "You can use steroids to treat it [in such cases]." High doses of steroids shut down immune activity and prevent immune cells from causing harm, but they don't help once damage has been done.

The gut is, in fact, a major immune organ, containing more immune cells than the rest of the body combined. The enteric nervous system interacts intimately with the immune system, and can affect mood and behavior by signaling the central nervous system.

Further, the gut brain may in fact be the only system that can refuse central signals. Says Gershon, "The gut brain can say no to the big brain, absolutely. In fact, there are nerve fibers that project towards the CNS, and if the [bowel] doesn't like the message, it can turn it off or cancel it."

Indeed, the vagus nerve mostly carries information from the enteric nervous system to the brain - for every one message sent by the brain to the gut, about nine are sent in the other direction. And recent research has found that stimulating this nerve can have antidepressant and even learning-enhancing effects - so "gut feelings" could genuinely be more than just a metaphor.

The similarities between the two nervous systems may also mean that they are vulnerable to similar toxins and disease processes. For example, in both Parkinson's disease and Alzheimer's, the degenerative processes seen in brain nerve cells are also seen in the neurons of the enteric system.

This link could also help explain the connection between psychological problems and gut problems - and could put to rest the myth that problems such as IBS are simply "neuroses" because they so often occur in people with other psychological disorders.

It may be that the real reason that bowel disorders often accompany psychological problems is that both brain and gut neurons are suffering simultaneously - in addition to the fact that having to spend a significant portion of one's life attending to bathroom functions is in itself depressing.

Simultaneous effects of drugs on both systems also account for the gastrointestinal "side effects" of Prozac and other drugs that act on serotonin metabolism - which actually may have more effect on the bowel than on the brain, because serotonin predominates in the bowel and the drug moves through the digestive system before reaching the brain.

Fortunately, in most people, the bowel quickly develops tolerance to these drugs, and gastrointestinal side effects usually subside within a few days or weeks of the start of treatment. In fact, low doses of SSRI (selective serotonin reuptake inhibitor) drugs may actually help patients with IBS. And since different serotonin receptors predominate in the brain and in the gut, new drugs may be developed to affect certain subtypes but not others.

"What's exciting," says Wingate, "is getting away from essentially anecdotal ways of categorizing patients by symptoms and being able to study [their problems] in a very systematic biological way."