Neurogastroenterologists Combine Old And New Research Approaches

Increasing interest in the innervation of the gastrointestinal (Gl) tract has led to the emergence of neurogastroenterology, a field that weds classic anatomy and physiology with contemporary neuroscience. The field has roots reaching back to Pavlovís dogs. Today, however, like other biomedical sciences, its researchers take a more molecular approach, tracking the neurons of the gut and the neurotransmitters and neuropeptides that they release.

Links between the nervous and digestive systems are well known. Diarrhea following intense fright and cramps before an exam clearly couple the two systems, because the brain registers the emotions that prompt the digestive responses. But some of the nerves in the GI tract can function without links to the brain, prompting researchers to dub them a "second brain."

The newly recognized importance of the enteric nervous system (ENS) is changing how physicians treat disorders of the GI tract. "Nowadays one cannot talk about gastroenterology without implicating the nervous system," says Michael Camilleri, a professor of medicine at the Mayo Clinic in Rochester, Minn.

Neurogastroenterology combines the expertise of gastroenterologists and neuroscientists. "There are a lot of important cross-overs between basic science and clinical medicine," notes Peter McNally, chief of gastroenterology at Fitzsimons Army Medical Center in Aurora, Colo., and public relations chairman for the Arlington, Va.-based American College of Gastroenterology.

"The enteric nervous system is to a large extent independent, and it is only fine-tuned by extrinsic nerves that connect it to the brain for motor functions," explains Camilleri. Like the more familiar central nervous system (brain and spinal cord) and peripheral nervous system (nervous tissue outside of the brain and spinal cord), the enteric system includes vast networks of neurons; their supportive glial cells; and messenger molecules, such as neurotransmitters, neuropeptides, and growth factors.

The existence of a nervous system in the gut that is distinct from, yet similar to, that of the brain suggests why drugs used to treat mood disorders have gastrointestinal side effects, and why brain disorders such as Parkinsonís disease have digestive symptoms. "Every class of neurotransmitter in the brain is found in the gut," states Michael Gershon, a professor and chairman of anatomy and cell biology at Columbia Universityís College of Physicians and Surgeons.

The emergence of the field is evident in the recent change in a key journalís title - the International Journal of Gastrointestinal Motility became Neurogastroenterology and Motility last year. "People in the field began to think that restricting the title to ëgastrointestinal motilityí wasnít appropriate, because the nervous system in the gut controls more than motility," Gershon points out. "It also controls absorption, secretion, and turnover of epithelium.

"The editors polled many people, we faxed our answers in, and the title ëNeurogastroenterologyí evolved," Gershon recounts. The journal is from the European Gastrointestinal Motility Society and is published by Oxford, U.K.-based Blackwell Scientific Publications.

Momentum is building in the field, according to James W. Freston, president of the American Gastroenterological Association in Bethesda, Md., and a professor and chairman of medicine at the University of Connecticut Health Center in Farmington. Freston notes that the number of research papers on nerve-gut interaction and related topics submitted to his groupís annual conference has increased by 31 percent over the last five years.

Funding is healthy as well. "The National Institutes of Health has recognized the importance of expanding the study of gastroenterology into neurology with a 60 percent increase in the funding of this area since 1987," observes Freston. He is referring specifically to funding in the neuroendocrinology program area within the digestive diseases program branch of the National Institute of Digestive and Kidney Diseases. Funding here increased from $7,059,536 in 1987 to $11,330,189 in 1995. This is for extramural research on basic and clinical studies on the ENS and its controls in the central nervous system, according to Frank A. Hamilton, chief of the branch. Funding also comes from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

Also supporting the field are patient-oriented groups such as the Miami-based National Parkinson Foundation and the New York-based Crohnís and Colitis Foundation of America Inc. Industrial funding comes from a long list of companies, including giant firms like Nutley, N.J.-based Hoffmann-La Roche Inc.; Philadelphia based SmithKline Beecham; and Procter and Gamble Co. in Cincinnati.

Like many biomedical sciences, neurogastroenterology adds a molecular slant to basic knowledge of anatomy and physiology. And the idea of a separate nervous system in the gut isnít new. "People in the 1800s thought that the digestive tract could go along on its own, with motility, contraction, and secretion all controlled right there," says T. Richard Houpt, a professor of physiology at Cornell Universityís College of Veterinary Medicine. "People knew the nerves were there, but doubted how independent was their control of digestion."

Early evidence for enteric nerves came from Hirschsprung disease, a disorder characterized by congenital, severe constipation and a distended abdomen, once lethal in children. In 1948, researchers discovered the anatomical basis for the condition and developed a surgical treatment.

"For many years, physicians didnít know the cause of the problem," says Aravinda Chakravarti, a professor of genetics at Case Western Reserve University School of Medicine. "Then, pathologists studying autopsies found that the large, distended areas werenít the portion where something was wrong. The distended portion dilates in reaction to whatís happening in the distal region of the colon, which doesnít have neurons," owing to genetic abnormalties.

The mutant genes that cause the disorder block migration of neurons to this portion of the digestive tract in the embryo. Without nerves, the distal colon cannot contract, causing constipation. Recent discoveries of genes that can cause disorder by Chakravarti and others may reveal its mechanism (M. Angrist et al., Nature Genetics, 4:351-6, 1993; S. Lyonnet, Nat. Gen., 4:346-50, 1993).

Complementing clinical conditions that fall into the realm of neurogastroenterology are anatomical studies using animal models. Renowned Russian physiologist Ivan Petrovich Pavlov, who noted that stimulating a dogís mouth causes its stomach to secrete acid, conducted some of the earliest basic research on the ENS in the late 1800s. At the turn of the century, English physiologists Ernest Starling and Sir William Bayliss, also working with dogs, further described the innervation of the digestive tract (W.M. Bayliss, E.H. Starling, Journal of Physiology, 28:325-53, 1902).

After Bayliss and Starling demonstrated the function of the ENS in dogs, others began identifying the transmitters that chemically connect its neurons in a variety of organisms. In the 1920s, according to Gershon, the idea that the autonomic (involuntary) nervous system had just two transmittersñacetylcholine and norepinephrineñwas popular. In the 1960s, Gershon changed that picture by tracking serotonin, a transmitter abundant in the brain but not known to be present in the gut. "The trail of serotonin led to the bowel, where more than 95 percent of the bodyís serotonin is located," he says. "It became clear that serotonin was an additional transmitter here."

Gershon published his findings, which he considers his key contribution (M.D. Gershon, A.D. Drakontides, L.L. Ross, Science, 149:197-9, 1965; M. Gershon, L.L. Ross, J. Physiol., 186:451-76, 477-92, 1966), but was disappointed in their reception. "My thought that serotonin might be a [gastrointestinal] transmitter here was greeted with howls of derision by my colleages," he recalls, adding that it was thought to be "immoral" to suggest that a third transmitter controlled gut function. "But looking at serotonin, I kept rediscovering Bayliss and Starling, who were correct in saying that the gut could mediate reflexes without input from the brain and spinal cord."

Once Bershon identified serotonin in the gut, reserachers began using immunocytochemistry to highlight and identify gut neurons by the specific molecules that they produce and bind. "In the late 1980s, neural tracers were developed, and their ability to identify particular neurons is what realy pushed the field forward," comments Terry Powley, a professor of psychological sciences and neurosciences at Purdue University. Gershon adds: "Transmitters, growth factors, and lots of peptides known in the brain were also found in the gut. The idea that there is a little brain in the gut began to be accepted."

The neurons and glia (supportive cells) of the ENS are distributed into two groups, or plexuses. The myenteric plexus lies between the two muscular layers of the Gl wall, and the submucosal plexus is within the connective tissue layer beneath the mucous membrane that lines the inside of the tract. On a cellular level, the components of the ENS resemble those of the brain more than those of peripheral nerves, notes Gershon. "Most peripheral neurons are supported by Schwann cells, but enteric glia look like astrocytes," which are in the brain, he adds.

At first investigators saw only a few axons approaching the GI tract, so they assumed there wasnít much neural tissue. "We found that axons, once in the gastrointestinal tract, ramify and branch and distribute in a way that no one anticipated," says Powley. He uses confocal microscopy to trace enteric nerves, and reported his work at last fallís Society for Neuroscience meeting.

The "little brain in the gut," it turns out, is not so little. "The mammalian small intestine has 100 million neurons, the same number as in the spinal cord," says Camilleri. "If you add the number in the stomach, esophagus, and colon, there are more neurons in the ENS than in the spine," Gershon points out.

The systemís size may explain its evolution. "Some people speculate that the enteric nervous system evolved because there was no room in the skull for the brain to accommodate this regulatory system," reports Emeran Mayer, a professor of medicine and physiology at the University of California, Los Angeles, School of Medicine. "So nature decided to put it between the layers of the gut."

To spot evolutionary trends, life scientists look to modern species of increasing complexity. While animals simpler than vertebrates have guts that move, they lack their own nerve supply. Truly enteric nerves first appear in amphioxus, an ancestral vertebrate, in a single plexus with a few neurotransmitters. Mammals have two plexuses and more transmitter types. "As the gut acquired functions, neural controls seem to have been peripheralized," says Gershon. "As the CNS became more complex, so did the enteric nervous system. The ENS is not just a brain leftover; it evolved in parallel with the upstairs brain."

Much current molecular research on the ENS has direct clinical applications. For example, identifying ENS-specific serotonin receptors relieves nausea from chemotherapy. "In the past, medications were given that put the vomiting center in the brain to sleep, but this also put the whole patient to sleep," remarks Camilleri. "Now we use serotonin type 3 antagonists, which appear to have a specific role in suppressing conducting messages from stomach to brain."

AIDS research also considers the ENS. Peter Anton, an assistant professor of medicine at the UCLA School of Medicine, studies substance P, a neuropeptide that binds to T cells and, possibly, mast cells, and contributes to inflammatory bowel disease and HIV-related diarrhea. "Non-HIV diarrhea is usually due to a single factor," explains Anton. "In HIV infection, it is several things, such as infections and drugs. It is also a neuroenteric disorder." Understanding how malfunctioning gut nerves contribute to HIV-related diarrhea could suggest new treatment approaches.

Another molecule receiving much research attention is the tiny neurotransmitter nitric oxide (NO). NO is responsible for peristalsis, the rhythmic contractions that propel food along the GI tract (S.Y. Yuan et al., British Journal of Pharmacology, 114:428-32, 1995). Researchers track NO by using histochemical reaction that produces a blue color when NO synthase, the enzyme required to produce NO, is present. Such studies reveal lack of NO in Hirschsprung disease (R. Tomita et al., Journal of Pediatric Surgery, 30[3]:437-40, 1995) and in pyloric stenosis, a blockage in the exit to the stomach caused by faulty innervation of circular muscle (E. Chung, American Journal of Human Genetics, 58:363-70, 1996).

Now that the biochemical players in the ENS have been identified, future research will continue to apply discoveries to find new ways to treat disorders of the gastrointestinal tract. Comments Freston: "The study of what has recently come to be known as neurogastroenterology holds untold possibilities for discovering and treating numerous ëmind-gutí disorders and reducing or eliminating the effects of neuro-GI drug interactions."

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