Researchers identify molecular alterations in patients with irritable bowel syndrome

October 13, 2003

BALTIMORE, Md. - Novel research shows that alterations in serotonin signaling in the gastrointestinal (GI) tract are present in patients with Irritable Bowel Syndrome (IBS). These data shed light on the alterations in gut motility, secretion, sensation, as well as the clinical manifestations of IBS, which include abdominal discomfort, pain, bloating, constipation and/or diarrhea.

The study findings were presented today by two lead investigators from the University of Vermont, Peter Moses, M.D., Associate Professor of Medicine and Director of Clinical Research in the Digestive Diseases, and Gary Mawe, Ph.D., Professor of Anatomy and Neurobiology, in an oral presentation during the plenary session at the 68th Annual Scientific Meeting of the American College of Gastroenterology in Baltimore.

"Serotonin is a critical signaling molecule necessary for normal gut function - when released, it causes gut motility and secretion, and triggers signals to the brain and spinal cord," said Moses. "Our finding that key elements of serotonin signaling are changed in IBS lends credibility to the notion that IBS is not simply a psychological or social disorder as was once thought, but instead due to altered gut biochemistry and interactions between the gut and the brain."

Serotonin (5-HT) is a naturally occurring neurotransmitter and signaling molecule. Ninety-five percent of all serotonin is localized in the GI tract where it plays a key role in the motor, sensory and secretory functions of the gut. For some time, scientists have suspected that alterations in serotonin may contribute to abnormal conditions in the GI tract.

"Now we have a perspective on molecular changes in the intestines of individuals with IBS that we did not have before," said Mawe. "We identified a significant decrease in the serotonin transporter in cells that form the inner lining of the bowel - the same serotonin transporter that is located in cells in the brain. In the gut, this transporter acts as a sponge to remove serotonin once it is released, and therefore stops its actions. Because the transporter is diminished in IBS, serotonin stays around longer, and this can lead to changes in motility, secretion and sensitivity."

The study examined tissue obtained from 43 healthy controls and 32 patients with IBS and 22 patients with inflammatory bowel disease (IBD). IBS patients were defined strictly using ROME II criteria. Each biopsy was evaluated by five parameters: immunohistochemical staining, histological assessment, serotonin content, serotonin release and the measurement of mRNA encoding. The study also examined the molecular components of serotonin signaling, including the serotonin re-uptake system.

Specifically, the investigators measured serotonin content, the endocrine cell number, serotonin release and presence of serotonin transporters (SERT). Serotonin transporters are regulatory molecules that control the activity of serotonin within nerve endings in the GI tract to coordinate motility, visceral sensitivity and intestinal secretion.

In patients with IBS, the study found a significant decrease in serotonin content and significantly higher endocrine cell (EC) populations in patients with IBS compared to controls, while the release of serotonin from EC cells was not significantly different. In terms of the way the body inactivates serotonin signaling, or the serotonin re-uptake system, SERT mRNA and SERT immunoreactivity were markedly reduced. This reduction led to a decrease in the capacity to remove serotonin from intracellular space once it was released, thus increasing serotonin availability.
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The study was sponsored through a research grant from Novartis Pharmaceuticals, maker of Zelnorm® (tegaserod maleate) for IBS-C. In addition to Moses and Mawe, members of the study team included Matthew Coates, Christine Mahoney, David Linden, Joanna Sampson and Eric Newton of the University of Vermont; Michael Gershon and Jason Chen of the Department of Anatomy and Cell Biology at Columbia University; Keith Sharkey of the Department of Physiology and Biophysics at the University of Calgary, and Michael Crowell of the Clinical Research department at Novartis Pharmaceuticals.

University of Vermont

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