Irritable bowl syndrome, or IBS, affects a rather large swath of the population in developed countries - estimates range from 10 million to 45 million people in the U.S. - and causes health care costs that exceed $25 billion annually.

But for all that, its mechanisms have been hard to pin down. As a paper published online by the Journal of Clinical Investigation Feb. 15, 2007, puts it, to date there is "an apparent absence of findings supporting an organic basis." Despite the fact that IBS is so common, "there are no biochemical, histopathological or diagnostic imaging criteria yet characterized that define the syndrome," the authors wrote.

Senior author Nathalie Vergnolle, associate professor at the University of Calgary in Alberta, Canada, told BioWorld Today that's partly because there are different forms of the disease. So while disease mechanisms for subgroups of patients have been discovered, she said that "no really common mediators have been found" to date.

Vergnolle and her team, though, have identified such a general mediator for the visceral pain that is part of IBS: proteases.

They focused on proteases, which cause pain in animal models of IBS. They first tested the protease activity of tissue biopsies from irritable bowel syndrome and irritable bowel disease, and found that they had higher proteolytic activity than those of controls. That proteolytic activity could be reversed by adding an NF-kappa B inhibitor. The samples had higher-than-normal levels of trypsin and tryptase.

When Vergnolle and her colleagues searched for the source of those enzymes, the usual suspect looked innocent at first. Mast cell levels, which are a major source of tryptase, were not elevated. However, Vergnolle noted that they still could be secreting more tryptase.

Another possibility that her team currently is investigating is whether the serine proteases are produced directly by the gut epithelium.

When supernatants of IBS patients were administered to mice, the animals showed both a decreased pain threshold and increased pain sensitivity. That is, stimulation that was not painful in controls was painful in the experimental group, and painful stimuli were more painful for animals that received IBS patient supernatants than for controls.

Mechanistically, those effects depended on the activation of proteinase-activated receptor 2 or PAR2-type receptors on sensory neurons of the bowel. PAR-2 receptors are G-protein coupled receptors that signal in response to proteinases - among them, mast-cell released tryptase.

There are currently two approved products for IBS: Zelnorm, by Basel, Switzerland-based Novartis AG, and Lotronex, by London-based GlaxoSmithKline plc.

Several biotechs also are working on additional drugs. PAR-2 antagonists are being targeted therapeutically, though currently not for IBS. Rockville, Md-based EntreMed Inc. is testing PAR-2 blockers in cancer and inflammatory disorders.

The results suggest that targeting serine proteases and/or PAR2 could be a way to treat the abdominal pain that is part of IBS.

Currently, "there is really no treatment for the pain," Vergnolle said. "You can treat the diarrhea, you can treat the constipation, but not the pain."