Molecular Defect Found for the First Time in IBS Patients
Wednesday June 9, 8:45 am ET
New Research Demonstrates that IBS is Not 'All in Your Head'
PHILADELPHIA, June 9 /PRNewswire/ -- New research published in the current issue of Gastroenterology identifies for the first time a molecular defect in the gastrointestinal (GI) tracts of patients with irritable bowel syndrome (IBS) that does not appear in those without the condition.
"IBS has long been classified as a purely psychosomatic condition," says GI expert Michael Gershon, M.D., professor and chairman, Department of Anatomy and Cell Biology, College of Physicians & Surgeons, Columbia University, New York. "Patients may have been treated solely for a condition that was supposedly 'all in their heads.' However, IBS is now associated with a very real abnormality in the gut and one that is as biochemical as any other."
Dr. Gershon, who collaborated on the research and authored "The Second Brain" about the independent operation of the gut by the enteric nervous system, says the discovery of a difference in the serotonin signaling function of the lining of the GI tract "should revolutionize the treatment of IBS."
The findings reinforce the critical role normal serotonin (5-HT) signaling plays in regulating GI function, pinpointing a difference in the way serotonin functions in certain cells lining the GI tract of IBS patients. This defect may underlie the clinical manifestations of IBS -- abdominal pain or discomfort, bloating, constipation and/or diarrhea -- that affect more than 40 million Americans.
Although serotonin generally is recognized as a chemical in the brain, only five percent of this naturally occurring neurotransmitter is found in the brain and central nervous system. The remaining 95 percent of serotonin resides in the cells lining the GI tract. In the gut, serotonin binds to 5-HT receptors on nerve cells, initiating intestinal movement. SERT (serotonin transporter), also found in cells lining the GI tract, initiate the uptake of serotonin by deactivating it when appropriate. Without this natural regulation, the mechanisms of digestion cannot function properly. In this study, patients with IBS were found to have decreased expression of SERT, which could lead to either over-stimulation of the gut (IBS with diarrhea) or receptor desensitization (IBS with constipation or IBS-C).
IBS is a common GI disorder affecting 15 to 20 percent of the U.S. population. It is a leading cause of workplace absenteeism, second only to the common cold, and costs the U.S. healthcare system an estimated $30 billion annually in direct and indirect costs. IBS is more prevalent in women, and patients spend approximately one out of every three days suffering with symptoms.
"The treatment of IBS has been extremely frustrating to physicians and patients alike," says Peter Moses, M.D., associate professor of Medicine and Director of Clinical Research in the Digestive Diseases, University of Vermont, and the study's co-lead investigator with Gary Mawe, Ph.D., professor of anatomy and neurobiology, University of Vermont. "We see our patients suffering. We know their problem is real. But until now, we have not been able to point to any specific physical difference in patients with IBS."
Dr. Gershon agrees, saying, "Functional diseases are a catch-all category for syndromes that cannot be explained by an anatomical or biochemical lesion. The definition of IBS as a 'functional disorder,' seems to imply that the problems experienced by IBS patients are somehow inferior to those with more 'serious' disorders, which are those associated with demonstrable anatomical or biochemical abnormalities. This is an unfair assessment, as the origins of IBS are clearly as biochemical as any other and its patients are equally deserving of compassion and the best treatment options available."
The research findings represent a major step forward into understanding the cause of chronic disorders of the gut, including IBS, according to the scientists. Dr. Moses says, "Six or seven new studies have been undertaken since we originally presented our research at the American College of Gastroenterology conference less than a year ago. In fact, even before our research started, new treatments that specifically address altered serotonin signaling were discovered, tested in clinical trials and approved for marketing. It is not uncommon to find drugs that work before knowing specifically how they address pathological conditions in the body."
Study Methods
The study examined tissue obtained from 43 healthy controls, 32 patients with IBS and 22 patients with inflammatory bowel disease (IBD). IBS patients were defined strictly using ROME II diagnostic 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). These regulatory molecules control the activity of serotonin within nerve endings in the GI tract to coordinate motility, visceral sensitivity and intestinal secretion.
Study Findings
In patients with both IBS and ulcerative colitis, the study found a significant decrease in serotonin content while the release of serotonin from endocrine (EC) cells was not significantly different compared to controls. In terms of the way the body inactivates serotonin signaling, or the serotonin re-uptake system, SERT mRNA and SERT immunoreactivity were markedly reduced in both patient populations compared to controls. This reduction is expected to decrease the capacity of epithelial cells to remove serotonin from intercellular space once it is released, thus increasing serotonin availability and ultimately causing abnormal bowel function.
"Now we have a perspective on molecular changes in the intestines of individuals with IBS that we did not have before. This is the first time we have been able to detect a sign of alterations in serotonin signaling in human subjects, and the data are very encouraging," said co-lead investigator Gary Mawe, Ph.D., professor of anatomy and neurobiology, University of Vermont.
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