# Molecular Defect Found for the First Time in IBS Patients



## Jeffrey Roberts

Press Release Source: Novartis Molecular Defect Found for the First Time in IBS PatientsWednesday 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 MethodsThe 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 FindingsIn 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.The study was sponsored through a research grant from Novartis Pharmaceuticals Corporation, marketers of Zelnormï¿½ (tegaserod maleate) for IBS with constipation. 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 Mayo Clinic, Scottsdale, Arizona.About ZelnormZelnorm is the first agent proven to provide women with relief from all three symptoms of IBS-C -- abdominal discomfort or pain, bloating and constipation, and it is the first in a novel class of drugs that act as an agonist at 5-HT4 (serotonin type 4) receptors. Zelnorm is indicated for the short-term treatment of women with IBS whose primary bowel symptom is constipation. The safety and effectiveness of Zelnorm in men have not been established.In patients with IBS-C, Zelnorm has been shown to restore effectively deficient serotonin signaling by activating 5-HT4 receptors to increase GI motility in the gut. Zelnorm mimics the natural effects of serotonin, strengthening transmission in critical neural pathways, which normalizes impaired motility in the GI tract, inhibits visceral sensitivity (pain perception) and stimulates intestinal secretion of salts and water necessary in normal bowel function.In IBS-C clinical trials, tolerability to Zelnorm was similar to placebo. The only adverse events reported significantly more often with Zelnorm than with placebo were headache (15 vs. 12 percent) and diarrhea (nine vs. four percent). The majority of patients reporting diarrhea had a single episode and in most cases, diarrhea occurred in the first week of treatment. Typically, diarrhea resolved with continued therapy. Serious consequences of diarrhea, including hypovolemia, hypotension, and syncope, have been reported in clinical studies (0.04 percent) and during marketed use of Zelnorm. In some cases, these complications have required hospitalization for rehydration.Zelnorm was developed by Novartis, and is known internationally as Zelmac. It is approved in more than 55 countries for IBS-C. Approximately three million patients worldwide have been treated with Zelnorm for IBS-C. Zelnorm also is approved for use in chronic constipation in Mexico and Latin America. Zelnorm currently is being reviewed by the U.S. Food and Drug Administration for potential use in treating chronic constipation, and it is being studied as a potential treatment for other important GI disorders, including gastroesophageal reflux disease (GERD) and dyspepsia.About Rome CriteriaRome II is a classification system for all functional GI disorders agreed on by a multinational committee of specialists. The criteria defines IBS as at least 12 weeks or more, which need not be consecutive, in the preceding 12 months, of abdominal discomfort or pain that has two out of three features: symptoms relieved by defecation; onset of symptoms associated with a change in frequency of stool; the onset of symptoms associated with a change in stool consistency.Forward-looking StatementThis release contains certain forward-looking statements relating to the Company's business, which can be identified by the use of forward-looking terminology such as "may," "encouraging," "potential," or similar expressions, or by discussions of strategy, plans or intentions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Zelnorm to be materially different from any future results, performance or achievements expressed or implied by such statements. Specifically, there are no guarantees that the data described above will result in the commercial success of Zelnorm. Any such success can be affected by, among other things, uncertainties relating to product development, future clinical trial results, adverse regulatory actions or delays, government regulation generally, the ability to obtain or maintain patent or other proprietary intellectual property protection, competition in general and other risks and factors referred to in the Company's current Form 20-F on file with the Securities and Exchange Commission of the United States.About NovartisNovartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is to improve people's lives by pioneering novel healthcare solutions.Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS - News), a world leader in pharmaceuticals and consumer health. In 2003, the Novartis Group's businesses achieved sales of USD 24.9 billion and a net income of USD 5.0 billion. The Group invested approximately USD 3.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 78,500 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com . Contacts: Carrie Callahan Kevin Bannon Novartis Pharmaceuticals Corp. Ruder Finn (862) 778-7065 (212) 715-1621 carrie.callahan###pharma.novartis.com bannonk###ruderfinn.com John McInerney Ruder Finn (516) 606-3516 mcinerneyj###ruderfinn.com--------------------------------------------------------------------------------Source: Novartis


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## DivaMom

Fantastic news. I feel more hopeful than I have in months.


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## auntyjay64

I always seem to read about IBS - C and IBS - D in all these studies, but I have been diagnosed with IBS - A, do you know of any medical papers written up about IBS - A? It would sure help, I've lost 36 pounds in 3 months and my doctor has put me on Modulon.


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## Jeffrey Roberts

IBS-A is tough, as there is is nothing directly for it at this time. I believe that a new class of medications which target the brain-gut axis from the brain side, will be more helpful for you.I would think that these would be entering phase II clinical studies soon.Jeff


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## john maher

Jeff,This is wonderful news.I have severe IBS D. What does this research mean in practical terms? Can we expect to see Seratonin related products that work for both men and women with IBS D any time soon? Remus


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## poet

lotronex seems to work for many men as well as women.tom


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## davidgee

Never doubted this was the case for a second.Thanks,Jeff.


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## RPMGINA

I have suffered with IBS-D for over 35 years! HELP please. I have tried everything. Except the lotronex which I doubt any doctor in ME has the authority to use. And would even KNOW about it!I just use Imodium EVERY single day of my life! Prayers to you all.. gina


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## auntyjay64

Hi Gina,Have you talked to your doctor about Modulon? It really helped me with my Diarreah, it slows down your digestive system. Hope this helps.


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## kazzy3

I agree there should be something for those of us with type A. I worry that the meds that are available will make things worse. If you are type A you don't want C or D. There are many of us with alternating c and d, therefore they should come up with something to help us too.


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## dusty61

I`m glad I found this site. My wife suffers from IBS-D we think. Her Dr treated her for the stress realated IBS and she was in the hospital for a couple weeks. He has offered no real meds to control IBS other than an anti depressant. What have ppl found for meds that help control IBS-D?? She going through a bad run as I type.. Please Help


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## SpAsMaN*

Dusty,i know activated charcoal slow and form the stool.Lets see if that can work for her.But for IBS-C it dosen't seems to really help.


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## Guest

I went online, got the prescribing physicians information from the Lotronex site, took it to my doctor and talked to him about the 30 years I have dealt with IBS-D. He did the registration procedures, and I have been on Lotronex for 3 months now. I am as a newborn baby.I am able to travel, shop, walk around in the neighborhood, go to movies and sit in the middle... can you imagine?I still have anxiety, from years of habit and worry, but that is getting better too.Your doctor can get Lotronex.


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## Gerbil623

I have suffered with IBS-D for over 15 years now. I am feeling so tired and frustrated, I am looking for a recommendation to a DR in Maine, NH or Mass that specializes in this and will not make me feel like I am wasting their time and should be seeing a psychiatrist. I have been on several mediciations and have had little relief. Several hospital admissions and have been on pain meds for the past 1 1/2 months. Now waiting to see a Gyne to see if endometriosis is back (had total hysterectamy) and adding to it. Please help!


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## SpAsMaN*

Products who should form stools and slow the things:-Questran-Activated Charcoal-Glutamic acid-Rice-Bananas-Opium tincture or Immdium or OpioidsSee all the gastroenterologist in your area,one must be good.


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## SpAsMaN*

Finally there is Lotronex and few others drug.A psychyatrist will probably be unhelpful unfortunaly.The all in the head theory is sooo ridiculous.


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## Gerbil623

I have tried bentyl, immodium (daily), lomotil, etc.. Have had a little help from some but not enough that is for sure. Local GI doctors are the ones who recommended psychiatrist. Just diagnosed with diverticulosis from CT scan this week. I have just gathered the info on Lotronex and will be bringing it to my primary dr.Have been on BRAT diet (bananas, rice, applesauce & toast) off and on for years now. I will be checking into the other med you listed.Thanks again


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## Guest

I guess what I am trying to say is,don't troll for Doctors already registered to prescribe Lotronex, because there are very few of them out there. Instead, go to the Lotronex site, and do the work for them. Print out the information and the physicians registration form, and have it with you when you go to see a doctor. Be ready with the latest articles on the seratonin findings, too.They can't tell you you are imagining this anymore, or you can tell them that they aren't up with current medical understanding.OK, so if you have done the pre-registration work for them, they may be inclined to follow through for you. I am very happy with my doctor for doing this for me, and I can't tell you what good relief I have gotten.I am feeling like I may have a life ahead of me.Don't give up.


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## eric

FYIFYIAliment Pharmacol Ther. 2004 Nov;20 Suppl 7:3-14. Related Articles, Links Review article: serotonin receptors and transporters - roles in normal and abnormal gastrointestinal motility.Gershon MD.Department of Anatomy & Cell Biology, Columbia University, New York, NY, USA.Summary The gut is the only organ that can display reflexes and integrative neuronal activity even when isolated from the central nervous system. This activity can be triggered by luminal stimuli that are detected by nerves via epithelial intermediation. Epithelial enterochromaffin cells act as sensory transducers that activate the mucosal processes of both intrinsic and extrinsic primary afferent neurones through their release of 5-hydroxytryptamine (5-HT). Intrinsic primary afferent neurones are present in both the submucosal and myenteric plexuses. Peristaltic and secretory reflexes are initiated by submucosal intrinsic primary afferent neurones, which are stimulated by 5-HT acting at 5-HT(1P) receptors. 5-HT acting at 5-HT(4) receptors enhances the release of transmitters from their terminals and from other terminals in prokinetic reflex pathways. Signalling to the central nervous system is predominantly 5-HT(3) mediated, although serotonergic transmission within the enteric nervous system and the activation of myenteric intrinsic primary afferent neurones are also 5-HT(3) mediated. The differential distribution of 5-HT receptor subtypes makes it possible to use 5-HT(3) antagonists and 5-HT(4) agonists to treat intestinal discomfort and motility. 5-HT(3) antagonists alleviate the nausea and vomiting associated with cancer chemotherapy and the discomfort from the bowel in irritable bowel syndrome; however, because 5-HT-mediated fast neurotransmission within the enteric nervous system and the stimulation of mucosal processes of myenteric intrinsic primary afferent neurones are 5-HT(3) mediated, 5-HT(3) antagonists tend to be constipating and should be used only when pre-existing constipation is not a significant component of the problem to be treated. In contrast, 5-HT(4) agonists, such as tegaserod, are safe and effective in the treatment of irritable bowel syndrome with constipation and chronic constipation. They do not stimulate nociceptive extrinsic nerves nor initiate peristaltic and secretory reflexes. Instead, they rely on natural stimuli to activate reflexes, which they strengthen by enhancing the release of transmitters in prokinetic pathways. Finally, when all the signalling by 5-HT is over, its action is terminated by uptake into enterocytes or neurones, which is mediated by the serotonin reuptake transporter. In inflammation, serotonergic signalling is specifically diminished in the mucosa. Transcripts encoding tryptophan hydroxylase-1 and serotonin reuptake transporter are both markedly decreased. Successive potentiation of 5-HT and/or desensitization of its receptor could account for the symptoms seen in diarrhoea-predominant and constipation-predominant irritable bowel syndrome, respectively. Symptoms associated with the down-regulation of the serotonin reuptake transporter in the human mucosa in irritable bowel syndrome are similar to the symptoms associated with the knockout of the serotonin reuptake transporter in mice. The observation that molecular defects occur in the human gut in irritable bowel syndrome strengthens the hand of those seeking to legitimize the disease. At least it is not 'all in your head'. The bowel contributes.PMID: 15521849


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## Guest

Yup. Thank you.


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## bwrhit

Although I probably have had IBS for over 30 years, diagnosis is new. At the present, I am taking dicyclomine and Metamucil as well as acidophilus supplements for symptoms. Things are better but not good. Any thoughts?Beth


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## bwrhit

Am I on? Anyone out there?


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## Kathleen M.

Your posts are showing up, but this is not a chat room, just a bulliten board.Under the post buttons is the link to the chat room. Sometimes people are there even when there is not a scheduled chat.K.


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## sarahzzz

I've had IBS-D for about 6 years and have found the following stuff useful...Ispaghula Husk - in a powdered drink called "Fybergel" or "Senacot".Peppermint Tea.Porridge (rolled oats with hot milk or water).Plain sponge cake made with eggs, flour, sugar etc.All help reduce symptoms and make me feel better. Particularly eating cake!


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## NZChick

Hi, Could someone please tell me what ibs type "A" is? Thanks.


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## Nath

Alternating between D and C


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