Irritable Bowel Syndrome Message Boards | UVM Researchers Identify Molecular Changes in IBS Patients

Shana, I understand what your saying however this doesn't have to do with the drugs, it is confirmed in other avenues and there is a huge body of research on it.

Also there are reasons why that drug might not have worked for you personally.

The two systems in major research that seem to be important in IBS research right now are the serotonin system and the HPA axis.

For example on serotonin and IBS,

From Medscape Gastroenterology

MEDLINE Abstracts: Serotonin Signaling and Visceral Hypersensitivity in IBS
Posted 10/23/2003

What's new concerning the role of serotonin signaling and mechanisms of visceral hypersensitivity in the pathophysiology of irritable bowel syndrome IBS? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Gastroenterology.

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Serotonin and Its Implication for the Management of Irritable Bowel Syndrome
Gershon MD
Rev Gastroenterol Disord. 2003;3suppl 2:S25-S34

Our understanding of the enteric nervous system ENS has evolved from the "classical" view, in which the brain controls all enteric behavior, to the current view, which holds that enteric innervation is one of local control within the bowel, modified by a bidirectional "dialogue" with the brain. The ENS independently controls enteric reflexes through intrinsic primary afferent neurons, which monitor intraluminal conditions. This monitoring is accomplished through the use of enteroendocrine cells in the mucosa, the best known of which are the serotonin-containing enterochromaffin cells. This article describes the roles that serotonin, specific serotonin-receptor subtypes, and the serotonin reuptake transporter play in the ENS and in the communication between the ENS and central nervous system. The way in which these findings have implicated serotonin in irritable bowel syndrome is discussed.

Systematic Review: Serotonergic Modulators in the Treatment of Irritable Bowel Syndrome--Influence on Psychiatric and Gastrointestinal Symptoms
Kilkens TO, Honig A, Rozendaal N, Van Nieuwenhoven MA, Brummer RJ
Aliment Pharmacol Ther. 2003 ;17:43-51

Background: Both central and peripheral serotonergic modulators are used in the treatment of irritable bowel syndrome. The majority of patients with irritable bowel syndrome presenting to a gastroenterologist demonstrate affective dysregulation. Serotonin may play a regulatory role in both gastrointestinal motility and sensitivity, as well as in affective dysregulation, in irritable bowel syndrome.
Aim: To analyse, systematically, randomized controlled trials studying the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome, in order to elucidate baseline irritable bowel syndrome symptomatology and possible differential effects of serotonergic modulation on this symptomatology.
Methods: A standardized qualitative analysis was performed of studies investigating the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome using a blind review approach. The studies were ranked according to their total quality score maximum 100 points.
Results: Eleven studies fulfilled the entry criteria, six of which scored above 55 points. An association between gastroenterological and psychiatric changes was present in five of the six studies.
Conclusions: The results strengthen the serotonergic association between gastroenterological and psychiatric symptoms. Adjusted guidelines for combined gastrointestinal and psychiatric assessments are recommended in order to further elucidate the serotonergic interaction between gastrointestinal and psychiatric symptoms.

Tegaserod and Other Serotonergic Agents: What Is the Evidence?
Chey WD
Rev Gastroenterol Disord. 2003;3suppl 2:S35-S40

Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin 5-HT plays a key role in the pathogenesis of irritable bowel syndrome IBS. In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.

Sex Differences of Brain Serotonin Synthesis in Patients With Irritable Bowel Syndrome Using Alpha-11CMethyl-L-Tryptophan, Positron Emission Tomography and Statistical Parametric Mapping
Nakai A, Kumakura Y, Boivin M, et al
Can J Gastroenterol. 2003;17:191-196

Background: Irritable bowel syndrome IBS is the most common functional bowel disorder and has a strong predominance in women. Recent data suggest that the brain may play an important role in the pathophysiology of IBS in the brain-gut axis. It is strongly suspected that serotonin 5-HT, a neurotransmitter found in the brain and gut, may be related to the pathophysiology of IBS. It is reported that a 5-HT3 antagonist is effective only in female patients with diarrhea-predominant IBS.
Objective: In the present study, 5-HT synthesis was measured using positron emission tomography, with alpha-11Cmethyl-L-tryptophan as the tracer, in patients with IBS. The aim of the present study was to compare 5-HT synthesis in the IBS patients with that in the controls, and to compare 5-HT synthesis between male and female IBS patients.
Methods: Six male and six female nonconstipated IBS patients were scanned. Age-matched healthy volunteers were scanned as controls. Eighty minute dynamic scans were performed. Functional 5-HT synthesis images were analyzed using statistical parametric mapping.
Results: 5-HT synthesis was greater only in the female IBS patients in the right medial temporal gyrus multimodal sensory association cortex compared with the female controls P<0.001.
Conclusions: The greater brain 5-HT synthesis in the female IBS patients than in the controls may be related to the pathological visceral pain processing of the IBS patients, a larger female predominance of the disorder, and the sex difference of the efficacy of the 5-HT3 antagonist in treatment.

Sex-Related Differences in IBS Patients: Central Processing of Visceral Stimuli
Naliboff BD, Berman S, Chang L, et al
Gastroenterology. 2003;124:1738-1747

Background & Aims: Women have a higher prevalence of irritable bowel syndrome IBS and possible differences in response to treatment, suggesting sex-related differences in underlying pathophysiology. The aim of this study was to determine possible sex-related differences in brain responses to a visceral and a psychological stressor in IBS.
Methods: Regional cerebral blood flow measurements using H 2 15 O positron emission tomography were compared across 23 female and 19 male nonconstipated patients with IBS during a visceral stimulus moderate rectal inflation and a psychological stimulus anticipation of a visceral stimulus.
Results: In response to the visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cortex, and left amygdala, whereas men showed greater activation of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Similar differences were observed during the anticipation condition. Men also reported higher arousal and lower fatigue.
Conclusions: Male and female patients with IBS differ in activation of brain networks concerned with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli.

Functional Brain Imaging in Irritable Bowel Syndrome With Rectal Balloon-Distention by Using fMRI
Yuan YZ, Tao RJ, Xu B, et al
World J Gastroenterol. 2003;9:1356-1360

Aim: Irritable bowel syndrome IBS is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the effect of rectal balloon-distention stimulus by blood oxygenation level-dependent functional magnetic resonance imaging BOLD-fMRI in visceral pain center and to compare the distribution, extent, and intensity of activated areas between IBS patients and normal controls.
Methods: Twenty-six patients with IBS and eleven normal controls were tested for rectal sensation, and the subjective pain intensity at 90 ml and 120 ml rectal balloon-distention was reported by using Visual Analogue Scale. Then, BOLD-fMRI was performed at 30 ml, 60 ml, 90 ml, and 120 ml rectal balloon-distention in all subjects.
Results: Rectal distention stimulation increased the activity of anterior cingulate cortex 35/37, insular cortex 37/37, prefrontal cortex 37/37, and thalamus 35/37 in most cases. At 120 ml of rectal balloon-distention, the activation area and percentage change in MR signal intensity of the regions of interest ROI at IC, PFC, and THAL were significantly greater in patients with IBS than that in controls. Score of pain sensation at 90 ml and 120 ml rectal balloon-distention was significantly higher in patients with IBS than that in controls.
Conclusion: Using fMRI, some patients with IBS can be detected having visceral hypersensitivity in response to painful rectal balloon-distention. fMRI is an objective brain imaging technique to measure the change in regional cerebral activation more precisely. In this study, IC and PFC of the IBS patients were the major loci of the CNS processing of visceral perception.

Role of Visceral Sensitivity in the Pathophysiology of Irritable Bowel Syndrome
Delvaux M
Gut. 2002;51 suppl 1:i67-i71

Visceral hypersensitivity has been recognised as a characteristic of patients with irritable bowel syndrome IBS. It may be involved in the pathogenesis of abdominal pain/discomfort, and seems to result from the sensitisation of nerve afferent pathways originating from the gastrointestinal tract. From a clinical point of view, hypersensitivity, although frequent, is not a constant finding among patients with IBS and cannot therefore be considered as a diagnostic marker of the condition. The advances made in understanding visceral hypersensitivity in patients with IBS are reviewed: the factors that influence abdominal distension are defined and different therapeutic perspectives are examined.

www.medscape.com/viewarti...02/7001/-1

This is from above and is very important to IBS.

"Both central and peripheral serotonergic modulators are used in the treatment of irritable bowel syndrome. The majority of patients with irritable bowel syndrome presenting to a gastroenterologist demonstrate affective dysregulation. Serotonin may play a regulatory role in both gastrointestinal motility and sensitivity, as well as in affective dysregulation, in irritable bowel syndrome."

Most people don't understand the complexities of how digestive works via sertonin or that the gut is lined with pressure sensitive cells. Here is some on that.

Ask The Expert
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Image of a cadeusus
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General Medical Questions
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Q: I have suffered from irritable-bowel syndrome for many years. I get diarrhea. The doctors I've seen have offered little help. Recently, my daughter suggested I try an over-the-counter medicine called "5-Hydroxy-tryptophan," made by a company called Natrol Inc. My daughter says it is a mild antidepressant. It seems to have helped quite a bit, but it also seems to slow me down and make me feel tired. Can you give me any information on this? What is it, exactly, and are there any serious side effects? The only other medicine I take is Synthroid.
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The Trusted Source
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Harold J. DeMonaco, M.S.

Harold J. DeMonaco, M.S., is senior analyst, Innovative Diagnostics and Therapeutics, and the chair of the Human Research Committee at the Massachusetts General Hospital. He is author of over 20 publications in the pharmacy and medical literature and routinely reviews manuscript submissions for eight medical journals.
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June 19, 2001
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A:

Irritable bowel syndrome is now recognized as a disorder of serotonin activity. Serotonin is a neurotransmitter in the brain that regulates sleep, mood (depression, anxiety), aggression, appetite, temperature, sexual behavior and pain sensation. Serotonin also acts as a neurotransmitter in the gastrointestinal tract.

Excessive serotonin activity in the gastrointestinal system (enteric nervous system) is thought to cause the diarrhea of irritable-bowel syndrome. The enteric nervous system detects bowel distension (expansion) on the basis of pressure-sensitive cells in the bowel lumen (opening). Once activated, these pressure-sensitive cells promote the release of serotonin, which in turn promotes both secretory function and peristaltic function (the contractions of the intestines that force the contents outward). At least four serotonergic receptors have been identified to be participants in the secretory and peristaltic response.

Patients with diarrhea-predominant IBS may have higher levels of serotonin after eating than do people without the disorder. This recognition led to the development of the first drug used specifically to treat diarrheal symptoms of IBS, alosetron (also known as Lotronex). Alosetron blocked the specific serotonin receptors responsible for recognizing bowel distention. In doing so, it blocked the effects of serotonin and reduced both bowel secretions and peristalsis. Constipation was the most common side effect seen. (Note: Alosetron was removed from the market by the manufacturer after repeated reports of a dangerous condition known as ischemic colitis became known.) Tegaserod (Zelmac) is another drug under development and under review by the U.S. Food and Drug Administration for approval. Tegaserod is indicated for the treatment of constipation-predominant IBS and works to increase enteric nervous system serotonin activity.

So, increasing serotonin activity in the enteric nervous system produces increased bowel secretions and peristalsis (and potentially diarrhea), whereas depressing serotonin activity produces reduced secretions and reduce peristalsis (and potentially constipation). Increasing serotonin activity in the brain would increase awareness and, in higher doses, produce anxiety, insomnia and restlessness. So I would have expected exactly the opposite effects of those that you experienced.

I am unable to identify any possible drug interactions between 5-HTP and Synthroid (levothyroxine) but the symptoms described suggest a check with your doctor may be in order. Persistent feelings of tiredness and constipation may be signs of an underactive thyroid (hypothyroidism).

June 19, 2001

This one is from Medscape and part of the above study.

"FYI

Pathophysiology
Altered Serotonin Signaling?
The pathogenesis of IBS remains obscure, and in particular, an explanation for alternating diarrhea and constipation has been elusive. In arguably one of the most important papers presented during this year's meeting, Moses and colleagues[21] studied potential deregulation of the gut's serotonin transporter in IBS.

It is known that serotonin (5-hydroxytryptamine or 5HT) is released from enteroendocrine (or enterochromaffin) cells in response to either chemical or mechanical stimulation of the gut mucosa. Serotonin in turn initiates peristalsis, and then the serotonin released is taken up in health by a highly selective serotonin transporter (SERT). One potential mechanism that could explain altered bowel function in IBS is an abnormality in the serotonin transporter itself. The study authors evaluated this hypothesis in patients with IBS with constipation and IBS with diarrhea compared with patients with ulcerative colitis and healthy controls. They were able to convincing show on blinded review that SERT immunoreactivity was less intense in patients with IBS with constipation and patients with ulcerative colitis.

If these findings are indeed correct, they represent a landmark observation. The findings suggest that patients with constipation and IBS may have a reduced capacity to reuptake serotonin, leading to excess free serotonin and then desensitization of these receptors, thus reducing motor function. In contrast, in the setting of diarrhea, serotonin uptake was normal. If the underlying abnormality in serotonin transporter function alternated, then this would in turn explain alternating constipation and diarrhea.

These data strongly suggest that IBS is a "real" gut disease and a potential diagnostic disease marker. They also suggest that it is valid to subdivide IBS into constipation and diarrhea symptom subgroups. This study also provides additional rationale for the use of serotonin-modulating agents in IBS and provides a new target for drug modulation. Confirmation of these very exciting initial findings in larger patient samples is awaited with great interest."

Also you might want to read this.

Report on the 5th International Symposium on Functional Gastrointestinal Disorders
April 4, 2003 to April 7, 2003 Milwaukee, Wisconsin

http://www.iffgd.org/symposium2003report.html

For detailed info in video here you go.

Lecture: An Integrated Approach to the Pathophysiology of Irritable Bowel Syndrome
Presenter: Douglas Drossman, MD

http://www.conference-cast.com/ibs/Lecture/RIDs/RID_BuildLecture.cfm?LectureID=2

These are the rest of them.

http://www.conference-cast.com/ibs/Lecture/RIDs/RID_BuildRegLecture.cfm

I can tell you for sure and I have been studying IBS indepth for the last four years and have help from some of the worlds best researcher personally and have had IBS for over thirty years, there is a problem with serotonin regulation in IBS patients, regarless of the drug companies.

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My website on IBS is www.ibshealth.com

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on a more laymans level this is whats going on in IBS, although they still do not have all the answers yet and there are more specific subgroups as well as poeple with more then one condition, other then IBS.

with permission

Irritable Bowel Syndrome
What is an Irritable Bowel?
Medically, irritable bowel syndrome (IBS) is known by a variety of other terms: spastic colon, spastic colitis, mucous colitis and nervous or functional bowel. Usually, it is a disorder of the large intestine (colon), although other parts of the intestinal tract -- even up to the stomach -- can be affected.

The colon, the last five feet of the intestine, serves two functions in the body. First, it dehydrates and stores the stool so that, normally, a well-formed soft stool occurs. Second, it quietly propels the stool from the right side over to the rectum, storing it there until it can be evacuated. This movement occurs by rhythmic contractions of the colon.

When IBS occurs, the colon does not contract normally. instead, it seems to contract in a disorganized, at times violent, manner. The contractions may be terribly exaggerated and sustained, lasting for prolonged periods of time. One area of the colon may contract with no regard to another. At other times, there may be little bowel activity at all. These abnormal contractions result in changing bowel patterns with constipation being most common.

A second major feature of IBS is abdominal discomfort or pain. This may move around the abdomen rather than remain localized in one area.

These disorganized, exaggerated and painful contractions lead to certain problems. The pattern of bowel movements is often altered. Diarrhea may occur, especially after meals, as the entire colon contracts and moves liquid stool quickly into the rectum. Or, localized areas of the colon may remain contracted for a prolonged time. When this occurs, which often happens in the section of colon just above the rectum, the stool may be retained for a prolonged period and be squeezed into small pellets. Excessive water is removed from the stool and it becomes hard.

Also, air may accumulate behind these localized contractions, causing the bowel to swell. So bloating and abdominal distress may occur.

Some patients see gobs of mucous in the stool and become concerned. Mucous is a normal secretion of the bowel, although most of the time it cannot be seen. IBS patients sometimes produce large amounts of mucous, but this is not a serious problem.

The cause of most IBS symptoms -- diarrhea, constipation, bloating, and abdominal pain -- are due to this abnormal physiology.

IBS is not a disease
Although the symptoms of IBS may be severe, the disorder itself is not a serious one. There is no actual disease present in the colon. In fact, an operation performed on the abdomen would reveal a perfectly normal appearing bowel.

Rather, it is a problem of abnormal function. The condition usually begins in young people, usually below 40 and often in the teens. The symptoms may wax and wane, being particularly severe at some times and absent at others. Over the years, the symptoms tend to become less intense.

IBS is extremely common and is present in perhaps half the patients that see a specialist in gastroenterology. It tends to run in families. The disorder does not lead to cancer. Prolonged contractions of the colon, however, may lead to diverticulosis, a disorder in which balloon-like pockets push out from the bowel wall because of excessive, prolonged contractions.

Causes
While our knowledge is still incomplete about the function and malfunction of the large bowel, some facts are well-known. Certain foods, such as coffee, alcohol, spices, raw fruits, vegetables, and even milk, can cause the colon to malfunction. In these instances avoidance of these substances is the simplest treatment.

Infections, illnesses and even changes in the weather somehow can be associated with a flare-up in symptoms. So can the premenstrual cycle in the female.

By far, the most common factor associated with the symptoms of IBS are the interactions between the brain and the gut. The bowel has a rich supply of nerves that are in communication with the brain. Virtually everyone has had, at one time or another, some alteration in bowel function when under intense stress, such as before an important athletic event, school examination, or a family conflict.

People with IBS seem to have an overly sensitive bowel, and perhaps a super abundance of nerve impulses flowing to the gut, so that the ordinary stresses and strains of living somehow result in colon malfunction.

These exaggerated contractions can be demonstrated experimentally by placing pressure- sensing devices in the colon. Even at rest, with no obvious stress, the pressures tend to be higher than normal. With the routine interactions of daily living, these pressures tend to rise dramatically. When an emotionally charged situation is discussed, they can reach extreme levels not attained in people without IBS. These symptoms are due to real physiologic changes in the gut -- a gut that tends to be inherently overly sensitive, and one that overreacts to the stresses and strains of ordinary living.

Diagnosis
The diagnosis of IBS often can be suspected just by a review of the patient's medical history. In the end it is a diagnosis of exclusion; that is, other conditions of the bowel need to be ruled out before a firm diagnosis of IBS can be made.

A number of diseases of the gut, such as inflammation, cancer, and infection, can mimic some or all of the IBS symptoms. Certain medical tests are helpful in making this diagnosis, including blood, urine and stool exams, x-rays of the intestinal tract and a lighted tube exam of the lower intestine. This exam is called endoscopy, sigmoidoscopy or colonoscopy.

Additional tests often are required depending on the specific circumstances in each case. If the proper medical history is obtained and if other diseases are ruled out, a firm diagnosis of IBS then can usually be made.

Treatment
The treatment of IBS is directed to both the gut and the psyche. The diet requires review, with those foods that aggravate symptoms being avoided.

Current medical thinking about diet has changed a great deal in recent years. There is good evidence to suggest that, where tolerated, a high roughage and bran diet is helpful. This diet can result in larger, softer stools which seem to reduce the pressures generated in the colon.

Large amounts of beneficial fiber can be obtained by taking over-the-counter bulking agents such as psyllium mucilloid (Metamucil, Konsyl) or methylcellulose (Citrucel).

As many people have already discovered, the simple act of eating may, at times, activate the colon. This action is a normal reflex, although in IBS patients it tends to be exaggerated. It is sometimes helpful to eat smaller, more frequent meals to block this reflex.

There are certain medications that help the colon by relaxing the muscles in the wall of the colon, thereby reducing the bowel pressure. These drugs are called antispasmodics. Since stress and anxiety may play a role in these symptoms, it can at times be helpful to use a mild sedative, often in combination with an antispasmodic.

Physical exercise, too, is helpful. During exercise, the bowel typically quiets down. If exercise is used regularly and if physical fitness or conditioning develops, the bowel may tend to relax even during non-exercise periods. The invigorating effects of conditioning, of course, extend far beyond the intestine and can be recommended for general health maintenance.

As important as anything else in controlling IBS is learning stress reduction, or at least how to control the body's response to stress. It certainly is well-known that the brain can exert controlling effects over many organs in the body, including the intestine.

Summary
Patients with IBS can be assured that nothing serious is wrong with the bowel. Prevention and treatment may involve a simple change in certain daily habits, reduction of stressful situations, eating better and exercising regularly.

Perhaps the most important aspect of treatment is reassurance. For most patients, just knowing that there is nothing seriously wrong is the best treatment of all, especially if they can learn to deal with their symptoms on their own.

http://www.gicare.com/pated/ecdgs03.htm

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My website on IBS is www.ibshealth.com

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