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Could anyone scientifically techincal goobledygook speaker - translate this document into english please?
My gastro doctor is one of those involved in the research and I'd like to know what they are rambling about - as no doubt my bottom has probably been involved in his research at some point!Is it saying they are finding evidence that IBS may have an organic basis?Irritable Bowel Syndrome: Physiology and ManagementNicholas J. Talley, MD, PhD DisclosuresIntroduction The field of irritable bowel syndrome (IBS) appears to be entering a new and exciting phase; evidence that at least some aspects of this disorder represent an organic or neurologic bowel disease has firmed, and novel management approaches are currently under investigation.At this year's Digestive Diseases Week meeting, data on current and emerging pharmacologic interventions and psychologic therapies were presented. This report reviews and discusses some of this novel and topical information.Postinfectious IBS One of the most exciting areas in terms of new research in IBS relates to the potential role of infection, inflammation, and its therapy within the setting of this syndrome. Composition of Colonic Inflammatory Infiltrate On routine histology, colonic biopsies appear normal in IBS. Studies by Gwee and colleagues,[1] and Spiller and coworkers,[2] among others, have shown that in at least a subset of IBS patients, there is a quantifiable, albeit modest, increase in colonic inflammatory cells. Hollerbach and associates[3] prospectively evaluated 20 patients with IBS (disease diagnosis based on Rome II criteria) and 15 healthy controls. Following careful histologic evaluation with quantitative morphometry, the study authors observed that patients with IBS had significantly greater numbers of (1) plasma cells in the rectum and sigmoid colon; (2) goblet cells in the transverse, descending, and sigmoid colon (as well as in the rectum); and (3) mast cells in the terminal ileum, cecum, and appendix. In contrast, the number of eosinophils was decreased in IBS patients compared with controls at all anatomic locations. Although these findings represented subtle differences, they appear to be real, and confirm that a residual inflammatory process is indeed present in some patients with classic IBS symptoms. Clinical Subtyping Dunlop and colleagues[4] also evaluated 76 patients with IBS and 40 healthy controls, applying immunohistochemical staining for lamina propria and intraepithelial lymphocytes, enteroendocrine (serotonin-containing) cells, and mast cells. They subdivided their patients into 3 groups, those with: (1) postinfectious IBS; (2) constipation-predominant IBS; and, (3) nonconstipated, non-postinfectious IBS. These investigators found that cell counts in constipation-predominant IBS were not significantly different from that of controls. In contrast, patients with diarrhea, but without a postinfectious history, showed increased CD3 and lamina propria lymphocytes, in addition to mast cells, whereas patients with postinfectious IBS had increased enteroendocrine cells, CD3, and lamina propria lymphocytes. These findings suggest that subgrouping of IBS by bowel symptoms may identify distinct histomorphic phenotypes within IBS, which in turn suggests that treatment may need to be tailored to symptom subgroups.Mast Cells Park and colleagues[5] applied electron microscopy and found that mast cell counts were significantly higher in the cecum among patients with IBS, and that the number of activated mast cells close to nerves was increased in IBS patients vs controls. Similarly, Barbara and coworkers[6] employed immunofluorescence and found that tryptase-containing mast cells were increased 3-fold in IBS patients compared with controls. They also found evidence of mast cell degranulation. Therapeutic Intervention* In view of the increasing evidence of histologic abnormalities in IBS, and providing that this is indeed a true organic bowel disease, might intervention to reduce the inflammation have utility? If such intervention was able to prevent the development or progression of IBS, then this would be of major clinical importance. Prednisolone. Therefore, Dunlop and colleagues[4] conducted the first randomized, double-blind, placebo-controlled trial of prednisolone in postinfectious IBS. Three or more months after their initial infection, 31 patients with postinfectious IBS received either oral prednisolone at a dose of 30 mg per day or placebo for a period of 3 weeks. They found that CD3 counts fell significantly and similarly, following both treatment with placebo and prednisolone. Enteroendocrine cells did not significantly change. Similarly, neither crypt nor surface intraepithelial lymphocytes nor mast cell counts decreased in either treatment group. There was no reduction in symptom scores with prednisolone therapy as was seen with placebo. Hence, prednisolone therapy, at least at the dose tested, was disappointingly ineffective. There may be a number of explanations for these results. First, it is possible that the mild inflammatory changes seen in IBS and the symptoms are not connected, just as Helicobacter pylori- induced gastritis is often entirely asymptomatic. Alternatively, in this study, the inflammatory cell changes were minimally influenced by prednisolone treatment, suggesting that more specific antiinflammatory therapy may need to be applied. Indeed, 3 months after infection may be too late for intervention; even earlier intervention trials may be needed. Cyclooxygenase (COX) inhibitors. An alternative, less toxic approach to intervention may involve the use of available COX inhibitors. Barbara and colleagues[8] have previously shown that transient acute infection can result in intestinal muscle hypercontractility that is persistent, but which can be reversed, with COX-2 inhibitors. Akiho and coworkers[9] showed in NIH Swiss mice infected with (or without) Trichinella spiralis that changes in muscle hypercontractility could be maintained by the presence of transforming growth factor-beta-1 in the muscularis externa, which induces COX-2 and promotes prostaglandin E2 production in the muscle cells. This finding suggests that COX-2 inhibition would warrant testing in postinfectious and postinflammatory IBS patients. Tryptase inhibitors and protease-activated receptor-2 antagonists may also have value in exploring postinfectious IBS because of the evidence for mast cell degranulation. This is clearly such a clinically important area of focus that much more research is required before an anti-inflammatory approach should be abandoned.Antibiotics and Probiotics in IBS*Antibiotic TherapyWhether antibiotics exacerbate or are protective in IBS is currently highly controversial, with conflicting evidence published in the literature.[10,11] Pimentel and colleagues[11] reviewed patients with symptoms of IBS presenting for breath testing because of the suspicion of small intestinal bacterial overgrowth. Broad-spectrum antibiotic therapy that reversed abnormal breath testing appeared to improve IBS symptoms in these patients. However, the study was not a randomized, placebo-controlled trial and could be difficult to interpret as it was potentially biased. Pimentel and colleagues[12] have followed up their initial work with a new trial evaluating neomycin, a nonabsorbed antibiotic, in IBS. They randomized IBS patients to neomycin 500 mg (n = 49) or placebo (n = 52) twice daily for 10 days. At entry and 7 days after the completion of treatment, subjects returned for a lactulose breath test. Based on an intention-to-treat analysis and defining response as greater than 50% improvement in symptoms, the study authors found that neomycin led to a 39% improvement in IBS symptom scores compared with 12% on placebo. Bowel habit improved in 40% of patients treated with neomycin but in only 15% treated with placebo. Those patients who had an abnormal breath test were the ones who tended to improve. In a separate study, Pimentel and associates[13] also showed that a 14-day elemental diet improved an abnormal lactulose breath test in 72% of patients, compared with just 21% of those treated with neomycin. Moayyedi and colleagues[14] have provided some supporting evidence to indicate that antibiotics may be protective in IBS. They reanalyzed a trial of H pylori therapy conducted in symptomatic and asymptomatic patients from the community, aged 40-49 years. Defining IBS by Manning's criteria (ie, > 2 of 6 symptoms present), patients given antibiotic therapy (clarithromycin and tinidazole) for H pylori infection were significantly less likely to have a diagnosis of IBS at the end of 2-year follow up (6%) than those who received placebo (9%). However, the number of patients with IBS who initially entered the study and who still had IBS at 2 years was similar in both groups. Of course, this was a hypothesis-generating study, but the concept that antibiotics may protect some patients from IBS warrants more extensive scrutiny. Commentary Many questions remain regarding the role of antibiotics in IBS. Do antibiotics change the host intestinal flora and predispose to IBS in some cases, while protecting in others? If antibiotics do benefit patients with IBS, which groups will respond and why? Is therapy required long term, and in whom? Are there safety issues, particularly with broad-spectrum antibiotics, including concern regarding bacterial resistance? The concept and findings suggesting that antibiotics may be useful for treating patients with IBS will need to be replicated and further investigated before the approach can be recommended. Probiotic Strategies Probiotic bacteria compete with pathogenic bacteria and also have anti-inflammatory effects on gut mucosa. For this reason, there has been increasing interest regarding the potential role of probiotics in IBS. Lactobacillus plantarum has been shown to reduce flatulence and abdominal pain but not bloating in IBS.[15] Quigley and colleagues[16] studied 77 patients with IBS who were randomized to receive either Lactobacillus spp or Bifidobacterium spp, added to a milk drink, for 8 weeks; the control group received the milk drink alone. Subjects who received Bifidobacterium had a significant improvement in pain, bloating, and stools. However, any benefit of Lactobacillus was limited to improvement in pain at only the second and seventh weeks. Hence, probiotic strain specificity may be important in determining the outcome in IBS. Probiotics represent a promising, safe therapeutic class in this clinical setting. Motility-Modifying Drugs: Serotonin Agonists and Antagonists Tegaserod Tegaserod is a partial 5HT4 receptor agonist that is effective in constipation-predominant IBS, although the efficacy appears to be restricted to women, with an approximately 10% therapeutic gain over placebo.[17] Schoenfeld and colleagues[18] performed a meta-analysis of the published and unpublished randomized controlled trials involving tegaserod. They concluded that tegaserod is effective and safe at a dose of 6 mg twice daily. The number needed to treat (NNT) was 10, meaning that of 10 patients prescribed the medication, 1 will have a definite benefit, representing modest efficacy. But how is tegaserod working in this setting, as a prokinetic action alone would likely only explain an improvement in constipation? Wei and associates[19] evaluated an isolated rat colorectal-inferior splanchnic nerve preparation to test the hypothesis that tegaserod modulates visceral pain signalling. They found that pretreatment with tegaserod inhibited high-threshold polymodal inferior splanchnic afferents induced by colonic distension. Studies to test the hypothesis that tegaserod is a visceral analgesic in humans are now awaited with interest. The 5HT3 Antagonists There is no longer any doubt that 5HT3 antagonists are useful in the treatment of diarrhea-predominant IBS.[17] Alosetron (originally marketed at a dose of 1 mg twice daily) may have limited rerelease in the United States in 2002 for this indication, despite reports of the drug causing severe constipation and ischemic colitis.[17] Cilansetron, another 5HT3 antagonist, also appears promising in diarrhea-predominant IBS. Caras and colleagues[20] reanalyzed data from two 12-week double-blind, placebo-controlled randomized trials, in an attempt to demonstrate that cilansetron improved outcome in patients who, at baseline, appeared more likely to have resistant symptoms. Unfortunately, this subanalysis, although positive, remains very difficult to interpret because the randomization process is no longer operational, and thus bias may account for the results. Despite this issue, there is continued interest in 5HT3 antagonists, and especially in finding ways to improve their safety profile. One approach is based on pharmacogenetics, because receptor polymorphisms may theoretically affect therapeutic outcomes. Camilleri and colleagues[21] investigated the potential relevance of polymorphisms of the serotonin transporter protein in patients with diarrhea-predominant IBS. They evaluated whether transit times were different in subgroups of patients with polymorphisms in the promoter region of the gene following a dose of alosetron administered at 1 mg twice daily for 6 weeks. The study authors found that there was a greater response to slowing of colonic transit after alosetron administration in patients with long allelic lengths (n = 8 patients) vs in those with long-short lengths (heterozygous, n = 11). Perhaps altering the dose of alosetron in patient subgroups based on transport protein status may help reduce side effects without any loss in efficacy. However, further work is required to confirm these results in larger and more representative IBS patient populations. Other Antidiarrheal Agents Loperamide improves diarrhea, but not pain, in patients with IBS.[17] Clonidine* is a central alpha-2 adrenergic agonist that relaxes the left colon, reduces pain thresholds, and increases fluid absorption. The latter may therefore be useful for treatment of diarrhea, pain, and urgency in IBS.[17] However, an overall problem with this drug class is postural hypotension associated with feelings of light-headedness and fatigue. Camilleri and colleagues[22] conducted a phase 2 trial of 40 patients given clonidine at doses of 0.5 mg and 0.1 mg vs placebo over a 4-week treatment period. The primary goal was to determine the sample size needed to assess the efficacy of clonidine. Overall, 67% of patients responded to 0.1 mg of clonidine, as defined by adequate relief; stool frequency, consistency, and ease of passage also improved. This finding was not significant; 90 patients per treatment arm would have been required to show a 20% benefit over placebo. Unfortunately, side effects were frequent with clonidine. Hence, titrating the dose to ensure efficacy with minimal side effects remains the challenge with all of the alpha-2 adrenergic agonists. Anticonstipation Agents* RU-0211 The novel compound RU-0211 is a bicyclic fatty acid that acts as a chloride channel-opener, increasing intestinal water secretion. Cuppoletti and associates[23] demonstrated that RU-0211 activated CIC-2 chloride channels in gastrointestinal epithelial cells in an in vitro model. Johanson and colleagues[24] evaluated the efficacy of RU-0211 in patients with chronic functional constipation (n = 129) in a 3-week randomized, placebo-controlled study. They showed that there was a significant improvement in spontaneous bowel movements as well as an improvement in stool consistency and bloating. Although nausea increased among patients receiving the drug, it appeared to otherwise be well tolerated. It is unclear at this time whether this class of agents would be superior to standard laxatives; the latter would require head-to-head trials. Whether this drug relieves abdominal pain also remains unclear. Trials involving RU-0211 specifically in the setting of IBS are therefore required. Polyethylene glycol (PEG) PEG is an osmotic laxative that appears to be better tolerated than the standard osmotic laxatives. No trials have tested this agent in patients with IBS. Pashankar and associates[25] reviewed the long-term use of PEG in children with constipation and/or encoparesis. They found that PEG was well tolerated and appeared to be effective in this patient population. A controlled trial in patients with IBS would therefore be of interest.CCK1 Central Receptor Antagonists Another potential drug class of value in constipation-predominant IBS are the CCK1 antagonists.[17] Dexloxiglumide is being investigated in large clinical trials currently under way. Using a rat model, Bonnafous and coworkers[26] showed that this drug reduced sensory thresholds in both the uninflamed and postinflammatory states, indicating that it may have visceral analgesic effects. The phase 3 trial results are awaited with interest. Opioid Antagonists Assuming opioid tone is increased in constipation-predominant IBS, opioid antagonists theoretically could reduce delays in intestinal transit and therefore relieve symptoms. Hawkes and colleagues[27] evaluated the efficacy of naloxone, an opioid antagonist, in a randomized, double-blind, placebo-controlled 8-week pilot study of 28 (22 female) patients with constipation-predominant IBS. These investigators prescribed 10-mg enteric-release naloxone tablets twice daily or identical placebo. They found that 43% of patients in the naloxone group were responders compared with 25% in the placebo group, based on the end point of adequate relief. Quality of life also improved. Surprisingly, no change in stool form or frequency was observed, suggesting that any prokinetic effect was very modest. These promising results need replication in larger, controlled trials, but do suggest that this class of agents may represent a novel and safe approach for at least a subset of patients with IBS.Visceral Analgesics* Asimadoline Visceral analgesics are theoretically "attractive" agents for treatment of IBS because they should blunt abdominal pain regardless of the primary mechanisms underlying the syndrome. The kappa-opioid agonist fedotozine, however, was relatively disappointing in patients with IBS.[17] Asimadoline is a new kappa-opioid receptor agonist that has shown efficacy in animal models. Delgado-Aros and colleagues[28] evaluated healthy subjects who were randomly assigned to receive either asimadoline 0.15 or 0.5 mg twice daily or placebo. Asimadoline 0.5 mg decreased colonic tone in the fasting state, but did not alter colonic compliance or transit. This finding suggests that patients who have postprandial exacerbations of IBS may benefit from such an agent, but, of course, clinical trials will be required to test this hypothesis prospectively.Tachykinin Receptor Antagonists Another class of potential visceral analgesics are the tachykinin receptor antagonists.[17] Gaultier and colleagues[29] showed that the NK2 and NK3 receptor antagonist SR 48968 and SR 142801, respectively, reduced rectal hyperalgesia induced by stress, as well as rectal allodynia induced by inflammation, in rat models. This class of agents can have a constipating effect, but at the dose used in these studies, the visceral analgesic change was induced without modifying colonic transit time. How this effect will translate into human studies is uncertain. Corticotrophin-Releasing Factor (CRF) AntagonistsYet another class of agents currently being explored for potential value in treating IBS are the CRF antagonists. In rats, a CRF1 antagonist was shown to prevent stress-induced visceral hyperalgesia and to reduce stress-induced increases in colonic transit.[30] Chronic stress does appear to be relevant in IBS, but how effective CRF antagonists will be in this setting remains speculative. AntispasmodicsAlthough the efficacy of antispasmodics in IBS remains controversial, a recent meta-analysis by Poynard and colleagues[31] that combined multiple small, often flawed controlled trials suggested that this class of agents is of benefit over placebo. Chalder and associates[32] evaluated patients with IBS in primary care in the United Kingdom to determine whether it was possible to predict who would respond to an antispasmodic regimen. They evaluated mebeverine, a popular antispasmodic papaverine-like agent not available in the United States, and found that neither symptoms, duration of illness, nor demographic factors predicted response to treatment. Thus, the hypothesis that agents that induce smooth muscle relaxation will also help IBS pain is not particularly convincing based on the available evidence.Antidepressants and Psychologic Treatments for IBS* Antidepressants There is increasing interest in the value of antidepressants for IBS. The tricyclic antidepressants appear to be effective in this setting,[33] but is this because they are central analgesics? Amitriptyline. Mertz and colleagues[34] evaluated the effect of amitriptyline on brain activation during stress. They evaluated 10 women with IBS who were randomized to either a month of amitriptyline therapy at a dose of 25-50 mg or to matching placebo; after washout they were crossed over to the other treatment. Colorectal distension was performed during stress (babies crying) or no stress (relaxing music) condition. Amitriptyline significantly reduced activation of the limbic system that had been induced during stress. What we still lack are clinical predictors of who is most likely to respond to this drug class; large trials remain warranted.Selective serotonin reuptake inhibitors (SSRIs). The efficacy of the SSRIs in IBS remains uncertain despite positive anecdotal reports,[33] as there are no published trials. Kuiken and colleagues[35] reported on the results of an important randomized trial evaluating fluoxetine 20 mg daily or placebo for 6 weeks in 40 patients with IBS. Although abdominal pain scores decreased with fluoxetine, this effect was restricted to female sex. What's more disappointing, global symptom relief was similar on active treatment and placebo. Quality of life also did not improve with fluoxetine. The study authors also determined rectal sensitivity to distension with a barostat balloon at entry and after 6 weeks of treatment; rectal thresholds were not altered by placebo or active treatment. These findings are contrary to a small, albeit positive, crossover study reported by Broekaert and associates[36] during last year's Digestive Disease Week meeting. It is notable that the number of patients included in the present trial by Kuiken and colleagues was relatively small, and it is conceivable, therefore, that the study "suffered" from a type 2 error (that is, it missed a real difference). Furthermore, it may be that only subgroups of patients with IBS respond to this treatment. For example, SSRIs tend to cause diarrhea, thus constipation-predominant IBS may be the optimal subgroup to target. Additional large studies are definitely well warranted with this class of agents. Psychologic Strategies The value of psychologic therapies for IBS is generally thought to be positive, although methodologic limitations have often inhibited interpretation of the clinical trials.[37] Hypnotherapeutic options. Hypnotherapy has been shown in randomized studies to improve IBS symptoms.[37] Simren and associates[38] evaluated 26 patients with refractory IBS; 13 were randomized to receive gut-directed hypnotherapy and 13 to receive supportive therapy. Colonic sensory thresholds were evaluated before and after lipid infusion. The study authors found that there were higher colonic baseline tones present in the hypnotherapy group compared with the control group at 3 months. Phasic motor events were similar in both groups, but hypnotherapy appeared to reduce colonic hypersensitivity to lipid infusion. Presumably, hypnotherapy alters colonic function via central mechanisms, but this remains to be ascertained. Gonsalkorale and colleagues[39] followed up with 239 patients who had undergone gut-directed hypnotherapy between 1 and 5 years previously. They found that 83% of patients reported that their symptoms had remained controlled since the end of hypnotherapy, and that only 17% had suffered some deterioration. Quality of life also remained improved, but these observations were uncontrolled. Therefore, gut-directed hypnotherapy should be considered an option for patients who have persistent symptoms despite standard therapy and who do not have significant psychologic comorbidity.Behavioral therapy. In another study, Darnley and colleagues[40] compared the efficacy of cognitive behavioral therapy (CBT) with mebeverine in primary care patients with IBS. These investigators showed that CBT was superior at both 12 weeks posttreatment and at subsequent 3-month follow-up.Self-management. Heitkemper and associates[41] evaluated women who were randomized to either (1) a self-management program (which comprised 8 standardized sessions with a masters-prepared nurse therapist covering the topics of stress management, relaxation, cognitive restructuring, and diet), (2) a 1-time brief self-management session, and (3) usual care. The full self-management program was superior to usual care, with reductions in pain, bloating, and constipation observed. It is interesting to note that women who received only the brief intervention program also significantly improved compared with usual care, implying that such a simple approach in physician practice may be applied effectively without the need for more costly intervention programs. The addition of standard CBT should be considered for IBS patients who fail to improve after usual treatment, although the cost benefit of this approach remains to be established. ConclusionsSeveral new and promising approaches for treatment of IBS are currently undergoing exploration. Additional work regarding anti-inflammatory strategies is warranted, despite disappointing results achieved with the prednisolone trial. Serotonin receptor agonists and antagonists appear to be efficacious in subgroups of IBS patients, but further work is needed to address how best to optimally target treatment in practice. Results of therapy with SSRIs appear disappointing, but it is too early to dismiss this class of agents.It must be emphasized that a simple but comprehensive nonpharmacologic management program is most likely to succeed in practice in terms of achieving the best outcomes in IBS. Drugs should generally remain second-line in IBS until agents with better efficacy and established safety profiles become available.*This section mentions off label uses for some medications. These may describe clinical uses for medications that have not been approved by the FDA.ReferencesGwee KA, Leong YL, Graham C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut. 1999;44:400-406.Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804-811.Hollerbach S, Kizil F, Reiser MM, Theegarten D, Morgenroth K, Schmiegel W. IBS patients exhibit subtle differences in the composition of the residual colonic inflammatory infiltrate. Gastroenterology. 2002;122:A-319. [Poster #M1531]Dunlop S, Jenkins D, Spiller R. Distinctive histological patterns of chronic inflammatory cells in rectal biopsies of patients with different clinical subtypes of IBS. Gastroenterology. 2002;122:A-316. [Poster #M1516]Park CH, Joo YE, Choi SK, Rew JS, Kim SJ, Lee MC. Colonic mast cells in irritable bowel syndrome. Gastroenterology. 2002;122:A-552. [Poster #W1029]Barbara G, Cottrell G, Grady E, et al. Expression and release of mast cell tryptase in irritable bowel syndrome (IBS). Gastroenterology. 2002;122:A-276. [Poster #M1136]Dunlop S, Jenkins D, Naesdal J, Borgaonker M, Collins S, Spiller R. Randomised double-blind placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome (PI-IBS). Gastroenterology. 2002;122:A-60. [Abstract #499]Barbara G, De Giorgio R, Deng Y, Vallance B, Blennerhassett P, Collins SM. Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice. Gastroenterology. 2001;120:1729-1736.Akiho H, Deng Y, Blennerhassett P, et al. The roles of TGFbeta and COX-2 in the maintenance of muscle hypercontractility in a murine model of post-infective irritable bowel syndrome. Gastroenterology. 2002;122:A-135. [Abstract #M958]Mendall MA, Kumar D. Antibiotic use, childhood affluence and irritable bowel syndrome (IBS). Eur J Gastroenterol Hepatol. 1998;10:9-62.Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503-3506.Pimentel M, Chow E, Lin HC. Neomycin leads to a dramatic improvement in IBS symptoms that depend on lactulose breath test findings: a double blind randomized placebo controlled study. Gastroenterology. 2002;122:A-60. [Abstract #500]Pimentel M, Bajwa M, Constantino TA, Kong Y, Lin HC. Elemental diet is more effective than antibiotics in normalizing lactulose breath test in IBS. Gastroenterology. 2002;122:A-323. [Poster #M1552]Moayyedi P, Duffett S, Mason S, Brown J, Axon ATR. The influence of antibiotics on irritable bowel syndrome: A randomised controlled trial. Gastroenterology. 2002;122: A-465. [Poster #T1487]Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2001;13:1143-1147.Quigley E, O'Mahony L, McCarthy J, et al. Probiotics for the irritable bowel syndrome (IBS): a randomized, double-blind, placebo-controlled comparison of lactobacillus and bifidobacterium strains. Gastroenterology. 2002;122:A-59. [Abstract #498]Talley NJ. Serotoninergic neuroenteric modulators. Lancet. 2001;358:2061-2068. Schoenfeld P, Chey WD, Drossman D, Kim HM, Thompson WG. Effectiveness and safety of tegaserod in the treatment of irritable bowel syndrome: a meta-analysis of randomized controlled trials. Gastroenterology. 2002; 122:A-465. [Poster #T1486]Wei JY, Wang YH, Mayer E. The 5-HT4 partial agonist, tegaserod, inhibits the colorectal distension-induced response of rat inferior splanchnic afferents in vitro. Gastroenterology. 2002; 122:A-317. [Poster #M1524]Caras S, Carter F, Allgood A, Driessen S, Krause G, Steinborn C. Cilansetron shows an increase in adequate relief rate in non-constipated IBS subjects who respond as having no adequate relief at baseline. Gastroenterology. 2002; 122:A-550. [Poster #W1019]Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin transport protein polymorphism in the pharmacogenetics of diarrhea-predominant irritable bowel syndrome (D-IBS). Gastroenterology. 2002;122:A-60. [Abstract #501]Camilleri M, Kim D-Y, McKinzie S, et al. Clonidine in diarrhea-predominant irritable bowel syndrome (D-IBS): A randomized, placebo-controlled, dose response study. Gastroenterology. 2002;122:A-59. [Abstract #497]Cuppoletti J, Malinowska DH, Tewari KP, Sherry AM, Patchen ML, Ueno R. Recombinant and native intestinal cell CIC-2 CL-channels are activated by RU-0211. Gastroenterology. 2002;122:A-538. [Poster #W955]Johanson JF, Gargano MA, Patchen ML, Ueno R. Efficacy and safety of a novel compound, RU-0211, for the treatment of constipation. Gastroenterology. 2002;122:A-315. [Poster #M1511]Pashankar DS, Loening-Baucke V, Bishop WP. Lon-term efficacy and safety of polyethylene glycol 3350 (PEG) for the treatment of chronic constipation and encopresis in children. Gastroenterology. 2002;122:AA-318. [Poster #M1526]Bonnafous C, Bueno L, Griffin PH, Schneier H, Rovati LC, D'Amato M. Influence of dexloxiglumide on visceromotor and pain response induced by rectal distension in rats. Gastroenterology. 2002;122:A-527. [Poster #W894]Hawkes ND, Rhodes J, Evans B, Hawthorne B, Thomas G. Naloxone treatment for irritable bowel syndrome - a pilot study. Gastroenterology. 2002;122:A-552. [Poster #W1032]Delgado-Aros S, Chial H, Ferber I, et al. The kappa-opioid agonist asimadoline decreases satiety and fasting colonic tone in humans. Gastroenterology. 2002;122:A-59. [Abstract #496]Gaultier E, Emonds-Alt X, Fioramonti J, Bueno L. Neurokinin 2 and neurokinin 3 receptor antagonists, SR48968 and SR142801, reduce colonic hypersensitivity induced by inflammation or stress in rats, but do not modify colonic transit time. Gastroenterology. 2002;122:A-526. [Poster #W893]Million M, McRoberts JA, Mayer E, Grigoriadis D, Tache Y. A novel water soluble CRF1 antagonist prevents stress-induced visceral hyperalgesia and colonic motor response in rats. Gastroenterology. 2002;122:A-527. [Poster #897]Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2001;15:355-361.Chalder T, Darnley SE, Kennedy T, Jones R, Wessley S, Holt R. Clinical aspects of irritable bowel syndrome (IBS) are not helpful in predicting response to antispasmodics. Gastroenterology. 2002;122:A-552. [Poster #W1031]Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther. 1994;8:409-416.Mertz H, Pickens D, Smith S, Morgan V. Amitriptyline reduces visceral sensitization and limbic activation induced by stress in IBS and improves symptoms. Gastroenterology. 2002;122:A-310. [Poster #M1487]Kuiken SD, Burgers P, Tytgat GNJ. Fluoxetine (Prozac) for the treatment of irritable bowel syndrome: a randomized, controlled clinical trial. Gastroenterology. 2002;122:A-551. [Poster #W1024]Broekaert D, Vos R, Gevers A-M, et al. A double-blind randomised placebo-controlled trial of citalopram, a selective serotonin reuptake inhibitor, in irritable bowel syndrome. Gastroenterology. 2001;120:A-641. [Abstract #3250] Talley NJ, Owen BK, Boyce P, Patterson K. Psychological treatments for irritable bowel syndrome: a critique of controlled treatment trials. Am J Gastroenterol. 1996;91:277-283.Simren M, Ringstrom G, Bjornsson E, Abrahamsson H. Hypnotherapy reduces lipid-induced colonic hypersensitivity in the irritable bowel syndrome (IBS). Gastroenterology. 2002;122:A-69. [Abstract #605]Gonsalkorale WM, Miller V, Afzal A, Whorwell PJ. Hypnotherapy for irritable bowel syndrome: improvement is long-lasting and reduces health care costs. Gastroenterology. 2002;122:A-69. [Abstract #604]Darnley SE, Kennedy T, Jones R, Chalder T, Wessley S. A randomised controlled trial of the addition of cognitive behavioural therapy (CBT) to antispasmodic therapy for irritable bowel syndrome (IBS) in primary care. Gastroenterology. 2002;122:A-69. [Abstract #603]Heitkemper M, Jarrett M, Cain K, et al. A comprehensive self-management program reduces symptoms and enhances quality of life in women with IBS. Gastroenterology. 2002;122:A-70. [Abstract #608]
 

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Clair,I think this is a really interesting and encouraging article. I selected a few parts that I found particularly helpful. What I get from the article is that there is a histological difference in patients with IBS indicating that it is indeed organic, just at the cellular level. There has been a lot of discussion of mast cells, and it appears that this article supports the idea that IBS sufferers not only have more mast cells, but more "sensitive" mast cells:
quote:park and colleagues[5] applied electron microscopy and found that mast cell counts were significantly higher in the cecum among patients with IBS, and that the number of activated mast cells close to nerves was increased in IBS patients vs controls.
also supporting this is
quote:On routine histology, colonic biopsies appear normal in IBS. Studies by Gwee and colleagues,[1] and Spiller and coworkers,[2] among others, have shown that in at least a subset of IBS patients, there is a quantifiable, albeit modest, increase in colonic inflammatory cells.
The other thing that I find interesting is the endorsement of the subgrouping theory, as that may lead to actually giving us better diagnoses and treatments instead of lumping us all together and providing many of us with little or no treatment. Right now, The Dx of IBS seems so all-encompassing that it can not be treated effectively because symptoms vary from person to person.
quote:These investigators found that cell counts in constipation-predominant IBS were not significantly different from that of controls. In contrast, patients with diarrhea, but without a postinfectious history, showed increased CD3 and lamina propria lymphocytes, in addition to mast cells, whereas patients with postinfectious IBS had increased enteroendocrine cells, CD3, and lamina propria lymphocytes. These findings suggest that subgrouping of IBS by bowel symptoms may identify distinct histomorphic phenotypes within IBS, which in turn suggests that treatment may need to be tailored to symptom subgroups.
I found the section on antibiotics especially interesting, because I was put on them twice, once before and once after my IBS diagnosis, and both times, particularly the 1st, I showed marked improvement. After the course my pain increased, so I don't know whether it was a response to the antibotics killing beneficial bacteria, or a recurrence of harmful bacteria. Now I'm on probiotics, so I may be an example of someone whose symptoms worsen with these. The bit on hypnotherapy is also really encouraging
quote:...Presumably, hypnotherapy alters colonic function via central mechanisms, but this remains to be ascertained...They found that 83% of patients reported that their symptoms had remained controlled since the end of hypnotherapy, and that only 17% had suffered some deterioration.
quote:In view of the increasing evidence of histologic abnormalities in IBS, and providing that this is indeed a true organic bowel disease, might intervention to reduce the inflammation have utility? If such intervention was able to prevent the development or progression of IBS, then this would be of major clinical importance.
Sounds good to me! Too bad the prednisone therapy didn't work, and the tegaserod data is discouraging, but I think your doctor is on to something.
 

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Basically they are confirming somethings we have been talking about.This is still really important."enterochromaffin cells store about 70 percent of the serotonin in the gut and are very important players also."Here is some more in regards to this."A lot of this has to do with previous infection that resides and leaves a person with IBS. They are confirming some of the processes of the brain gut dysregulation and the here and the whys. Mast cells and release both serotonin and histimine. enterochromaffin cells store about 70 percent of the serotonin in the gut and are very important players also. We have mentioned an altered fight or flight responce that triggers the hpa axis numerous times. "However, the enteric nervous system can be more subtle. It turns out that a danger signal from the brain in the skull causes the immune system to kick into gear and help protect the body from modern hazards, like switchblades and bad situation comedies (not). Could you be more specific? I'll try. When the brain signals danger, it tells so-called mast cells in the lining of the small intestine and/or colon to release histamine (defined) and other chemicals. These chemicals trigger an inflammatory response inside the small intestine, attracting immune cells from the bloodstream into the area. Voila, the body is ready for trauma, which often introduces dirty -- infectious -- material into the colon. " This is what some of the new IBS drugs are based on. "Let's talk therapeutics The point of understanding the enteric nervous system is not just to brag about how elegant evolution is, but to cure disease. Scientists have figured out that a substance called substance P triggers mast cells to release histamine, which in turn attracts immune cells. And substance P links to a receptor called NK1 receptor on the mast cells. Knowledge of this mechanism has prompted several pharmaceutical companies to try to devise drugs to block the chain of events that lead to ulcerative colitis." http://whyfiles.org/026fear/physio2.html This is also starting to fit into IBS. Its also looking like a convergenge between IBS, fibro and CFS For d people the attack can put people in the danger mode of fight or flight. This triggers the HPA axis and histimine and serotonin. These emotions are also not always concious. "The emotional gut response of fear stimulates the lower gut (sigmoid colon and rectum), which can cause diarrhea, cramping, and abdominal pain. From the perspective of evolution, this response program or pattern evolved in order to reduce exposure of the gut to ingested food and waste material while energy is shunted to the cardiovascular and musculoskeletal systems in order to maximize the effects of the fight and flight response and survival potential. In other words, the last thing that your body needs to be doing when your life is threatened is to be digesting your lunch! And to emphasize the point again, all of this emotional gut response can occur without your being consciously aware of the emotional feeling of fear. " http://www.parkviewpub.com/parksub/n5.html Hence triggering an immune responce in IBS and inflammtion of cells. The fight or flight responce being overly activated in IBS. The problem need to be looked at holistically at the whole organism, not just one immune responce, as all these things are players in the symptoms. Gastroenterology 2002 Jun;122 7:2032-48 Related Articles, Books, LinkOut Evolving pathophysiologic models of functional gastrointestinal disorders. Mayer EA, Collins SM. CURE Neuroenteric Disease Program, UCLA Division of Digestive Diseases and Brain Research Institute, Los Angeles, California; and Department of Gastroenterology, McMaster University, Hamilton, Ontario. In contrast to most other disorders of the digestive system, functional disorders of the gut continue to be defined by symptom criteria rather than by biological markers. At the same time, animal models of functional gastrointestinal disorders in which to test pathophysiologic hypotheses are lacking. The aim of this report is to critically review recently proposed conceptual as well as animal models of functional gastrointestinal disorders. Converging disease models have been proposed that postulate an enhanced responsiveness of neural, immune, or neuroimmune circuits in the central nervous system or in the gut to exteroceptive psychosocia or interoceptive tissue irritation, inflammation, infection perturbations of the organism's homeostasis. The enhanced responsiveness results in dysregulation of gut motility, epithelial function immune, permeability, and visceral hypersensitivity, which in turn produce irritable bowel syndrome symptoms. These conceptual models provide plausible mechanisms for irritable bowel syndrome symptom generation and are consistent with extensive epidemiologic and pathophysiologic data. Several animal models have recently been proposed that mimic key features of these conceptual disease models. They fall into models triggered by centrally targeted stimuli neonatal stress, post-traumatic stress disorder or those triggered by peripherally targeted stimuli infection, inflammation. Depending on the timing of the trigger neonatal vs. adult, the changes induced in the animal may be permanent or transient. Future development of existing and novel models involves the use of transgenic and knockout animals, as well as the demonstration of predictive validity in terms of responsiveness to candidate drugs. PMID: 12055608 J Gastroenterol Hepatol 1998 Oct;13(10):980-9 Related Articles, Books, LinkOut Mast cells: a possible link between psychological stress, enteric infection, food allergy and gut hypersensitivity in the irritable bowel syndrome. Gui XY. University of Sydney Department of Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia. Intestinal mast cell activation degranulation, which results from previous enteric infection and/or intestinal allergy, may play a central role in the gut hypersensitivity in both motor response and visceral perception in the Irritable Bowel syndrome. This occurs through various mediators acting on enteric neurons and smooth muscle cells. Psychological stress may trigger this sensitive alarm system via the brain-gut axis. Publication Types: Review Review, Tutorial PMID: 9835312 Dig Dis 2001;13:201-11 Related Articles, Books, LinkOut Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Monnikes H, Tebbe JJ, Hildebrandt M, Arck P, Osmanoglou E, Rose M, Klapp B, Wiedenmann B, Heymann-Monnikes I. Department of Medicine, Division of Hepatology and Gastroenterology, Universitatsklinikum Charite, Campus Virchow-Klinikum, Humboldt-Universitat zu Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Psychological stress is widely believed to play a major role in functional gastrointestinal GI disorders, especially irritable bowel syndromeIBS, by precipitating exacerbation of symptoms. The available data clearly demonstrate that inhibition of gastric emptying and stimulation of colonic transit is the most consistent pattern in the motility response of the GI tract to acute or short-term stress. Thus, one might propose that these alterations might play a pathophysiological role in dyspeptic symptoms and alterations in stool frequency and consistency in patients with stress-related functional GI disorders. Taken together, the above-mentioned studies suggest that the colonic motor response to stress is exaggerated in IBS. There is evidence that an increased emotional response is associated with this difference in colonic, and perhaps also gastric motor responses to certain stressors. However, almost no valid data are available so far from human studies addressing the question if differences in motility responses to stress between patients with functional GI disorders and healthy subjects are due to an altered stress response associated with an imbalance of the autonomic nervous system or increased stress susceptibility. We can summarize that in experimental animals the most consistent pattern of GI motor alterations induced by various psychological and physical stressors is that of delaying gastric emptying and accelerating colonic transit. Endogenous corticotropin-releasing factor(CRF in the brain plays a significant role in the central nervous system mediation of stress-induced inhibition of upper GI and stimulation of lower GI motor function through activation of brain CRF receptors. The inhibition of gastric emptying by CRF may be mediated by interaction with the CRF-2 receptor, while CRF-1 receptors are involved in the colonic and anxiogenic responses to stress. Endogenous serotonin, peripherally released in response to stress, seems to be involved in stress- and central CRF-induced stimulation of colonic motility by acting on 5HT-3 receptors. Taken together, the limited data available from investigations in healthy subjects and patients with functional GI disorders provide some evidence that stress affects visceral sensitivity in humans. Acute psychological stress seems to facilitate increased sensitivity to experimental visceral stimuli, if the stressor induces a significant emotional change. In summary, studies in experimental animals suggest that stress-induced visceral hypersensitivity is centrally mediated by endogenous CRF and involvement of structures of the emotional motor system, e.g. the amygdala. Stress-induced activation or sensitization of mucosal mast cells in the GI tract seem to be involved in stress-associated alterations of visceral sensitivity. Copyright 2001 S. Karger AG, Basel Publication Types: Review Review, Tutorial PMID: 11752838 If you want to learn more about this although its very complex. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?SUBMIT=y Nigel Bunnett, PhD University of California School of Medicine Department of Surgery and Physiology Accumulating evidence indicates that sensory nerves play a major role in inflammation of multiple tissues, and that communication between the nervous system and mast cells is of particular importance. Dr. Bunnett�s lecture will highlight recent experimental evidence that mast cell proteases signal to sensory nerves through novel receptors that couple to the release of proinflammatory peptides, and that defects in this mechanism result in uncontrolled inflammation and disease. Dr. Bunnett will present evidence that therapies designed to block signaling by neuropeptides and proteases are attractive treatments for inflammation. Esther Sternberg, MD Chief, Section on Neuroendocrine Immunology and Behavior Director, Molecular, Cellular and Behavioral Integrative Neuroscience Program National Institute of Mental Health, National Institute of Health A pioneer in the field of neural-immune interactions, Dr. Sternberg will present the scientific evidence proving molecular, neuroanatomical and hormonal links between the brain and immune system and will discuss the role that disruptions of such links play in inflammatory/autoimmune disease. Jack Wood, PhD Professor of Physiology and Internal Medicine Chairman Emeritus, Department of Physiology The Ohio State University College of Medicine Dr. Wood was the first to use microelectrodes to record the electrical and synaptic behavior of neurons in the enteric nervous system. He coined the term "brain-in-the-gut" in view of emerging evidence that the enteric nervous system had neurophysiological properties like the brain and spinal cord. In recent years he has focused on signaling interactions between the enteric immune system and the brain-in-the-gut during infectious enteritis and food allergy. In this lecture he shows how the central nervous system, enteric nervous system and intestinal immune system are integrated during physical and emotional stress to produce irritable bowel symptoms of diarrhea and abdominal pain and discomfort." http://www.conference-cast.com/ibs/GUIs/bios.cfm
 

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ADDENDA:A portion of the various mechanisms behind the symptom generating mechanisms, especially tthe aberrant inflammatory response, seen in the bowel of D-type IBS patients has been described.However, the scope must be widened to include ALL mechanisms if one is to understand fully symptom-generation in d-types and thus the therapeutic modalities which will be maximally effective.There is more to the picture than has been included to understand the complete integrative model. The best way to see MOST of the whole integrated picture, and then ADD to it the other circulating immunocyte responses, such as T-cell responses, is to get a copy of: ________________________Alimentary Pharmacology and Therapeutics Vol. 15 Issue 4 Page 439 April 2001 Food hypersensitivity and irritable bowel syndrome S. Zar, D. Kumar, M. J. Bensonhttp://www.blackwell-synergy.com/servlet/userag ent?func=synergy&synergyAction=showFullText&doi=10.1046/j.1365-2036.2001.00951.x[/URL]____________________________In particular study this schematic in the tutorial:"Figure 1 . Pathogenesis of food hypersensitivity induced irritable bowel syndrome."____________________________To complete the picture of the fully integrated mechanisms (gastroneuroimmunoendoexocrine systems) and how they interract in symptom generation, one has to add the circulating immunocytes, which are activated by other mechanisms and in addition to gut mast cells.Also one must take into account the various immunologic mechanisms, sometimes overlooked unless you are talking to a researcher who has studied them, which also can be primary in triggering the inflammatory response, especially in patients absent a history of gut infection and who do have a d-type IBS symptom set.Much of this can be added as well, and reading a ton of various papers on the matter that span 40 years can be avoided, by a read of these books:"FOOD ALLERGIES AND FOOD INTOLERANCE: THE COMPLETE GUIDE TO THEIR IDENTIFICTION AND TREATMENT", Professor Jonathan Brostoff , M.D.. Allergy, Immunology and Environmental Medicine, Kings' College, Londonhttp://www.amazon.com/exec/obidos/ASIN/089...r=2-1/102-64875 08-3420903[/URL]and IBS: A DOCTORS PLAN FOR CHRONIC DIGESTIVE TROUBLESBy Gerard Guillory, M.D.; Vanessa Ameen, M.D.; Paul Donovan, M.D.; Jack Martin, Ph.D. http://www.amazon.com/exec/obidos/search-h...9085785-1742301 The basic summation is that studies on c-types more and more strongly suggest that a different set of mechanisms is responsible for symptom generation than in d--types, and that the mechanisms of symptom generation in the d-types who developed IBS after infection (persistent post inflammatory response) present a distinctive pattern of inflammatory response in the gut from those whose d-component IBS developed without am apparent precursor event.In any case, the EC Cell and Mast cell mediators can be and are released in response to other primary stimuli than neurologic/stress induced mechanisms...this is but one...one has to also examine the various primary immune-mechanisms which can precipitate cell activation within the gut wall. PLUS one now must also pay attention to the other circulating immunocyte reactions, especially lymphocytes which patrol the gut wall, lymphatics, and blood vessels in their journeys as their mediators when released precipitates a host of secondary responses which also are at times involved in upregulating the gut.Other mediators and "markers" have been recovered from the bowel of IBS-d types, which are provocative, than just mast cell and EX cell mediators (keep in mind there are up to about 100 known so far). These include mediators from a number of different immunocyte classification, but the lymphocyte-types are at the top of the list…but not exclusive of even machrophage and platelet activation (another big warehouse of 5ht in the gut and elsewhere).It is very hard for many to visualize how thoroughly ALL the mechanisms are interdependent, since I cannot put the diagram in question up here, and that any of the mechanisms can be primary, rendering the others "secondary" or "reactive" to the primary mechanism. This accounts for both the ability to show the gut can be upregulated both through CNS activation AND through direct provocation by dietary components to which d-types have lost tolerance, and that this provoked the inflammatory response seen.This has been most elegantly studied using jejunal isolation techniques (direct instillation to the small bowel through indwelling catheter various foodstuffs in IBS-d types and then with "before and after" analysis of the jejunal washings and/or biopsy, isolating which foods each different patient has grown sensitive to (which ones provoked immunocyte activation when instilled nto the isolated bowel segment). Hence the need to study all the material, and articles like Zars', so as to get the complete picture of all the mechanisms involved, not just a [portion].The diagram, again, in that article is probably one of the most useful tools to help people look at how all the systems are interractive...thus each patients therapeutic plan needs to be approached by assessing what are the mechanisms at play for each specific patient.Eat well. think well. be well.MNL
 
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