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Cremon C. La Sindrome Digestiva Funzionale: non solo colon irritabile. ASMaD 2013

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  • - The normal intestinal mucosa is considered in a constant state of physiological or controlled inflammation since it contains a large number of immunocytes. Data from our and many other laboratories have demonatrated that compared to healthy controls, IBS patients on average contain a significantly higher number of immunocytes in their intestinal mucosa. The number of immunocytes identified in the colonic mucosa of IBS patients is significantly higher that that identifyable in recognizewd inflammatory conditions of the colon including microscopoic colitis and UC in remission or active. <br /> - The question is whether we can use the number of immune cells as a biomarker of IBS. <br /> - If we look at this graph we clearly identify a wide overlap between IBS and controls as well as IBS and other inflammatory conditions, suggesting that the sensitivity and specificity of crude immune cell numbers may be low. <br />
  • This slide summarises a paper that we published a couple of years ago in which we demonstrated an increased IHC stainig for tryptase positive mast cells in the colonic mucosa of IBS patients as compared with controls. The increased number of tryp positive mast cells was detectable in both PI-IBS and non specific IBS patients, and this was related with an increased amount of histamine and tryptase release from mast cells. Interestingly we found that in the colonic mucosa of IBS patients MC were more closely associated with enteric nerves, suggesting that activated mast cells in close proximity to nerve endings may have an increased chanche to affect the physiology of those nerves. Accordingly, we found a nice correlation between activated mast cells in close proximity to nerve endings and both the severity and the frequency of abdominal pain. <br />
  • This slide shows the single value of immune cell count in the colonic mucosa of healthy controls, patients with IBS and patients with ulcerative colitis. By applying quantitative H&E histology, as you can see, we showed a significant increase of immune cell count in the colonic mucosa of patients with IBS in comparison with healthy controls, although there was a substantial overlap between the two groups. As expected, immune infiltration in IBS was much less than that detected in patients with active or inactive ulcerative colitis. <br />
  • This slide shows the single value of mast cell count in the colonic mucosa of healthy controls, patients with IBS and patients with ulcerative colitis. A you can see, we showed a significant increase amount of mast cells in the colonic mucosa of patients with IBS in comparison with healthy controls. We also evaluated mast cell count in a subgroup of ten patients with mild active ulcerative colitis. A you can see, mast count was significantly increase in comparison with healthy controls. In contrast, there was not significant difference in comparison with patients with IBS, although mast cell infiltration was greater in patients with IBS in comparison with patients with ulcerative colitis. <br />

Cremon C. La Sindrome Digestiva Funzionale: non solo colon irritabile. ASMaD 2013 Cremon C. La Sindrome Digestiva Funzionale: non solo colon irritabile. ASMaD 2013 Presentation Transcript

  • La Sindrome Digestiva Funzionale: non solo colon irritabile Cesare Cremon Policlinico S.Orsola – Malpighi Azienda Ospedaliero - Universitaria di Bologna (1088 – 2013)
  • Disordini Funzionali Gastro-Intestinali >40% popolazione generale lamenta sintomi digestivi Ho la pancia gonfia Ho la pancia gonfia eemi fa male mi fa male Ho mal di pancia Ho mal di pancia Mi sento piena Mi sento piena Mi brucia ililpetto Mi brucia petto Ho mal di stomaco Ho mal di stomaco Sono stitica Sono stitica Ho spesso diarrea Ho spesso diarrea
  • The FGID and the Rome III Process A. Functional esophageal disorders A1. Functional heartburn A2. Functional chest pain of presumed esophageal origin A3. Functional dysphagia A4. Globus – – B1. Functional dyspepsia • B1a. Postprandial distress syndrome • B1b. Epigastric pain syndrome B2. Belching disorders • B2a. Aerophagia • B2b. Unspecified excessive belching B3. nausea and vomiting disorders • B3a. Chronic idiopathic nausea • B3b. Functional vomiting • B3c. Cyclic vomiting syndrome B4. Rumination syndrome in adults – – – – – C1. Irritable bowel syndrome C2. Functional bloating C3. Functional constipation C4. Functional diarrhea C5. Unspecified functional bowel disorder – – – E1. Functional gallbladder disorder E2. Functional biliary SO disorder E3. Functional pancreatic SO disorder – – Symptom-based diagnostic criteria not explained by other pathologically based disorders – – – – F1. Functional fecal incontinence F2. Functional anorectal pain • F2a. Chronic proctalgia – F2a1. Levator ani syndrome – F2a2. Unspecified functional anorectal pain • F2b. Proctalgia fugax F3. Functional defecation disorders • F3a. Dyssynergic defecation • F3b. Inadequate defecatory propulsion B. Functional gastroduodenal disorders – – C. Functional bowel disorders D. Functional abdominal pain syndrome E. Functional gallgallbladder and Sphincter of Oddi disorders F. Functional anorectal disorders FGIDs: 6 major domains for adults 28 disorders – Drossman DA. Gastroenterology 2006;130:1377–90
  • The Challenge of Functional Gastrointestinal Disorders (FGID) Variable combination of chronic or recurrent gastrointestinal symptoms Variable combination of chronic or recurrent gastrointestinal symptoms not explained by structural //biochemical abnormalities not explained by structural biochemical abnormalities • Highly prevalent conditions (female-to-male ratios of 2-3:1) • Significant burden on health-care systems • Economic impact (direct and indirect costs: work absenteism x3) • Reduced patient’s QoL • Pathophysiology poorly understood • Poorly effective therapy
  • FGID – Conceptual Model Early Life •Genetics •Environment Psychosocial Factors •Life stress •Psychologic state •Coping •Social support Brain CNS Physiology Gut ENS FGID •Symptoms •Behavior Outcome •Medications •MD visits •Daily function •Quality of life •Motility •Sensation •Inflammation •Altered bacterial flora Drossman DA. Gastroenterology 2006;130:1377–90
  • New pathophysiologic aspects in FGID Stress (CRF) anxiety, depression Genetic polymorphisms (IL-10, TGF-β, TNF-α, IL-6, SERT, TNFSF15 ) Gene expression Increased mucosal permeability (↓ ZO-1) Mucosal immune activation Altered enteroendocrine metabolism (serotonin) Neuroplasticity (SP, NGF) Food hypersensitivity (gluten? FODMAP?) BAM Transient infection Altered microbiota (dysbiosis?) Barbara G and Stanghellini V. Gut 2009;58:1571-5
  • Prevalence of FGIDs (Rome III criteria) in a randomized population-based study Prevalence of FGIDs (%) one-year recall time 25 A community random sample: 900 residents of Olmsted Country, Minnesota 20 15 10 5 0 IBS Chronic constipation Functional dyspepsia PDS EPS Rey E et al., Aliment Pharmacol Ther 2010;31:1237-47
  • Functional Gastro-Intestinal Disorders the old days… ”a young anxious woman”, “an exclusion diagnosis” the present… ”a positive diagnosis”
  • The FGID and the Rome III Process A. Functional esophageal disorders Symptom-based diagnostic criteria not explained by other pathologically based disorders – – – – A1. Functional heartburn A2. Functional chest pain of presumed esophageal origin A3. Functional dysphagia A4. Globus B. Functional gastroduodenal disorders – B1. Functional dyspepsia – • B1a. Postprandial distress syndrome • B1b. Epigastric pain syndrome B2. Belching disorders • B2a. Aerophagia • B2b. Unspecified excessive belching B3. nausea and vomiting disorders • B3a. Chronic idiopathic nausea • B3b. Functional vomiting • B3c. Cyclic vomiting syndrome B4. Rumination syndrome in adults – – – – C2. Functional bloating C3. Functional constipation C4. Functional diarrhea C5. Unspecified functional bowel disorder – – – E1. Functional gallbladder disorder E2. Functional biliary SO disorder E3. Functional pancreatic SO disorder – – F1. Functional fecal incontinence F2. Functional anorectal pain • F2a. Chronic proctalgia – F2a1. Levator ani syndrome – F2a2. Unspecified functional anorectal pain • F2b. Proctalgia fugax F3. Functional defecation disorders • F3a. Dyssynergic defecation • F3b. Inadequate defecatory propulsion – – C. Functional bowel disorders – C1. Irritable bowel syndrome D. Functional abdominal pain syndrome E. Functional gallgallbladder and Sphincter of Oddi disorders F. Functional anorectal disorders FGIDs: 6 major domains for adults 28 disorders – Drossman DA. Gastroenterology 2006;130:1377–90
  • Rome III Criteria* for Functional Dyspepsia One or more (at least several times per week) of: • Bothersome postprandial fullness • Early satiation • Epigastric pain • Epigastric burning No evidence of structural disease (upper endoscopy) Postprandial Distress Syndrome Epigastric Pain Syndrome *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis Tack J et al., Gastroenterology 2006;130:1466–79
  • Pathophysiology complicated … Psychsocial factors Visceral hypersensitivity Delayed gastric emptying Decreased fundic accommodation Gastric acid Overdistended antrum Mild inflammation (Helicobacter pylori) … or poorly understood ? Tack J et al., Gastroenterology 2006;130:1466–79
  • Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia Odds ratio Delayed gastric emptying: 33.5% of dyspeptics 30 15 0 Female sex Postprandial fullness Vomiting * * * * * * Stanghellini V et al., Gastroenterology 1996;110:1036-42
  • Diagnostic Algorithm for Functional Dyspepsia * *Alarm features include age, unintentional weight loss, symptoms that awaken the patient at night, dysphagia, lymphadenopathy, abdominal mass, and signs of anemia Tack J and Talley NJ. Am J Gastroenterol 2010; 105:757–63
  • Rome III Criteria* for IBS Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following: Improvement with defecation Onset associated with change in frequency of stool Onset associated with change in form of stool *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis Longstreth et al., Gastroenterology 2006;130:1480-91
  • Localization of abdominal pain in IBS Back pain 68-81% 52% 20% 31% 58% Agreus et al., Gastroenterology 1995;109:671-80 Maxton et al., Gut 1991;32:784-6
  • Pain Comorbidity in IBS  Frequent overlap Migraine Other GI  Prevalence in female IBS Fibromyalgia Dyspareunia Interstitial Cystitis  Similar epidemiology  Psychiatric co-morbidity  Common pathophysiological aspects Barsky AJ et al., Ann Intern Med 1999;130:910-21
  • Overlap between IBS, functional dyspepsia and GERD 144 patients with IBS IBS Dyspepsia GERD IBS 22.9% 22.9% 8.3% IBS GERD 45.8% IBS Dyspepsia Cremon et al., Am J Gastroenterol 2009;104:392-400 Cremon et al., DDW 2013
  • IBS diagnosis Positive diagnosis (Rome III Criteria)  Recurrent abdominal pain or discomfort* at least 3 days per month in the last 3 months with symptoms onset at least 6 months prior to diagnosis *unconfortable sensation not described as pain  Associated with 2 or more of the following 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool Exclusion of alarm features (red flags) Age (> 50 yrs) Family history of CR- ca., IBD, CD Rectal bleeding Anemia Fever, ↑ ESR Weight loss Major change in symptoms Abdominal mass Longstreth et al., Gastroenterology 2006;130:1480-91 Mayer EA. N Engl J Med 2008;358:1692-9
  • Probability of organic disease in patients with symptom-based diagnosis of IBS Organic Disease IBS (%) General Popul. (%) Colitis / IBD 0.5 - 1.0 0.3 - 1.2 Colon Cancer 0 - 0.5 4-6 Celiac Disease 4. 7 0.2 - 0.5 0 - 1.7 n.v. 6 5–9 GI Infections Thyroid Dysfunction Cash BD et al., Am J Gastroenterol 2002;97:2812–289
  • Diagnostic Algorithm for IBS Spiller RC and Thompson WG. Am J Gastroenterol 2010;105:775-785
  • Take Home Messages • Oltre il 40% della popolazione lamenta sintomi digestivi (in larga parte di natura funzionale) • FGIDs: combinazione variabile di sintomi gastrointestinali cronici o ricorrenti, in assenza di anomalie strutturali o biochimiche • Sfida per il MMG e il Gastroenterologo (alta prevalenza, enorme impatto sulla QoL ed economico per la società) • I tre più comuni sono: la sindrome dell’intestino irritabile, la dispepsia funzionale e la stipsi cronica (>90% di tutti i FGIDs) • Criteri di Roma → diagnosi positiva (non più diagnosi di esclusione) → segni e/o sintomi di allarme
  • Take Home Messages • La dispepsia funzionale è distinta in 2 sottogruppi: “Postprandial Distress Syndrome” (forma “simil-motoria”) e “Epigastric Pain Syndrome” (forma “simil-ulcerosa”) • Distinti meccanismi fisiopatologici e distinti trattamenti • Il dolore/fastidio addominale è il sintomo cardine della sindrome dell’intestino irritabile • “Grande mimo” e frequente overlap con altri disordini funzionali • L’assenza di segni/sintomi di allarme dovrebbe rassicurare il clinico che la diagnosi è corretta → necessità di limitati accertamenti diagnostici (escludere malattia celiaca)
  • Breath test • Breath test: test del respiro • Esami non invasivi → diagnosi di: intolleranze alimentari (ad es. lattosio, fruttosio), la presenza di Helicobacter pylori o la presenza di batteri in esubero nel piccolo intestino (SIBO) • Parte dei gas prodotti dalla fermentazione batterica diffonde nel sangue ed è escreta con il respiro
  • Small Intestinal Bacterial Overgrowth (SIBO) • Presenza microbiologica di almeno 105 unità formanti colonie (CFU) per millilitro (mL) nell’aspirato digiunale • Tipo 1: batteri Gram+ del tratto respiratorio superiore • Tipo 2: incremento in batteri colici • Diagnosi – Test invasivi: aspirato di succo digiunale ed esame colturale (gold standard) – Test non-invasivi: misure di prodotti del metabolismo batterico Lin. JAMA 2004;292:852-8
  • Gasbarrini et al., Aliment Pharmacol Ther 2009;29 (Suppl 1):1-49
  • Diagnostic value of breath test in detecting SIBO Lactulose BT - sensitivity - specificity - +ve predictive value - -ve predictive value - diagnostic accuracy 52.4% 85.7% 61.5% 53.6% 55.1% Glucose BT - sensitivity - specificity - +ve predictive value - -ve predictive value - diagnostic accuracy 62.5% 81.8% 80.0% 65.5% 71.7% Role, indication and methodology of H2BT in Digestive Disorders Consensus conference Rome, December 2007 Gasbarrini et al., Aliment Pharmacol Ther 2009;29 (Suppl 1):1-49
  • Gasbarrini et al., Aliment Pharmacol Ther 2009;29 (Suppl 1):1-49
  • Current Management of IBS IBS Symptoms Constipation • Reassurance/diet • Increase fiber (20 g) • Osmotic laxative Diarrhea Gas/Bloating First Line • Reassurance/diet • Loperamide • Diphenoxylate • Reassurance/diet • Reassurance/diet • Treat the • Treat constipation/diarrhea • Antispasmodics constipation (e.g. PEG) • Stool softener • Bisacodyl • Prokinetics • Tegaserod* • Prucalopride** • Secretory stimulators • Lubiprostone* • Linaclotide* Pain (e.g. otilonium bromide, trimebutine, peppermint oil) Second Line • Alosetron* • Bile acid sequestran • Antibiotics • Probiotics *Not available in Europe **Approved in Europe for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief • Antibiotics • Probiotics • Antibiotics • Probiotics • Tricyclic antidepressants • Selective serotonin reuptake inhibitors Adapted from Mayer EA. N Engl J Med 2008;358:1692-9
  • Major claims of probiotics in IBS • • • • • Restore intestinal dysbiosis Modulate gastrointestinal motility Reduce visceral hypersensitivity Reduce low grade mucosal immune activation Improve epithelial permeability All these claims are based on convincing experimental evidence from preclinical studies
  • Major claims of probiotics in IBS • • • • • Restore intestinal dysbiosis Modulate gastrointestinal motility Reduce visceral hypersensitivity Reduce low grade mucosal immune activation Improve epithelial permeability All these claims are based on convincing experimental evidence from preclinical studies
  • The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review • 185 trials screened (RCT, adults patients, any definition of IBS, probiotics versus placebo for at least 7 days) • 18 trials eligible for inclusion • Lactobacilli = 6 • Bifidiobacteria = 3 • Streptococci = 1 • Combination = 9 Moayyedi et al., Gut 2010;59:325-332
  • Forest plot of trials comparing probiotics with placebo on overall IBS symptoms (dichotomous outcome) 10 studies with 918 participants NNT = 4 High heterogeneity X2 = 28.3 No differences between different type of probiotic, all showing small benefit Moayyedi et al., Gut 2010;59:325-32
  • Placebo controlled clinical trials of probiotics in IBS Simren M, Barbara G, et al., Gut 2013;62:159-76
  • Drawbacks of probiotics in IBS • Several different formulations have been tested • Strain, dose, and mechanism of action are not fully clarified • Same formulation gave contraddictory results • Different patient populations included in studies (eg, IBS definition, bowel habit, source), frequently not controlled for concomitant therapies • Long-term studies are not currently available • Safety-data are not fully established
  • New pathophysiologic aspects in FGID Stress (CRF) anxiety, depression Genetic polymorphisms (IL-10, TGF-β, TNF-α, IL-6, SERT) Gene expression Increased mucosal permeability (↓ ZO-1) Mucosal immune activation Altered enteroendocrine metabolism (serotonin) Neuroplasticity (SP, NGF) Food hypersensitivity (gluten?) BAM Transient infection Altered microbiota (dysbiosis?) Barbara and Stanghellini Gut 2009;58:1571-5
  • New pathophysiologic aspects in IBS • IBS is a multifactorial disease • Application of novel thechniques discovers the participation of cellular and molecular mechanisms in IBS pathophysiology • During the last years, the role of the intestinal microbiota in IBS pathophysiology has received great interest • Microbiota committee evaluating the role of the intestinal microbiota in functional gastrointestinal disorders • Evidence of microbiota changes (dysbiosis) in IBS?
  • Post-Infectious IBS Gastrointestinal infection • Campylobacter • Shigella • Salmonella •… 1.4 episodes/yr Acute Symptoms Dysbiosis Recovery Post-Infectious IBS (6-17%) Persistent dysbiosis? Spiller et al., Gastroenterology 2009;136:1979-88
  • Salmonella outbreak in Bologna (October 19, 1994) • Tuna sauce contaminated with Salmonella enteritidis D • Delivered for lunch to 36 schools in the Bologna area – 1770 subjects infected (acute symptoms) • 1684 pupils (95%) – children 3-10 yrs • 86 teachers or other school employees (5%) – adults 19-59 yrs • 1543 (87.2%) completed a symptom questionnaire and underwent repeated stool cultures (every 3 wks for 3 months) • Positive fecal cultures decreased from 100% to 1.5% at 3 months post-infection • 6% of patients complained of PI symptoms (vomiting, abdominal pain, diarrhea) at 3 months (negative culture in all cases) Barbara et al., Aliment Pharmacol Ther 2000;14:1127-31
  • Salmonella outbreak in Bologna (…16 years later) Non-exposed Exposed IBS 50 *P = 0.007 OR = 2.05 (95% C.I.= 1.22-3.42) * Prevalence of IBS (%) 40 58/151 (38.4%) 30 20 32/137 (23.4%) 10 0 Cremon et al., DDW 2013; submitted
  • Microbiological revolution: What have we learned? Agar plate culture • Long time to culture • 60-80% unculturable • Molecular biology • 16S rRNA • Number of microbiota genes > 100 time of human genome • 1000-1150 bacterial species identified • Each individual harbours >160 species • “A silent organ” with high metabolic activity (biomass ≈ liver) Gill SR, et al. Science 2006;312:1355–1359
  • 1.5 Different composition of fecal microbiota in IBS vs healthy Multivariate analysis (RDA) • 62 primary care IBS (Rome II), 46 HC HC IBS • Deep molecular analysis Axis2 (20.3%) • 2-fold ↑ Firmicutes/Bacteroidetes ratio • Multivariate analysis identifies 2 distinct enterotypes -1.5 C V -1.5 Axis1 (50%) • IBS symptoms correlated with 18 phylogenetic groups (R = 0.29-0.43) 1.5 Rajilić-Stojanović et al., Gastroenterology 2011;141:1792-801
  • Irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota Sequenced 30.000 16S rRNA gene V4 region amplicons per subjects High Firmicutes:Bacteroidetes ratio IBS (red) Normal Firmicutes:Bacteroidetes ratio IBS (blu) ↑HAD depression score in normal-like IBS group Jerrery IB et al., Gut 2012,61:997-1006
  • New pathophysiologic aspects in FGID Stress (CRF) anxiety, depression Genetic polymorphisms (IL-10, TGF-β, TNF-α, IL-6, SERT) Gene expression Increased mucosal permeability (↓ ZO-1) Mucosal immune activation Altered enteroendocrine metabolism (serotonin) Neuroplasticity (SP, NGF) Food hypersensitivity (gluten?) BAM Transient infection Altered microbiota (dysbiosis?) Barbara and Stanghellini Gut 2009;58:1571-5
  • A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) diet is more effective than standard dietary advice for symptom control in IBS Standard diet (NICE guidelines) Low FODMAP 100 80 % of IBS patients with symptom improvement * * * * * * * 60 40 IBS? 20 0 Bloating Abdominal pain Flatulence Diarrhoea Constipation Nausea Composite score Staudacher et al., J Hum Nutr Diet 2011;24:487-95
  • FODMAP Diet
  • Between Celiac Disease and Irritable Bowel Syndrome: The Gluten Sensitivity Genetic suscetibility Factors that alter barrier function Immune tolerance to gluten Gluten sensitivity (HLA-DQ2/DQ8) Loss of tolerance Potential celiac: CD3+ T cell infiltrate + Ttg AB+/no atrophy Gluten-sensitive: CD3+ T cell infiltrate +/Ttg AB-/no atrophy Symptomatic response to GFD Celiac disease (AB+, atrophy) Refractory sprue Enteropathy-associated lymphoma Verdu et al., Am J Gastroenterol 2009;104:1587-94
  • Gluten-free diet in patients with IBS-D Gluten-containing diet (GCD) associated with: • higher small bowel permeability; • significant decreases of expression of ZO-1, claudin-1 and occludin in the rectosigmoid mucosa These effects were significantly greater in HLA-DQ2/8 positive patients Gluten alters bowel barrier functions in patients with IBS-D (reversible mechanism for the disorder?) Vazquez-Roque MI et al., Gastroenterology 2013;144:903-11
  • New pathophysiologic aspects in FGID Stress (CRF) anxiety, depression Genetic polymorphisms (IL-10, TGF-β, TNF-α, IL-6, SERT) Gene expression Increased mucosal permeability (↓ ZO-1) Mucosal immune activation Altered enteroendocrine metabolism (serotonin) Neuroplasticity (SP, NGF) Food hypersensitivity (gluten?) BAM Transient infection Altered microbiota (dysbiosis?) Barbara and Stanghellini Gut 2009;58:1571-5
  • Mucosal immune cells in the colon: Comparison among different inflammatory disorders 80 *# 70 60 *# 50% * P<0.001 vs HC # P<0.001 vs IBS *# * 50 40 30 20 10 0 “physiologic inflammation” HC IBS Microscopic colitis Inactive UC Active UC Cremon et al., Am J Gastroenterol 2009;104392-400
  • Innate and adaptive immune activation in the colonic mucosa of patients with IBS * HC IBS * * * * Cremon et al., Am J Gastroenterol 2009;104392-400
  • Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome Severity of abdominal pain (VAS) Tryptase +ve MC NSE +ve nerves Mast cell • More closely apposed to nerves 3 2 1 0 0.0 Nerve r = 0.75 p = 0.001 4 0.5 1.0 1.5 N° mast cells < 5 µm to nerves 2.0 • Activated when close to nerves • Mucosal supernatants evoke increased activation of sensory nerve pathways in rodents • MC-nerve vicinity correlated with severity of abdominal pain Barbara et al., Gastroenterology 2004;126:693-702 Barbara et al., Gastroenterology 2007;132:26-37 Cenac et al., J Clin Invest 2007;117:636-47
  • Immune cell count in the colonic mucosa Best cutoff range between IBS and HC: 20.2%-20.3% HC IBS UC 1,0 0,9 0,8 Sensitivity 0,7 0,6 0,5 0,4 0,3 50 µm 50 µm 50 µm 0,2 0,1 * P<0.001 vs HC # P< 0.001 vs IBS 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Specificity Best cutoff range between UC and IBS: 33.8%-34% 1,0 0,9 0,8 0,7 Sensitivity * # 0,0 * 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Specificity Cremon et al., DDW2013
  • Mast cell count in the colonic mucosa HC IBS UC Best cutoff range between IBS and HC: 4.3%-4.7% 1,0 0,9 0,8 50 µm 0,7 50 µm * *# ** P<0.001 vs HC # P=0.098 vs UC ** P=0.009 vs HC Sensitivity 50 µm 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Specificity Cremon et al., DDW2013
  • Diagnostic accuracy of mucosal immune biomarkers in IBS vs HC Biomarkers Best cutoff range Immune cell count Mast cell count TLR-4 mRNA IFN-γ mRNA 20.2-20.3% 4.3-4.7% 1.063-1.149 0.001-0.257 Diagnostic accuracy 80.6% 87.3% 83.3% 86.7% Sensitivity 77.1% 93.8% 80.0% 85.0% Specificity 87.5% 73.5% 90.0% 90.0% +ve predictive value 92.5% 88.2% 94.1% 94.4% -ve predicitive value 65.6% 84.7% 69.2% 75.0% Cremon et al., DDW2013
  • Diagnostic accuracy of mucosal immune biomarkers in UC vs IBS Biomarkers Best cutoff range Immune cell count Mast cell count TLR-4 mRNA IFN-γ mRNA 33.8-34.0% --- 1.536-1.653 6.764-8.674 Diagnostic accuracy 90.0% --- 88.9% 96.3% Sensitivity 87.5% --- 85.7% 100.0% Specificity 91.7% --- 90.0% 95.0% +ve predictive value 87.5% --- 75.0% 87.5% -ve predicitive value 91.7% --- 97.7% 100.0% Cremon et al., DDW2013
  • New pathophysiologic aspects in IBS • IBS is a multifactorial disease • Application of novel thechniques discovers the participation of cellular and molecular mechanisms in IBS pathophysiology • During the last years, the role of the intestinal microbiota in IBS pathophysiology has received great interest • Microbiota committee evaluating the role of the intestinal microbiota in functional gastrointestinal disorders • Evidence of microbiota changes (dysbiosis) in IBS?
  • The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome Mean improvements after 10 weeks follow-up • A double blind placebo-controlled study • 10 days of treatment (400 mg t.i.d) • Significant improvement in IBS symptoms • Prolonged effect (2 ½ months) Global improvement % • 87 IBS patients (Rome I) * p = 0.020 45 * 40 35 36.40% (SD, 31.46%) 30 25 20 15 Placebo 5 0 21.00% (SD, 22.08%) Rifaximin 10 1 2 3 4 5 6 7 8 9 10 Time beyond treatment, wk Pimentel M et al., Ann Intern Med 2006;145:557-563
  • Rifaximin for patients with IBS without constipation % Responders 50 Primary End-point * *P<0.001 40 30 20 10 0 Placebo Rifaximin • Two identically designed, phase 3, multicentre, double blind, placebo-controlled studies (TARGET 1 and TARGET 2) in 1260 patients with IBS Pimentel et al., N Engl J Med 2011;364:22-32
  • Subtyping IBS by predominant stool pattern 100 75 50 IBS-C IBS-M IBS-U IBS-D 25 % Hard or Lumpy Stols (type 1, 2) Bristol Stool Form Scale 0 25 50 75 100 % Loose or Watery Stools (type 6, 7) Bowel pattern subtypes are highly unstable - 75% of patients changes subtypes over 1 year - 29% switch between IBS-C and IBS-D Drossman DA et al., Gastroenterology 2005,128:580-9 Longstreth et al., Gastroenterology 2006;130:1480-91
  • Diagnosis and treatment of chronic constipation: a European perspective Tack J, Muller-Lissner S, Stanghellini V, et al., Neurogastroenterol Motil 2011;23:697–710
  • Prucalopride is effective in severe chronic constipation • Prucalopride: highly selective 5-HT4 receptor agonist • In October 2009, prucalopride (Resolor) received EU approval for the treatment of chronic constipation in women in whom laxatives fail to provide adequate relief Camilleri et al., N Engl J Med 2008;358:2344-54
  • Current Management of IBS IBS Symptoms Constipation • Reassurance/diet • Increase fiber (20 g) • Osmotic laxative Diarrhea Gas/Bloating First Line • Reassurance/diet • Loperamide • Diphenoxylate • Reassurance/diet • Reassurance/diet • Treat the • Treat constipation/diarrhea • Antispasmodics constipation (e.g. PEG) • Stool softener • Bisacodyl • Prokinetics • Tegaserod* • Prucalopride** • Secretory stimulators • Lubiprostone* • Linaclotide* Pain (e.g. otilonium bromide, trimebutine, peppermint oil) Second Line • Alosetron* • Bile acid sequestran • Antibiotics • Probiotics *Not available in Europe **Approved in Europe for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief • Antibiotics • Probiotics • Antibiotics • Probiotics • Tricyclic antidepressants • Selective serotonin reuptake inhibitors Adapted from Mayer EA. N Engl J Med 2008;358:1692-9
  • Linaclotide: mechanism of action • Linaclotide, a novel peptide agonist of guanylate cyclase-C receptors • Binding to GC-C results in the conversion of GTP to cGMP • cGMP accumulation→ phosphorylation of the cystic fibrosis transmembrane regulator (CFTR) → chloride / bicarbonate secretion • Inhibition exchanger of the sodium/hydrogen • cGMP may act to inhibit colonic nociceptors Brierley SM. Curr Opin Pharmacol 2012;12:632-40
  • FDA and EMA end-points in clinical trials of linaclotide in patients with IBS-C Rao S et al., Am J Gastroenterol 2012;107:1714-24 (trial 31) Chey WD et al., Am J Gastroenterol 2012;107:1702-12 (trial 302)