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BACKGROUND & AIMS: Although functional gastrointestinal disorders (FGIDs), now called disorders of gut-brain interaction, have major economic effects on health care systems and adversely affect quality of life, little is known about their global prevalence and distribution. We investigated the prevalence of and factors associated with 22 FGIDs, in 33 countries on 6 continents. METHODS: Data were collected via the Internet in 24 countries, personal interviews in 7 countries, and both in 2 countries, using the Rome IV diagnostic questionnaire, Rome III irritable bowel syndrome questions, and 80 items to identify variables associated with FGIDs. Data collection methods differed for Internet and household groups, so data analyses were conducted and reported separately. RESULTS: Among the 73,076 adult respondents (49.5% women), diagnostic criteria were met for at least 1 FGID by 40.3% persons who completed the Internet surveys (95% confidence interval [CI], 39.9-40.7) and 20.7% of persons who completed the household surveys (95% CI, 20.2-21.3). FGIDs were more prevalent among women than men, based on responses to the Internet survey (odds ratio, 1.7; 95% CI, 1.6-1.7) and household survey (odds ratio, 1.3; 95% CI, 1.3-1.4). FGIDs were associated with lower quality of life and more frequent doctor visits. Proportions of subjects with irritable bowel syndrome were lower when the Rome IV criteria were used, compared with the Rome III criteria, in the Internet survey (4.1% vs 10.1%) and household survey (1.5% vs 3.5%). CONCLUSIONS: in a large-scale multinational study, we found that more than 40% of persons worldwide have FGIDs, which affect quality of life and health care use. Although the absolute prevalence was higher among Internet respondents, similar trends and relative distributions were found in people who completed Internet vs personal interviews., Ironwood; Shire; AllerganAllergan; TakedaTakeda Pharmaceutical Company Ltd; Fundamental Research Grant Scheme (FRGS) of the Ministry of Education of Malaysia [203.PPSP.6171192]; Takeda-Israel; Romanian Society of Neurogastroenterology, The study was funded, in part, by research grants from Ironwood, Shire, Allergan, and Takeda. The study in Malaysia was funded by the Fundamental Research Grant Scheme (FRGS) of the Ministry of Education of Malaysia (Reference: 203.PPSP.6171192). The study in Israel was funded by Takeda-Israel. The study in Romania was funded by the Romanian Society of Neurogastroenterology. None of the funders was involved in the planning, design, implementation, statistical analyses or any other aspect of the study including preparation of the paper or knowledge of its contents.

Background & Aims: The central nervous system regulates gut functions via complex interactions between the enteric nervous and immune systems. The aim of this study was to investigate whether mast cell mediators are released into the human jejunal lumen during stress. Methods: A closed-segment perfusion technique was used to investigate jejunal release of tryptase, histamine, prostaglandin D 2 , and water flux in response to the cold pressor test in 8 healthy subjects and 9 patients with food allergy. In 6 food-allergic patients, jejunal biochemical responses to cold pain stress were compared with those induced by food intraluminal challenge. Results: Cold pain stress elevated heart rate and blood pressure and increased luminal release of mast cell mediators and jejunal water secretion in both groups. Stress-induced release of tryptase and histamine, but not of prostaglandin D 2 and water flux, was greater in food-allergic patients than in healthy volunteers. In food-allergic patients, jejunal biochemical responses induced by cold pain stress were similar to those induced by antigen challenge. Conclusions: These results show the ability of the central nervous system to modulate intestinal mast cell activity and suggest that mast cells have a role in stress-related gut dysfunction. GASTROENTEROLOGY 1998;114:640-648

Background & Aims Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropin-releasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. Methods Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers ( 51 Cr-EDTA, fluorescein isothiocyanate–dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). Results Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), α-helical CRF(9–41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. Conclusions We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation.

Irritable bowel syndrome (IBS), a highly prevalent disorder among women, has been associated with life stress, but the peripheral mechanisms involved remain largely unexplored.A 20-cm jejunal segment perfusion was performed in 2 groups of young healthy women, equilibrated by menstrual phase, experiencing either low (LS; n = 13) or moderate background stress (MS; n = 11). Intestinal effluents were collected every 15 minutes, for 30 minutes under basal conditions, and for 1 hour after cold pain stress. Cardiovascular and psychological response, changes in circulating stress and gonadal hormones, and epithelial function (net water flux, albumin output and luminal release of tryptase and alpha-defensins) to cold stress were determined.Cold pain induced a psychological response stronger in the MS than in the LS group, but similar increases in heart rate, blood pressure, adrenocorticotrophic hormone, and cortisol, whereas estradiol and progesterone remained unaltered. Notably, the jejunal epithelium of MS females showed a chloride-related decrease in peak secretory response (Delta[15-0 minutes]: LS, 97.5 [68.4-135.0]; MS, 48.8 [36.6-65.0] microL/min/cm; P.001) combined with a marked enhancement of albumin permeability (LS(AUC), 6.35 [0.9-9.6]; MS(AUC), 13.97 [8.3-23.1] mg/60 min; P = .008) after cold stress. Epithelial response in both groups was associated with similar increases in luminal tryptase and alpha-defensins release.Increased exposure to life events determines a defective jejunal epithelial response to incoming stimuli. This abnormal response may represent an initial step in the development of prolonged mucosal dysfunction, a finding that could be linked to enhanced susceptibility for IBS.

Introduction: Irritable bowel syndrome with diarrhea (IBS-D) is a chronic, functional gastrointestinal disorder with symptoms of abdominal pain and diarrhea that significantly impact health-related quality of life (HRQoL). Eluxadoline is an investigational, locally active, mixed mu opioid receptor agonist and delta opioid receptor antagonist that significantly improved both pain and diarrhea in two Phase 3 IBS-D trials (IBS3001 and IBS3002). Aim: To evaluate the impact of eluxadoline treatment on HRQoL in patients with IBS-D in two Phase 3 trials. Methods: Adults meeting Rome III criteria for IBS-D were randomized to twice-daily oral treatment with eluxadoline (75 or 100 mg) or placebo for 26 weeks in IBS3002 and 52 weeks in IBS3001. The Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire, which consists of 34 items, each with a 5-point response scale (1=not at all, 5=extremely or a great deal), was completed at baseline and Weeks 4, 8, 12, 18, and 26 in both trials, and at Week 30 in IBS3002 and Weeks 36, 44, and 52 in IBS3001. Mean IBS-QOL overall scores were evaluated for trends by treatment groups by employing a longitudinal mixedeffects polynomial model fitted to pooled data to estimate treatment effects of eluxadoline. Cumulative distribution functions for changes from baseline to Weeks 12, 26, and 52 in IBS-QOL overall scores were plotted. Results: The longitudinal mixed-effects model showed a significant treatment main effect (t=4.45, p

BACKGROUND & AIMS: Intestinal mast cell activity is modulated by the central nervous system, but the mechanisms are not well established. The aim of this study was to investigate whether cerebral thyrotropin- releasing hormone (TRH) activates intestinal mast cells and to elucidate the mechanisms involved, specifically, the contribution of mast cells to vagally stimulated luminal protein release. METHODS: In anesthetized rats, mast cell activation was assessed by measuring the release of the specific mucosal rat mast cell protease II (RMCP II) and prostaglandin (PG) D2 into the intestinal lumen. Luminal protein release was measured as an index of epithelial permeability to macromolecules. RESULTS: Intracisternal injection of the TRH analogue RX 77368 (30 ng) induced a transient increase in intestinal release of RMCP II and PGD2 that was abolished by dox-antrazole. RX 77368- stimulated RMCP II release was also abolished by vagotomy and reduced by atropine by 65%. However, both systemic capsaicin and indo-methacin enhanced RMCP II release. RX 77368-stimulated luminal protein release was abolished by vagotomy and reduced by doxantrazole. CONCLUSIONS: Central vagal activation by TRH stimulates intestinal mast cell secretion, in part via peripheral muscarinic receptors, and is modulated by PGs and capsaicin-sensitive afferent innervation. Intestinal mast cell activation contributes to the TRH analogue- stimulated luminal protein release. (Gastroenterology 1996 Dec;111(6):1465-73)