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Inflammatory Bowel Diseases (IBD) are chronic, reoccurring, and debilitating conditions characterized by inflammation in the gastrointestinal tract, some of which can lead to more systemic complications and can include autoimmune dysfunction, a change in the taxonomic and functional structure of microbial communities in the gut, and complicated burdens in a person's daily life. Like many diseases based in chronic inflammation, research on IBD has pointed towards a multifactorial origin involving factors of the person's lifestyle, immune system, associated microbial communities, and environmental conditions. Treatment currently exists only as palliative care, and seeks to disrupt the feedback loop of symptoms by reducing inflammation and allowing as much of a return to homeostasis as possible. Various anti-inflammatory options have been explored, and this review focuses on the use of diet as an alternative means of improving gut health. Specifically, we highlight the connection between the role of sulforaphane from cruciferous vegetables in regulating inflammation and in modifying microbial communities, and to break down the role they play in IBD.

Humans are inextricably linked to each other and our natural world, and microorganisms lie at the nexus of those interactions. Microorganisms form genetically flexible, taxonomically diverse, and biochemically rich communities, i.e., microbiomes that are integral to the health and development of macroorganisms, societies, and ecosystems. Yet engagement with beneficial microbiomes is dictated by access to public resources, such as nutritious food, clean water and air, safe shelter, social interactions, and effective medicine. In this way, microbiomes have sociopolitical contexts that must be considered. The Microbes and Social Equity (MSE) Working Group connects microbiology with social equity research, education, policy, and practice to understand the interplay of microorganisms, individuals, societies, and ecosystems. Here, we outline opportunities for integrating microbiology and social equity work through broadening education and training; diversifying research topics, methods, and perspectives; and advocating for evidence-based public policy that supports sustainable, equitable, and microbial wealth for all.

For fecal microbiota transplantation (FMT) to be successful in immune diseases like inflammatory bowel disease, it is assumed that therapeutic microbes and their beneficial functions and immune interactions must colonize a recipient patient and persist in sufficient quantity and for a sufficient period of time to produce a clinical benefit. Few studies, however, have comprehensively profiled the colonization and persistence of transferred microbes along with the transfer of their microbial functions and interactions with the host immune system. Using 16S, metagenomic, and immunoglobulin A (IgA) sequencing, we analyzed hundreds of longitudinal microbiome samples from a randomized controlled trial of 12 patients with ulcerative colitis who received fecal transplant or placebo for 12 weeks. We uncovered diverse competitive dynamics among donor and patient strains, showing that persistence of transferred microbes is far from static. Indeed, one patient experienced a dramatic loss of donor bacteria 10 weeks into the trial, coinciding with a bloom of pathogenic bacteria and worsening symptoms. We evaluated the transfer of microbial functions, including desired ones, such as butyrate production, and unintended ones, such as antibiotic resistance. By profiling bacteria coated with IgA, we identified bacteria associated with inflammation and found that microbial interactions with the host immune system can be transferred across people, which could play a role in gut microbiome therapeutics for immune-related diseases. Our findings shed light on the colonization dynamics of gut microbes and their functions in the context of FMT to treat a complex disease—information that may provide a foundation for developing more-targeted therapeutics. IMPORTANCE Fecal microbiota transplantation (FMT)—transferring fecal microbes from a healthy donor to a sick patient—has shown promise for gut diseases such as inflammatory bowel disease. Unlike pharmaceuticals, however, fecal transplants are complex mixtures of living organisms, which must then interact with the microbes and immune system of the recipient. We sought to understand these interactions by tracking the microbes of 12 inflammatory bowel disease patients who received fecal transplants for 12 weeks. We uncovered a range of dynamics. For example, one patient experienced successful transfer of donor bacteria, only to lose them after 10 weeks. We similarly evaluated transfer of microbial functions, including how they interacted with the recipient’s immune system. Our findings shed light on the colonization dynamics of gut microbes, as well as their functions in the context of FMT—information that may provide a critical foundation for the development of more-targeted therapeutics.

Background Fecal microbiota transplantation (FMT) is a promising new strategy in the treatment of Inflammatory Bowel Disease, but long-term delivery systems are lacking. This randomized study was designed as a safety and feasibility study of long-term FMT in subjects with mild to moderate UC using frozen, encapsulated oral FMT (cFMT). Methods Subjects were randomized 1:1 to receive FMT induction by colonoscopy, followed by 12 weeks of daily oral administration of frozen encapsulated cFMT or sham therpay. Subjects were followed for 36 weeks and longitudenal clinical assessments included multiple subjective and objective markers of disease severity. Ribosomal 16S bacterial sequencing was used to assess donor-induced changes in the gut microbiota. Changes in T regulatory (Treg) and mucosal associated invariant T (MAIT) cell populations were evaluated by flow cytometry as an exploratory endpoint. Results Twelve subjects with active UC were randomized: 6 subjects completed the full 12-week course of FMT plus cFMT, and 6 subjects received sham treatment by colonic installation and longitudinal oral placebo capules. Chronic administration of cFMT was found to be safe and well-tolerated but home storage concerns exist. Protocol adherence was high, and none of the study subjects experienced FMT-associated treatment emergent adverse events. Two subjects that received cFMT achieved clinical remission versus none in the placebo group (95% CI = 0.38-infinity, p = 0.45). cFMT was associated with sustained donor-induced shifts in fecal microbial composition. Changes in MAIT cell cytokine production were observed in cFMT recipients and correlated with treatment response. Conclusion These pilot data suggest that daily encapsulated cFMT may extend the durability of index FMT-induced changes in gut bacterial community structure and that an association between MAIT cell cytokine production and clinical response to FMT may exist in UC populations. Oral frozen encapsulated cFMT is a promising FMT delivery system and may be preferred for longterm treatment strategies in UC and other chronic diseases but further evaluations will have to address home storage concerns. Larger trials should be done to explore the benefits of cFMT and to determine its long-term impacts on the colonic microbiome. Trial registration: ClinicalTrials.gov (NCT02390726). Registered 17 March 2015, https://clinicaltrials.gov/ct2/show/NCT02390726?term=NCT02390726&draw=2&rank=1.

ObjectiveTo generate real-world evidence for the epidemiology of gastroparesis in the UK, we evaluated the prevalence, incidence, patient characteristics and outcomes of gastroparesis in the Clinical Practice Research Datalink (CPRD) database.DesignThis was a retrospective, cross-sectional study. Prevalence and incidence of gastroparesis were evaluated in the CPRD database, with linkage to Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics mortality data. Prevalence and incidence were age and sex standardised to mid-2017 UK population estimates. Descriptive analyses of demographics, aetiologies, pharmacological therapies and mortality were conducted.ResultsStandardised prevalence of gastroparesis, as documented in general practice records, was 13.8 (95% CI 12.6 to 15.1) per 100 000 persons in 2016, and standardised incidence of gastroparesis rose from 1.5 (95% CI 1.1 to 1.8) per 100 000 person-years in 2004 to 1.9 (95% CI 1.4 to 2.3) per 100 000 person-years in 2016. The most common disease aetiologies were idiopathic (39.4%) and diabetic gastroparesis (37.5%), with a similar distribution of type 1 and type 2 diabetes among the 90% who had type of diabetes documented. Patients with diabetic gastroparesis had a significantly higher risk of mortality than those with idiopathic gastroparesis after diagnosis (adjusted HR 1.9, 95% CI 1.2 to 3.0). Of those with gastroparesis, 31.6% were not offered any recognised pharmacological therapy after diagnosis.ConclusionThis is, to our knowledge, the first population-based study providing data on epidemiology and outcomes of gastroparesis in Europe. Further research is required to fully understand the factors influencing outcomes and survival of patients with gastroparesis.

BACKGROUND/OBJECTIVE: Partially covered self-expandable metal stents (SEMS) and polyethylene stents (PES) are both commonly used in the palliation of malignant biliary obstruction. Although SEMS are significantly more expensive, they are more efficacious than PES. Accordingly, a cost-effectiveness analysis was performed.METHODS: A cost-effectiveness analysis compared the approach of initial placement of PES versus SEMS for the study population. Patients with malignant biliary obstruction underwent an endoscopic retrograde cholangiopancreatography to insert the initial stent. If the insertion failed, a percutaneous transhepatic cholangiogram was performed. If stent occlusion occurred, a PES was inserted at repeat endoscopic retrograde cholangiopancreatography, either in an outpatient setting or after admission to hospital if cholangitis was present. A third-party payer perspective was adopted. Effectiveness was expressed as the likelihood of no occlusion over the one-year adopted time horizon. Probabilities were based on a contemporary randomized clinical trial, and costs were issued from national references. Deterministic and probabilistic sensitivity analyses were performed.RESULTS: A PES-first strategy was both more expensive and less efficacious than an SEMS-first approach. The mean per-patient costs were US$6,701 for initial SEMS and US$20,671 for initial PES, which were associated with effectiveness probabilities of 65.6% and 13.9%, respectively. Sensitivity analyses confirmed the robustness of these results.CONCLUSION: At the time of initial endoscopic drainage for patients with malignant biliary obstruction undergoing palliative stenting, an initial SEMS insertion approach was both more effective and less costly than a PES-first strategy.

Preview Iron deficiency occurs in about 2% of US adults over age 50 and is a common cause of anemia. Opinions differ on the approach to evaluation of iron deficiency anemia in older patients, and studies have yielded conflicting results. What is the best diagnostic strategy? The authors review study results for the various options and recommend a stepwise, systematic approach to evaluation.

Methane-producing archaea have recently been associated with disorders of the gastrointestinal tract and dysbiosis of the resident microbiota. Some of these conditions include inflammatory bowel disease (Crohn’s disease (CD) and ulcerative colitis (UC)), chronic constipation, small intestinal bacterial overgrowth, gastrointestinal cancer, anorexia, and obesity. The causal relationship and the putative mechanism by which archaea may be associated with human disease are poorly understood, as are the strategies to alter methanogen populations in humans. It is estimated that 30–62% of humans produce methane detectable in exhaled breath and in the gastrointestinal tract. However, it is not yet known what portion of the human population have detectable methanogenic archaea. Hydrogen and methane are often measured in the breath as clinical indicators of intolerance to lactose and other carbohydrates. Breath gas analysis is also employed to diagnose suspected small intestinal bacterial overgrowth and irritable bowel syndrome, although standards are lacking. The diagnostic value for breath gas measurement in human disease is evolving; therefore, standardized breath gas measurements combined with ever-improving molecular methodologies could provide novel strategies to prevent, diagnose, or manage numerous colonic disorders. In cases where methanogens are potentially pathogenic, more data are required to develop therapeutic antimicrobials or other mitigation strategies.

Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal (GI) tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes.Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without occurrence of constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and release levels were determined by enzyme immunoassay, and mRNA levels for the synthetic enzyme tryptophan hydroxylase-1 (TpH-1) and serotonin-selective reuptake transporter (SERT) were assessed by quantitative real-time reverse transcription PCR.CC was associated with increases in TpH-1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript levels were not altered. No changes in these elements of 5-HT signaling were detected in opiate-induced constipation (OIC).These findings demonstrate that CC is associated with a pattern of altered 5-HT signaling that leads to increased 5-HT availability but does not involve a decrease in SERT expression. It is possible that increased 5-HT availability due to increased synthesis and release contributes to constipation due to receptor desensitization. Furthermore, the finding that elements of 5-HT signaling were not altered in the mucosa of individuals with OIC indicates that constipation as a condition does not lead to compensatory changes in 5-HT synthesis, release, or signal termination.

Background & Aims: Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. Methods: Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. Results: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. Conclusions: These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.

Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.

Background and aims: The precise aetiology of achalasia is unknown although autoimmunity has been implicated and is supported by several studies. We screened sera from patients with achalasia or gastro-oesophageal reflux disease (GORD) to test for circulating antimyenteric neuronal antibodies. Methods: Serum was obtained from 45 individuals with achalasia, 16 with GORD, and 22 normal controls. Serum was used in immunohistochemistry to label whole mount preparations of ileum and oesophagus of the guinea pig and mouse. Also, sections of superior cervical and dorsal root ganglia, and spinal cord were examined. Results: Positive immunostaining of the myenteric plexus was detected in significantly more achalasia and GORD samples than control samples (achalasia, p

The aims of this study were to determine if there was a difference in procedure-related abdominal discomfort or willingness to return for subsequent screening examinations between patients undergoing colonoscopy and those undergoing flexible sigmoidoscopy.Two groups were compared: patients referred for screening flexible sigmoidoscopy and patients referred for screening colonoscopy. All patients were asymptomatic for colorectal cancer. Four university-based gastroenterologists performed all procedures. Patients received conscious sedation for colonoscopy but not for flexible sigmoidoscopy. A research nurse blinded to the procedure performed and the study purpose administered a standardized telephone questionnaire assessing and quantifying peri-procedural discomfort.A cohort of 466 patients underwent screening examinations, and 87% were contacted subsequent to their examination. Procedure-related discomfort, postprocedural discomfort, or discomfort at either of these two times ("peri-procedural discomfort") occurred in 28% (68/243), 14% (34/243), and 36% (88/243) of patients undergoing colonoscopy, respectively. Procedure-related discomfort, postprocedural discomfort, or discomfort at either of these two times occurred in 58% (94/162), 16% (26/162), and 62% (100/162) of patients undergoing flexible sigmoidoscopy, respectively. Peri-procedural discomfort was significantly more common in patients undergoing flexible sigmoidoscopy than with colonoscopy (p0.0005). Patients undergoing screening colonoscopy were more willing to undergo the procedure again than those undergoing screening flexible sigmoidoscopy (p0.0005).Patients undergoing screening colonoscopy with conscious sedation are less likely to experience peri-procedural discomfort than those undergoing screening flexible sigmoidoscopy. Although most patients are willing to undergo subsequent screening examinations, patients undergoing screening colonoscopy are significantly more willing to undergo a subsequent examination than those undergoing screening flexible sigmoidoscopy.

Bile leak after cholecystectomy is well described, with the cystic duct remnant the site of the leak in the majority of cases. Endoscopic retrograde cholangiopancreatography (ERCP) with biliary stent placement has a high success rate in such cases. When ERCP fails, options include surgery, and percutaneous and endoscopic transcatheter occlusion of the site of bile leak. Here, we describe a case of endoscopic transcatheter occlusion of a persistent cystic duct bile leak after cholecystectomy using N-butyl cyanoacrylate glue. A 51-year-old man had persistent pain and bilious drainage following a laparoscopic cholecystectomy. The bile leak persisted after endoscopic placement of a biliary stent for a confirmed cystic duct leak. A repeat ERCP was carried out and the cystic duct was occluded with a combination of angiographic coils and N-butyl cyanoacrylate glue. The patient's pain and bilious drainage resolved. A follow-up cholangiogram confirmed complete resolution of the cystic duct leak and a patent common bile duct.

Hepatitis C virus (HCV) is a single-stranded, lipidenveloped, positive-sense RNA virus that frequently results in a chronic hepatitis and may be complicated by a marked humoral immune response and associated immune complex disease (1, 2). A number of extrahepatic, immune-mediated syndromes, including mixed cryoglobulinemia, have been associated with chronic hepatitis C infection. Antibodies to HCV are seen in 98% of sera from patients with mixed essential cryoglobulinemia (3). Renal disease develops in approximately one half of patients with mixed cryoglobulinemia; the principal renal lesion is membranoproliferative glomerulonephritis (MPGN). We describe two patients with chronic hepatitis, mixed cryoglobulinemia, and MPGN who developed renal failure, which resolved after treatment with interferon-a 2b.

To compare efficacy and complications of partially covered self-expandable metal stent (pcSEMS) to plastic stent (PS) in patients treated for malignant, infrahilar biliary obstruction.Multicenter prospective randomized clinical trial with treatment allocation to a pcWallstent(®) (SEMS) or a 10 French PS. Palliative patients aged ≥ 18, for infrahilar malignant biliary obstruction and a Karnofsky performance scale index60% from 6 participating North American university centers. Primary endpoint was time to stent failure, with secondary outcomes of death, adverse events, Karnofsky performance score and short-form-36 scale administered on a three-monthly basis for up to 2 years. Survival analyses were performed for stent failure and death, with Cox proportional hazards regression models to determine significant predictive characteristics.Eighty-five patients were accrued over 37 mo, 42 were randomized to the SEMS group and 83 patients were available for analyses. Time to stent failure was 385.3 ± 52.5 d in the SEMS and 153.3 ± 19.8 d in the PS group, P = 0.006. Time to death did not differ between groups (192.3 ± 23.4 d for SEMS vs 211.5 ± 28.0 d for PS, P = 0.70). The only significant predictor was treatment allocation, relating to the time to stent failure (P = 0.01). Amongst other measured outcomes, only cholangitis differed, being more common in the PS group (4.9% vs 24.5%, P = 0.029). The small number of patients in follow-up limits longitudinal assessments of performance and quality of life. From an initially planned 120 patients, only 85 patients were recruited.Partially covered SEMS result in a longer duration till stent failure without increased complication rates, yet without accompanying measurable benefits in survival, performance, or quality of life.

Gastrointestinal blood loss is the primary cause of iron deficiency anemia in older adults. Bidirectional endoscopy (combined colonoscopy and esophagogastroduodenoscopy) is highly sensitive and specific in its ability to locate gastro-intestinal lesions resulting in iron deficiency anemia. Although the diagnostic yield of esophagogastroduodenoscopy is higher than that of colonoscopy, the possibility of malignant disease dictates that initial colonoscopy be performed in all but a few cases involving distinct upper gastrointestinal risk factors and symptoms. If neither colonoscopy nor esophagogastroduodenoscopy identifies a source of blood loss, a safe course is to observe the patient and provide supplemental iron. Patients who fail to respond to supplemental iron or who become transfusion-dependent require further evaluation. Small-bowel evaluation has a role in selected patients.

Bile leak after cholecystectomy is well described, with the cystic duct remnant the site of the leak in the majority of cases. Endoscopic retrograde cholangiopancreatography (ERCP) with biliary stent placement has a high success rate in such cases. When ERCP fails, options include surgery, and percutaneous and endoscopic transcatheter occlusion of the site of bile leak. Here, we describe a case of endoscopic transcatheter occlusion of a persistent cystic duct bile leak after cholecystectomy using N-butyl cyanoacrylate glue. A 51-year-old man had persistent pain and bilious drainage following a laparoscopic cholecystectomy. The bile leak persisted after endoscopic placement of a biliary stent for a confirmed cystic duct leak. A repeat ERCP was carried out and the cystic duct was occluded with a combination of angiographic coils and N-butyl cyanoacrylate glue. The patient's pain and bilious drainage resolved. A follow-up cholangiogram confirmed complete resolution of the cystic duct leak and a patent common bile duct.

Alterations in motility, secretion and visceral sensation are hallmarks of irritable bowel syndrome. As all of these aspects of gastrointestinal function involve serotonin signalling between enterochromaffin cells and sensory nerve fibres in the mucosal layer of the gut, potential alterations in mucosal serotonin signalling have been explored as a possible mechanism of altered function and sensation in irritable bowel syndrome. Literature related to intestinal serotonin signalling in normal and pathophysiological conditions has been searched and summarized. Elements of serotonin signalling that are altered in irritable bowel syndrome include: enterochromaffin cell numbers, serotonin content, tryptophan hydroxylase message levels, 5-hydroxyindoleacedic acid levels, serum serotonin levels and expression of the serotonin-selective reuptake transporter. Both genetic and epigenetic factors could contribute to decreased serotonin-selective reuptake transporter in irritable bowel syndrome. A serotonin-selective reuptake transporter gene promoter polymorphism may cause a genetic predisposition, and inflammatory mediators can induce serotonin-selective reuptake transporter downregulation. While a psychiatric co-morbidity exists with IBS, changes in mucosal serotonin handling support the concept that there is a gastrointestinal component to the aetiology of irritable bowel syndrome. Additional studies will be required to gain a more complete understanding of changes in serotonin signalling that are occurring, their cause and effect relationship, and which of these changes have pathophysiological consequences.

Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders.Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples.Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls.These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.

Disorders of gastrointestinal function are common and significantly reduce quality-of-life, as well as negatively impacting healthcare costs. Consequently, there is much interest in understanding the pathogenesis of these disorders. Increasing, albeit as yet limited, evidence has implicated alterations in 5-hydroxytryptamine (5-HT) release, and the subsequent interaction of 5-HT with specific 5-HT receptor subtypes, in the altered gut function of patients with irritable bowel syndrome (IBS) and other functional bowel diseases. Alterations to enterochromaffin cells and/or 5-HT signaling can result in gastrointestinal dysmotility, visceral hypersensitivity and secretomotor abnormalities in the gut. Evidence is beginning to link disturbed 5-HT physiology with the pathophysiology of diarrhea and constipation in IBS, and with slow-transit constipation. This review discusses the current evidence on the pathobiology of these systems.

The exact cause of inflammatory bowel disease remains undiscovered, but its destructive nature is clearly recognized. In this article, the authors summarize what is known about the pathogenesis and epidemiology of ulcerative colitis and Crohn's disease and how to distinguish between the two, both clinically and pathologically. They also describe disorders that may mimic inflammatory bowel disease. In part 2 of this article, beginning on page 86, the authors discuss some of the therapeutic options that are the commonly used as well as some that are investigational but show promise for patients with this chronic and relapsing disease.

Key elements of serotonin signaling are altered in IBD and IBS: support for a molecular basis of the irritable bowel syndrome

Background & Aims 5-hydroxytryptamine receptor (5-HT 4 R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT 4 receptors are expressed in the colonic epithelium and that 5-HT 4 R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. Methods Mucosal expression of the 5-HT 4 R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT 4 R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl − secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT 4 R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. Results Mucosal 5-HT 4 receptors were present in the small and large intestines. In the distal colon, 5-HT 4 receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT 4 Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl − secretion. Luminal administration of 5-HT 4 R agonists accelerated propulsive motility; a 5-HT 4 R antagonist blocked this effect. Bath application of 5-HT 4 R agonists did not affect motility. Oral or intracolonic administration of 5-HT 4 R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT 4 R antagonist. Conclusions Mucosal 5-HT 4 receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT 4 R agonists. Colon-targeted, intraluminal delivery of 5-HT 4 R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.

*S1574 BIS Values Correlate with Clinical Sedation Scores During Midazolam/Narcotic or Propofol Sedation for Endoscopy Peter L. Moses, John J. Vargo, Roger D. Mitty, Douglas K. Pleskow, John A. Walker, Douglas K. Rex BIS is an EEG-based monitoring technology which tracks sedative effect and has been demonstrated to have clinical utility in sedation management. Bower et al. determined that a BIS range of 75-85 provided adequate sedation during propofolbased sedation for endoscopy. In aprevious study,we reported thatBISwas able to track sedative effects, arousal and emergence from traditional sedation and correlated with endoscopist satisfaction (Moses et al.). Methods: To confirm these results, we studied 72 sedated patients with informed consent undergoing scheduled endoscopies (Colonoscopies = 44, EGD = 13, EUS = 12, Bidirectional = 3) in an IRB-approved prospective, observational trial. Sedation was provided using either a standard technique (STD) with midazolam and a narcotic (meperidine or fentanyl) or a pure-hypnotic technique using propofol alone (PRO). The Modified Observer’s Assessment of Alertness and Sedation Scale (MOAAS)was used to evaluate the level of sedation.Additionally, BIS (Rev. 4.1, Aspect Medical Systems) values were recorded. The variation of BIS values with MOAAS scores was analyzed using ANOVA with Bonferroni correction for post-hoc comparisons between individual MOAAS scores. Results: There was a statistically significant variation in BIS values withMOAAS scores (p < 0.001). For patients in the STDgroup, there were statistically significant differences in BIS values betweenMOAAS levels 4 vs. 2 (p=0.008); 4 vs. 5 (p

Health-related quality of life (HRQOL) subsequent to esophageal adenocarcinoma staging with endoscopic ultrasound (EUS)