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Background It has been suggested that GastroPanel might be a useful tool for the diagnosis of chronic atrophic gastritis (CAG) measuring four biomarkers in blood: basal gastrin-17 (G17), pepsinogen I and II (PGI and PGII), and Helicobacter pylori antibodies. Aim To determine the accuracy of GastroPanel for the diagnosis of CAG. Methods This was a prospective, blinded, multicenter study that included dyspeptic patients. G17, PGI, and PGII were determined by enzyme immunoassays. Three antrum and two corpus biopsies were obtained for standard histological analysis and rapid urease test. Biopsies were analyzed by a single blinded expert pathologist. Results Ninety-one patients were included (77% women, mean age 44 years, 51% H. pylori positive, 17% with CAG). G17 was reduced in patients with antrum CAG (5.4 vs. 13.4 pmol/l; P

Melanin-concentrating hormone (MCH) was identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, similarly to most of the brain peptides, MCH is also produced in the gastrointestinal system and can act locally as an immunomodulator. We have previously reported high expression of MCH and its receptor MCHR1 in the affected mucosa of patients with inflammatory bowel disease. Furthermore, MCH deficiency in mice attenuated experimental colitis, pointing to MCH as a mediator of intestinal inflammation. In the present study, in order to gain further insights into the underlying mechanisms of such effects of MCH, we treated mice with established experimental colitis due to IL-10 deficiency with a MCHR1 antagonist (DABA-822). While treatment with the same drug was successful in attenuating TNBS-induced colitis in previous studies, it offered no benefit to the IL-10 knockout mouse model, suggesting that perhaps IL-10 is a downstream target of MCH. Indeed, in experiments focusing on monocytes, we found that treatment with MCH inhibited LPS-mediated IL-10 upregulation. Conversely, in the same cells, exogenous IL-10 prevented LPS-induced MCHR1 expression. Taken together, these findings indicate a functional cross-talk between MCH and IL-10 which prevents resolution of inflammation.

Chronic constipation is a common disorder in the general population, with higher prevalence in the elderly, and is associated with worse quality of life and with greater health care utilization. Lubiprostone is an intestinal type-2 chloride channel activator that increases intestinal fluid secretion, small intestinal transit, and stool passage. Lubiprostone is currently approved by the US Food and Drug Administration for the treatment of chronic idiopathic constipation and of irritable bowel syndrome with predominant constipation. This review outlines current approaches and limitations in the treatment of chronic constipation in the elderly and discusses the results, limitations, and applicability of randomized, controlled trials of lubiprostone that have been conducted in the general and elderly population, with additional focus on the use of lubiprostone in constipation in Parkinson's disease and in opioid-induced constipation, two clinical entities that can be comorbid in elderly patients.

Instruments that enable to select individuals that will benefit most from bariatric surgery (BS) are necessary to increase its cost-efficiency. Our goal was to assess if intake capacity, measured with a standardized test, predicts response to BS. Patients with criteria for BS were randomly allocated to laparoscopic gastric bypass (LRYGB) or sleeve gastrectomy (LSG). We measured caloric intake capacity before and 1 year after surgery using a standardized nutrient drink test. We evaluated if pre-surgery satiation could predict satiation and weight loss (%) 1 year after surgery using multiple regression modeling. Descriptive statistics are given as mean ± SD. Fourteen women (48 ± 9 years old, BMI 41 ± 3 kg/m2) were evaluated before and 11 ± 2.6 months after surgery (seven LRYGB, seven LSG). Caloric intake capacity diminished after surgery (−950 ± 85 kcal on average [70 ± 8 % decrease over basal intake capacity]; p = 0.002) and similarly in both LRYGB (72 ± 7 % decrease) and LSG groups (68 ± 8 % decrease); p = 0.5. There was a significant weight reduction after surgery (-32 ± 10 kg [30 ± 8 % of total basal weight]) with a mean post-surgery BMI of 29 ± 2 kg/m2. The best predictive model of weight loss (%) after surgery (R 2 = 89 %, p = 0.0009) included: BMI (p = 0.0004), surgery type (p = 0.01) and pre-surgery intake capacity (p = 0.006). Weight loss was higher in heavier patients and those undergoing LRYGB. Patients with higher intake capacity had a poorer outcome independently of basal BMI and surgery type. Caloric intake capacity, as measured by a standard nutrient drink test, helps to predict weight loss after bariatric surgery. This test might be useful in algorithms of obesity treatment decision.

Beatriz Gras-Miralles, Efi KokkotouGastroenterology Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USAAbstract: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects about 9%–13% of the general population. IBS is one of the main reasons to consult a primary care physician, and nearly 30% of visits to a gastroenterologist are for IBS. The diagnosis of IBS relies on subjective, patient-reported symptoms, thus making urgent the need for IBS-specific biomarkers. The same biomarkers, or perhaps different ones, can also be used to monitor disease evolution and response to treatment. A significant number of studies have looked in the immune system for establishing IBS biomarkers, based on the concept that IBS might represent a condition of immune dysregulation somewhere in the spectrum between health and inflammatory bowel disease. Such biomarkers can be detected in blood, intestinal biopsies, or luminal contents. Overall, results are rarely consistent between studies; small sample size, patient and disease heterogeneity, presence of comorbidities, and variation in sampling might contribute to these discrepancies. So far, studies have failed to provide a diagnostic immune biomarker for IBS, but they have considerably advanced our understanding of the disease pathophysiology, including the role of the individual's genetic make-up, and of the host–microbial interactions. High throughput analysis of a large number of well characterized patients holds promise for developing appropriate biomarkers for IBS.Keywords: neuroimmune interactions, mast cells, genetic polymorphisms, cytokines, toll-like receptors

Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD.

Beatriz Gras-Miralles,1 Filippo Cremonini1,21Gastroenterology Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 2Southern Nevada VA Healthcare System, Las Vegas, NV, USAAbstract: Chronic constipation is a common disorder in the general population, with higher prevalence in the elderly, and is associated with worse quality of life and with greater health care utilization. Lubiprostone is an intestinal type-2 chloride channel activator that increases intestinal fluid secretion, small intestinal transit, and stool passage. Lubiprostone is currently approved by the US Food and Drug Administration for the treatment of chronic idiopathic constipation and of irritable bowel syndrome with predominant constipation. This review outlines current approaches and limitations in the treatment of chronic constipation in the elderly and discusses the results, limitations, and applicability of randomized, controlled trials of lubiprostone that have been conducted in the general and elderly population, with additional focus on the use of lubiprostone in constipation in Parkinson's disease and in opioid-induced constipation, two clinical entities that can be comorbid in elderly patients.Keywords: irritable bowel syndrome, Parkinson's disease, opioid-induced constipation, chronic constipation

Background & Aims Altered levels and functions of microRNAs (miRs) have been associated with inflammatory bowel diseases (IBDs), although little is known about their roles in pediatric IBD. We investigated whether colonic mucosal miRs are altered in children with ulcerative colitis (UC). Methods We used a library of 316 miRs to identify those that regulate phosphorylation of signal transducer and activator of transcription 3 (STAT3) in NCM460 human colonocytes incubated with interleukin-6. Levels of miR-124 were measured by real-time polymerase chain reaction analysis of colon biopsies from pediatric and adult patients with UC and patients without IBD (controls), and of HCT-116 colonocytes incubated with 5-aza-2′-deoxycytidine (5-AZA). Methylation of the MIR124 promoter was measured by quantitative methylation-specific polymerase chain reaction. Results Levels of phosphorylated STAT3 and the genes it regulates (encoding vascular endothelial growth factor (VEGF), BCL2, BCLXL, and matrix metallopeptidase 9 [MMP9]) were increased in pediatric patients with UC compared with control tissues. Overexpression of miR-124, let-7, miR-125, miR-26, or miR-101 reduced STAT3 phosphorylation by ≥75% in NCM460 cells; miR-124 had the greatest effect. miR-124 was down-regulated specifically in colon tissues from pediatric patients with UC and directly targeted STAT3 messenger RNA (mRNA). Levels of miR-124 were decreased, whereas levels of STAT3 phosphorylation increased in colon tissues from pediatric patients with active UC compared with those with inactive disease. In addition, levels of miR-124 and STAT3 were inversely correlated in mice with experimental colitis. Down-regulation of miR-124 in tissues from children with UC was attributed to hypermethylation of its promoter region. Incubation of HCT-116 colonocytes with 5-AZA up-regulated miR-124 and reduced levels of STAT3 mRNA. Conclusions miR-124 appears to regulate the expression of STAT3. Reduced levels of miR-124 in colon tissues of children with active UC appear to increase expression and activity of STAT3, which could promote inflammation and the pathogenesis of UC in children. © 2013 by the AGA Institute.

Background Melanin-concentrating hormone (MCH) is an evolutionary conserved hypothalamic neuropeptide that in mammals primarily regulates appetite and energy balance. We have recently identified a novel role for MCH in intestinal inflammation by demonstrating attenuated experimental colitis in MCH deficient mice or wild type mice treated with an anti-MCH antibody. Therefore, targeting MCH has been proposed for the treatment of inflammatory bowel disease. Given the link between chronic intestinal inflammation and colorectal cancer, in the present study we sought to investigate whether blocking MCH might have effects on intestinal tumorigenesis that are independent of inflammation. Methodology Tumor development was evaluated in MCH-deficient mice crossed to the APCmin mice which develop spontaneously intestinal adenomas. A different cohort of MCH−/− and MCH+/+ mice in the APCmin background was treated with dextran sodium sulphate (DSS) to induce inflammation-dependent colorectal tumors. In Caco2 human colorectal adenocarcinoma cells, the role of MCH on cell survival, proliferation and apoptosis was investigated. Results APCmin mice lacking MCH developed fewer, smaller and less dysplastic tumors in the intestine and colon which at the molecular level are characterized by attenuated activation of the wnt/beta-catenin signaling pathway and increased apoptotic indices. Form a mechanistic point of view, MCH increased the survival of colonic adenocarcinoma Caco2 cells via inhibiting apoptosis, consistent with the mouse studies. Conclusion In addition to modulating inflammation, MCH was found to promote intestinal tumorigenesis at least in part by inhibiting epithelial cell apoptosis. Thereby, blocking MCH as a therapeutic approach is expected to decrease the risk for colorectal cancer.

AIM: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum distinguished by relapsing and remitting gastrointestinal and systemic symptoms. Mesalamine (5-aminosalicylic acid; 5-ASA) has proven efficacy in the induction and maintenance of disease remission in patients with mild-to-moderate UC. This phase 1, multicenter, randomized, open-label study (NCT01130844) assessed the pharmacokinetic and safety profiles of 5-ASA and its major metabolite, acetyl-5-ASA (Ac-5-ASA), after administration of once-daily MMX mesalamine to children and adolescents with UC. METHODS: Study participants aged 5-17 years, with a UC diagnosis of ≥3 months were randomized to MMX mesalamine 30, 60, or 100 mg/kg/day (stratified by body weight) for 7 days. To achieve these doses in children, smaller-sized 300 mg and 600 mg tablets were developed for this study to augment the existing approved 1200 mg MMX mesalamine tablet. Patients were administered MMX mesalamine at home on Days 1-4 and on site on Days 5-7 when subjects attended for pharmacokinetic blood and urine sampling and for safety assessments. Plasma and urine concentrations of 5-ASA and Ac-5-ASA were determined by a validated LC/MS/MS assay. Key pharmacokinetic parameters for 5-ASA and Ac-5-ASA included maximum concentration (Cmax,ss), time of Cmax,ss (tmax), area under the curve for one dose interval (AUCss), and renal clearance (CLR), and percent of dose absorbed. RESULTS: A total of 52 patients (30F:22M with mean [standard deviation] age of 13.3 [3.06] years and median [range] time since UC diagnosis of 1.83 [0.2, 9.6] years) were randomized and treated: 21 at 30 mg/kg; 22 at 60 mg/kg; and 9 at 100 mg/kg. Steady state plasma concentrations for 5-ASA and Ac5-ASA were attained by Day 5 for all doses. On Day 7, mean AUCss and Cmax,ss for 5-ASA and Ac-5-ASA increased in a dose proportional manner between 30 and 60 mg/kg/day doses. Mean percentage of 5-ASA absorbed from MMX mesalamine was 29.4%, 27.0%, and 22.1%, for 30, 60, and 100 mg/kg/day doses, respectively. Mean CLR ranged from 5.0-6.5 L/h for 5-ASA and 10.0-16.2 L/h for Ac-5-ASA. The incidence of treatment-emergent adverse events was 19.2% overall. Events were similar among different dose and age groups, with no novel safety signals reported. CONCLUSIONS: The pharmacokinetic profile of 5-ASA and Ac-5ASA in children/adolescents with UC receiving MMX mesalamine across all dose levels was similar to the pharmacokinetic profile in historical adult data. MMX mesalamine was welltolerated at all doses and in all age groups; no new safety signals were identified.

Background: Melanin-concentrating hormone (MCH), an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD). Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzenesulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown. Methods: In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. Results: Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours postchallenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. Conclusions: Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.

Correspondence: Efi Kokkotou Beth Israel Deaconess Medical Center, Division of Gastroenterology, 330 Brookline Avenue, DA-501, 02215, Boston, MA, USA Tel +1 617 667 0549 Fax +1 617 667 2767 Email ekokkoto@bidmc.harvard.edu Abstract: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects about 9%–13% of the general population. IBS is one of the main reasons to consult a primary care physician, and nearly 30% of visits to a gastroenterologist are for IBS. The diagnosis of IBS relies on subjective, patient-reported symptoms, thus making urgent the need for IBS-specific biomarkers. The same biomarkers, or perhaps different ones, can also be used to monitor disease evolution and response to treatment. A significant number of studies have looked in the immune system for establishing IBS biomarkers, based on the concept that IBS might represent a condition of immune dysregulation somewhere in the spectrum between health and inflammatory bowel disease. Such biomarkers can be detected in blood, intestinal biopsies, or luminal contents. Overall, results are rarely consistent between studies; small sample size, patient and disease heterogeneity, presence of comorbidities, and variation in sampling might contribute to these discrepancies. So far, studies have failed to provide a diagnostic immune biomarker for IBS, but they have considerably advanced our understanding of the disease pathophysiology, including the role of the individual’s genetic make-up, and of the host–microbial interactions. High throughput analysis of a large number of well characterized patients holds promise for developing appropriate biomarkers for IBS.

G A A b st ra ct s fibrosis. CP patients have lesser FN and PFAN, with fibrosis morphologically limiting the damage. This may be related to reduction of lipolytic flux by fibrosis between adipocytes and acinar cells, thereby limiting the damage due to unsaturated fatty acids generated by the lipolytic degradation of adipocyte triglyderide. Therefore, fibrosis may be responsible for reducing the severity of acute exacerbations in CP.

G A A b st ra ct s increase of CD11c+ cells in the lamina propria of which are 90% CD11b+ and 40% β2-AR positive. Conclusion: Stimulation of the β2-AR expressed by BMDC results in a significant anti-inflammatory cytokine profile compared to the inflammatory phenotype with high levels of IL-12p70, IL-6, TNFα and low IL-10 of vehicle treated BMDC. In T cell dependant colitis there is a significant increase of CD11c+CD11b+ DC in the lamina propria which express the β2-AR. Treating IBD patients with β2-AR agonists might have the same effect on inflammatory DC as in BMDC and could potentially ameliorate disease activity.

Antecedentes En estudios previos GastroPanel se ha descrito como una herramienta util para el diagnostico de la gastritis atrofica, mediante la determinacion de cuatro marcadores sericos: Gastrina-17 basal (G-17), pepsinogeno I (PGI), pepsinogeno II (PGII) y anticuerpos frente a H. pylori (Hp-ac). Objetivo Determinar la eficacia del GastroPanel para el diagnostico de gastritis atrofica. Metodos Estudio multicentrico, prospectivo, ciego, incluyendo pacientes dispepticos. Se determinaron G-17, PGI, PGII y Hp-ac mediante EIA (Biohit plc, Helsinki, Finlandia). Se obtuvieron tres biopsias de antro y 2 de cuerpo para su estudio histologico estandar y para el test rapido de la ureasa. Las biopsias fueron analizadas por un unico patologo experto que desconocia el resultado del GastroPanel. Resultados Se incluyeron 83 pacientes (76% mujeres, edad media 45 anos, 53% H. pylori-positivos y 9,6% con gastritis cronica atrofica). Las concentraciones basales de G-17, PGI, PGII, cociente PGI/PGII y Hp-ac en pacientes con y sin gastritis atrofica fueron respectivamente: 30 vs 11 pmol/l, 85 vs 120 μg/l, 29 vs 22 μg/l, 5,4 vs 6,6, y 259 vs 175 EIU. Los resultados del GastroPanel se compararon con los del estudios histologico evaluado por un unico patologo experto (patron de referencia), con los siguientes resultados de exactitud diagnostica: Sensibilidad 63%; especificidad 77%; valor predictivo positivo (VPP) 23%; valor predictivo negativo (VPN) 95%; cociente de probabilidades positivo (CP+) 2,8; cociente de probabilidades negativo (CP−) 0,48. La exactitud de cada uno de estos marcadores para el diagnostico de gastritis atrofica en la poblacion de estudio se muestra en la tabla. Marcador ROC Pto. Corte Sensibilidad Especificidad VPP VPN CP+ CP− G-17 0,76 8 pmol/l 75% 69% 21% 96% 2,4 0,36 PGI 0,65 30,9 μg/l 63% 88% 36% 96% 5,2 0,40 PGII 0,62 19,5 μg/l 75% 69% 21% 96% 2,4 0,36 PGI/PGII 0,61 5,5 63% 55% 9,1% 92% 1,0 0,94 Hp-ac 0,75 48,5 EIU 79% 71% 77% 75% 2,7 0,30 ROC: Area bajo la curva ROC. Conclusion Los resultados del presente estudio no muestran suficiente evidencia para justificar el uso sistematico del GastroPanel en el diagnostico de gastritis atrofica.