Accuracy of GastroPanel for the diagnosis of atrophic gastritis.

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<0.01) and increased in patients with corpus CAG (11 vs. 24 pmol/l; P<0.05), but its accuracy was only acceptable in the case of corpus localization [area under the receiver operating characteristic curve (AUC), 74%]; PGII difference was almost statistically significant only when testing for corpus atrophy (33 vs. 21 µg/l; P=0.05; AUC=72%). The PGI and PGI/PGII ratio showed no significant differences (AUCs were all unacceptably low). Helicobacter pylori antibody levels were higher in H. pylori-infected patients (251 vs. 109 EIU, P=0.01; AUC=70). The accuracy of GastroPanel for the diagnosis of CAG was as follows: sensitivity 50%; specificity 80%; positive 25% and negative 92% predictive values; and positive 2.4 and negative 0.6 likelihood ratios. CONCLUSION: GastroPanel is not accurate enough for the diagnosis of CAG; thus, its systematic use in clinical practice cannot be recommended.

Caloric intake capacity as measured by a standard nutrient drink test helps to predict weight loss after bariatric surgery.

BACKGROUND: 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. METHODS: 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. RESULTS: Fourteen women (48 ± 9 years old, BMI 41 ± 3 kg/m(2)) 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/m(2). 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. CONCLUSIONS: 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.

Inflammation-induced functional connectivity of melanin-concentrating hormone and IL-10.

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.

Intestinal upregulation of melanin-concentrating hormone in TNBS-induced enterocolitis in adult zebrafish.

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 trinitrobenzene-sulfonic 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 post-challenge, 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.

MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis.

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.

Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis.

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-ß 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.

A critical appraisal of lubiprostone in the treatment of chronic constipation in the elderly.

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.

Increased susceptibility of melanin-concentrating hormone-deficient mice to infection with Salmonella enterica serovar Typhimurium.

Melanin-concentrating hormone (MCH) was initially identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, the wide distribution of MCH receptors in peripheral tissues suggests additional functions for MCH which remain largely unknown. We have previously reported that mice lacking MCH develop attenuated intestinal inflammation when exposed to Clostridium difficile toxin A. To further characterize the role of MCH in host defense mechanisms against intestinal pathogens, Salmonella enterocolitis (using Salmonella enterica serovar Typhimurium) was induced in MCH-deficient mice and their wild-type littermates. In the absence of MCH, infected mice had increased mortality associated with higher bacterial loads in blood, liver, and spleen. Moreover, the knockout mice developed more-severe intestinal inflammation, based on epithelial damage, immune cell infiltrates, and local and systemic cytokine levels. Paradoxically, these enhanced inflammatory responses in the MCH knockout mice were associated with disproportionally lower levels of macrophages infiltrating the intestine. Hence, we investigated potential direct effects of MCH on monocyte/macrophage functions critical for defense against intestinal pathogens. Using RAW 264.7 mouse monocytic cells, which express endogenous MCH receptor, we found that treatment with MCH enhanced the phagocytic capacity of these cells. Taken together, these findings reveal a previously unappreciated role for MCH in host-bacterial interactions.

Reduced intestinal tumorigenesis in APCmin mice lacking melanin-concentrating hormone.

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.