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Tissue maintenance and repair depend on the integrated activity of multiple cell types 1 . Whereas the contributions of epithelial 2 , 3 , immune 4 , 5 and stromal cells 6 , 7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease 8 . Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ–EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ–EGC–CXCL10 axis in immune response and tissue repair after infectious challenge. Enteric glial cells have tissue-wide immunoregulatory roles through the upregulation of IFNγ-dependent genes both at steady state and after parasite infection, promoting immune homeostasis and CXCL10-mediated tissue repair after pathogen-induced intestinal damage in mice.

Background Endoscopic retrograde cholangiopancreatography (ERCP) is commonly used in both the diagnosis and the treatment of biliary and pancreatic disorders. The aim of this study is to evaluate the effects of OB usage during ERCP on duodenal motility, the tolerability of the procedure (by patients) and the difficulty of the procedure (by the endoscopist). Method The study was conducted in Konya Training and Research Hospital General Surgery Endoscopy Unit in randomized prospective pattern. The patients were divided into the two groups as spasmolytic and control groups. The procedure was performed under topical anesthesia and sedation. Results There were 100 cases included into the study (50 cases in each group). The mean duodenal motility score was found to be 1.9 ± 0.5 in the study group and 3 ± 0.6 in the control group. In the study group, the tolerability of the procedure score by the endoscopist was moderate in 16 % and well/very well in 78 % of the cases. On the other hand, in the control group, the scores were poor in 21 %, moderate in 71 %, and well/very well in 24 % of the cases. In terms of patient satisfaction, in study group 42 % of the cases reported the procedure as moderate and 58 % reported as well/very well. However, in the control group 16 % of the cases reported the procedure as poor, 58 % moderate, and 26 % as well/very well. Conclusion Otilonium bromide is a safe agent with low side effects. It can be used before the ERCP procedure to decrease the duodenal motility. It eases the procedure, moreover, it increases the patients’ satisfaction.

Background: Patients with functional gut disorders manifest poor tolerance to intestinal gas loads but the mechanism of this dysfunction is unknown. Aim: Our aims were firstly, to explore the relative importance of the amount of intestinal gas versus its distribution on symptom production, and secondly, to correlate gut motility and perception of gas loads. Subjects: Fourteen healthy subjects with no gastrointestinal symptoms. Methods: In each subject a gas mixture was infused (12 ml/min) either into the jejunum or rectum for one hour during blocked rectal gas outflow, and subsequently gas clearance was measured over one hour of free rectal evacuation. We measured abdominal perception, distension, and gut tone by duodenal and rectal barostats. Results: Similar magnitude of gas retention (720 ml) produced significantly more abdominal symptoms with jejunal compared with rectal infusion (perception score 4.4 (0.4) v 1.5 (0.5), respectively; p<0.01) whereas abdominal distension was similar (15 (2) mm and 14 (1) mm girth increment, respectively). Jejunal gas loads were associated with proximal contraction (by 57 (5)%) and colonic loads with distal relaxation (by 99 (20)%). Conclusion: The volume of gas within the gut determines abdominal distension whereas symptom perception depends on intraluminal gas distribution and possibly also on the gut motor response to gas loads.

Embryogenesis offers a real laboratory for pattern formation, buckling, and postbuckling induced by growth of soft tissues. Each part of our body is structured in multiple adjacent layers: the skin, the brain, and the interior of organs. Each layer has a complex biological composition presenting different elasticity. Generated during fetal life, these layers will experience growth and remodeling in the early postfertilization stages. Here, we focus on a herringbone pattern occurring in fetal intestinal tissues. Common to many mammalians, this instability is a precursor of the villi, finger-like projections into the lumen. For avians (chicks’ and turkeys’ embryos), it has been shown that, a few days after fertilization, the mucosal epithelium of the duodenum is smooth, and then folds emerge, which present 2 d later a pronounced zigzag instability. Many debates and biological studies are devoted to this specific morphology, which regulates the cell renewal in the intestine. After reviewing experimental results about duodenum morphogenesis, we show that a model based on simplified hypothesis for the growth of the mesenchyme can explain buckling and postbuckling instabilities. Being completely analytical, it is based on biaxial compressive stresses due to differential growth between layers and it predicts quantitatively the morphological changes. The growth anisotropy increasing with time, the competition between folds and zigzags, is proved to occur as a secondary instability. The model is compared with available experimental data on chick’s duodenum and can be applied to other intestinal tissues, the zigzag being a common and spectacular microstructural pattern of intestine embryogenesis.

ObjectiveThe enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes.DesignWe measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human.ResultsWe found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic.ConclusionsUsing a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

RationaleHunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin.ObjectivesTo study the relationship between hunger and MMC phases (I–III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite.FindingsIn fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (β=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower.ConclusionsMotilin-induced gastric phase III is a hunger signal from GIT in man.

4-Dimethylaminoazobenzene (DAB, methyl yellow, or butter yellow), a human carcinogen, has been banned for use in foods since 1988. In 2014, DAB adulteration in Tofu occurred in Taiwan. We hypothesize that DAB can form [DAB•SBP]adduct adduct with soybean protein (SBP) which could damage Gastro-Duodenal-Hepatic axis. Sprague-Dawley rats gavage fed [DAB•SBP]adduct adduct revealed severely reduced body weight and damaged duodenum, liver, hepatic mitochondria, and spleen. Hepatic levels of glutathione and ATP were severely reduced. Serum GOT and GPT were substantially elevated. Analysis by the adsorption isotherm clearly revealed DAB formed very stable [DAB•SBP]adduct adduct at 1:1 molar ration (Phase A). The equilibrium constant of this colloidal adduct [DAB•SBP]adduct was KeqA = ∝, behaving as the most stable and toxic species. At higher protein concentration (Phase C) it formed conjugate [DAB×SBPgross]conjugate, with KeqC = 3.23×10-2 mg/mL, implicating a moderately strong adsorption. The in vitro pepsin digestibility test showed apparently reduced digestibility by 27% (by Ninhydrin assay) or 8% (by Bradford assay). Conclusively, this is the first report indicating that [DAB•SBP]adduct potentially is capable to damage the Gastro-Duodenal-Hepatic axis.

Gpr40 Is Expressed in Enteroendocrine Cells and Mediates Free Fatty Acid Stimulation of Incretin Secretion Sara Edfalk , Pär Steneberg and Helena Edlund From the Umeå Center for Molecular Medicine, University of Umeå, Umeå, Sweden Corresponding author: Helena Edlund, helena.edlund{at}ucmm.umu.se Abstract OBJECTIVE— The G-protein–coupled receptor Gpr40 is expressed in β-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion ( 1 – 4 ). However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5′-flanking region of Gpr40 ( 5 ), implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1 ) Gpr40 is expressed in the intestine and 2 ) Ipf1/Pdx1 function is required for Gpr40 expression. RESEARCH DESIGN AND METHODS— In the present study, Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1 -null and β-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice. RESULTS— Here, we show that Gpr40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in β-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS— Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from β-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 2 June 2008. P.S. and H.E. are joint senior authors of this work. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 27, 2008. Received March 3, 2008. DIABETES

This study aims identifying candidate genes and pathways associated with feed efficiency (FE) in pigs. Liver and duodenum transcriptomes of 37 gilts showing high and low residual feed intake (RFI) were analysed by RNA-Seq. Gene expression data was explored through differential expression (DE) and weighted gene co-expression network analyses. DE analysis revealed 55 and 112 differentially regulated genes in liver and duodenum tissues, respectively. Clustering genes according to their connectivity resulted in 23 (liver) and 25 (duodenum) modules of genes with a co-expression pattern. Four modules, one in liver (with 444 co-expressed genes) and three in duodenum (gathering 37, 126 and 41 co-expressed genes), were significantly associated with FE indicators. Intra-module analyses revealed tissue-specific candidate genes; 12 of these genes were also identified as DE between individuals with high and low RFI. Pathways enriched by the list of genes showing DE and/or belonging to FE co-expressed modules included response to oxidative stress, inflammation, immune response, lipid metabolism and thermoregulation. Low overlapping between genes identified in duodenum and liver tissues was observed but heat shock proteins were associated to FE in both tissues. Our results suggest tissue-specific rather than common transcriptome regulatory processes associated with FE in pigs.

Purpose of Review The gastroduodenal mucosal layer is a complex and dynamic system that functions in an interdependent manner to resist injury. We review and summarize the most updated knowledge about gastroduodenal defense mechanisms and specifically address (a) the mucous barrier, (b) membrane and cellular properties, and vascular, hormonal, and (c) gaseous mediators. Recent Findings Trefoil factor family peptides play a crucial role in cellular restitution by increasing cellular permeability and expression of aquaporin channels, aiding cellular migration and tissue repair. Additionally, evidence suggests that the symptoms of functional dyspepsia may be attributed to alterations in the duodenum, including low-grade inflammation and increased mucosal permeability. Summary The interaction of the various mucosal protective components helps maintain structural and functional homeostasis. There is increasing evidence suggesting that the upper GI microbiota plays a crucial role in the defense mechanisms. However, this warrants further investigation.