Duodenal Mucosal Injury Research Articles

WeiNaiAn capsule attenuates intestinal mucosal injury and regulates gut microbiome in indomethacin-induced rat

Indomethacin, as a non-steroidal anti-inflammatory drugs, is widely used in the clinic. However, it can cause severe injury to the gastrointestinal tract and the incidence is increasing. It has become an essential clinical problem in preventing intestinal damage. Teprenone has been reported to have a significant positive effect on intestinal mucosal lesions, but long-term use of teprenone can elicit adverse reactions. WeiNaiAn capsule is a traditional Chinese medicine formulation used widely in the treatment of gastric and duodenal mucosal injury. However, how WeiNaiAn protects against intestinal mucosal injury and its mechanism of action are not known. In this study, WeiNaiAn capsule or Teprenone treatment improved the intestinal mucosal pathological score and antioxidant level in indomethacin-induced rats. 16 S rRNA sequence data showed WeiNaiAn capsule reverted the structure community and replenished the beneficial bacteria. Furthermore, fingerprint analysis revealed multiple components of WeiNaiAn capsule, including calycosin glucoside, ginsenoside Rg1, ginsenoside Rb1, taurocholic acid sodium, formonetin, and calycosin glucoside. The components of WeiNaiAn capsule promoted the wound healing of the epithelial cell in vitro. Moreover, the components of WeiNaiAn capsule inhibited the protein expressions of phosphoinositide 3-kinase /protein kinase B /mammalian target of rapamycin in hydrogen peroxide or lipopolysaccharides-induced cell model. In conclusion, WeiNaiAn capsule improves intestinal mucosal injury by regulating cell migration, enhancing antioxidant activity, and promoting the structure of the bacterial community homeostasis, the multiple targets provide the parameters for the treatment in the clinic.

Deciphering the function of Xiangsha-Liujunzi-Tang in enhancing duodenal mucosal barrier by inhibiting MC/Tryptase/PAR-2 signaling pathway in functional dyspepsia rats

Ethnopharmacological relevanceXiangsha-Liujunzi-Tang (XSLJZT) is a classical formula for treating the diseases of digestive system, which can effectively and significantly improve the symptoms of functional dyspepsia (FD) patients. The main function of XSLJZT is to benefit Qi and spleen, and harmonize stomach. Aim of the studyThe purpose of this study was to investigate the intervention effect of XSLJZT on duodenal mucosal injury in FD rats and the response mechanism of MC/Tryptase/PAR-2 signal pathway. Materials and methodsUltra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to qualitatively and quantitatively identify the chemical component of XSLJZT. A comprehensive modeling method (iodoacetamide infusion + irregular diet + swimming exhaustion) was used to construct the FD rat model. XSLJZT decoction was given to intervene FD rats for 2 weeks. The indicators of digestive function including body mass, 3-h food intake, visceral sensitivity, gastric emptying rate and intestinal propulsion rate were routinely measured for FD rats. The pathological changes of duodenum and microstructure of intestinal epithelial cells were observed by HE staining and transmission electron microscopy respectively. The inflammatory factors (VCAM-1, IL-6, TNF-α, and ICAM-1) and histamine content were evaluated by enzyme-linked immunosorbent assay (ELISA). The expression levels of Tryptase, PAR-2, ZO-1, β-catenin, p–NF–κBp65 and p-ERK1/2 in duodenal tissues were measured by Western blot (WB) and immunofluorescence colony-staining (IFC). ResultsXSLJZT administration significantly improved the survival of FD rats, increased body mass and 3-h food intake, improved visceral sensitivity, and restored gastric emptying rate and intestinal propulsion rate. HE staining showed that XSLJZT recovered the structure of duodenal mucosal and reduced inflammatory infiltration. ELISA revealed that XSLJZT reduced the content of inflammatory factors (VCAM-1, IL-6, TNF-α, and ICAM-1) and histamine. In addition, WB and IFC uncovered that the protein levels of ZO-1 and β-catenin were up-regulated and MC/Tryptase/PAR-2 signaling pathway was inhibited by XSLJZT. ConclusionXSLJZT significantly improved the integrity of duodenal mucosa and decreased the inflammation in FD rats through the inhibition of MC/Tryptase/PAR-2 signaling pathway response.

Effects of the probiotic, Lactobacillus rhamnosus GG, on ulcer pathogenesis, HSP70 stress protein and nitric oxide levels in stress induced ulcer

ABSTRACT Peptic ulcer is a gastric or duodenal mucosal injury; psychological stress may participate in development of the lesions. Heat shock protein-70 (HSP70) is a molecular chaperone that is responsible for cellular healing; it is an early biomarker of cellular damage. Nitric oxide (NO) is an intra- and intercellular messenger in the gastrointestinal system that protects mucosal integrity. Lactobacillus rhamnosus is among the microflora of the intestinal tract; it is resistant to gastric acidity. We investigated the efficacy of L. rhamnosus administration on ulcer pathogenesis, stress protein HSP70 and NO levels in experimental stress induced ulcer. The proton pump inhibitor, pantoprazole, was used for comparison with the gastroprotective effect of the probiotic. We administered 10 mg/kg pantoprazole and L. rhamnosus at doses of 3 × 108 cfu/ml (M1), 15 × 108 cfu/ml (M5), 30 × 108 cfu/ml (M10) to rats according to McFarland-1, McFarland-5, McFarland-10 standards, respectively. Rats were stressed by immobilization at 4 °C, then sacrificed. The pH, amounts of gastric mucus, NO and HSP70 levels were measured and the histological structure of stomach was assessed. We found increased NO levels in the M5 group and increased HSP70 expression in the pantoprazole group. Significant epithelial damage was observed in the stressed groups and minimal epithelial damage was observed in M5 group compared to controls. The probiotic, L. rhamnosus, may be useful for preventing stress induced ulcers.

Repeat Biopsy to Assess Duodenal Healing in Children With Celiac Disease and Eosinophilic Gastrointestinal Disorders.

A retrospective chart review was performed of children with CD and EGID seen at the Children's Hospital of Philadelphia between 2003 and 2018. Data collected included duodenal biopsy pathology, celiac serology including tTG-IgA, and symptom reports. Duodenal healing was defined as normal villous architecture and no intraepithelial lymphocytes. These data were compared with tTG-IgA level. Data were analyzed with Fisher exact test and t test methods. Thirty-nine patients had normal IgA and diagnoses of both CD and EGID. At second biopsy, 44% (17/39) of patients showed no histologic evidence of active CD and 36% (14/39) of patients had negative tTG-IgA values. Sixty percent (9/15) of patients with no evidence of CD on biopsy had abnormal tTG-IgA levels, and 57% (8/14) of patients with normal tTG-IgA levels had evidence of active disease on biopsy. The data show that an abnormal tTG-IgA drawn after initiation of a gluten-free diet is not correlated with duodenal mucosal injury in pediatric patients with CD and EGID. This suggests that serologic surveillance with tTG-IgA is not sufficient to monitor CD intestinal healing in this patient cohort. Persistent elevations of tTG-IgA in CD patients with normal duodenal biopsies should prompt investigation into other potential causes.

Pigmented Corn Varieties as Functional Ingredients for Gluten-Free Products.

Oxidative stress, one among the several factors responsible for the gluten toxicity in celiac disease, together with inflammation and duodenal mucosal injury, are only partially reduced by the gluten-free diet. Thanks to their phenolic profile, the pigmented varieties of corn could be an interesting source of dietary antioxidants for the formulation of new gluten-free ingredients. The aim of this research was: (1) to characterize the phenolic profile and the associated antioxidant properties of corn samples with different pigmentation, using spectrophotometric and chromatographic techniques and (2) to assess the stability of anthocyanins during the gastro-intestinal digestion. The pigmented varieties showed a significantly higher content of polyphenols compared to the common yellow varieties and, as a consequence, a higher antioxidant activity. Although corn is among the cereals most frequently used in gluten-free products, it can produce an inflammatory response in some celiac patients. Therefore, after the chemical characterization, the safety of the pigmented varieties for celiac patients was confirmed using different in vitro models (cell agglutination test and the measure of transepithelial electrical resistance). Although in vivo studies are necessary, the data collected in this study underline that the pigmented corn could have a role in reducing the oxidative stress at the intestinal level in celiac subjects.

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease

BackgroundIn celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.MethodsIn a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).ResultsOf the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells (95% CI, −7.6 to 2.2) in the 10-mg group, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) in the 50-mg group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.ConclusionsIn this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.)

Effect of Weikang Capsule () on Aspirin-Related Gastric and Small Intestinal Mucosal Injury.

To investigate the effects of Weikang Capsule (, WKC) on aspirin-related gastric and small intestinal mucosal injury by magnetically controlled capsule endoscopy (MCCE). Patients taking enteric-coated aspirin aged 40-75 years were enrolled in Beijing Anzhen Hospital, Capital Medical University from January 2019 to December 2019. The patients continued taking aspirin Tablet (100 mg per day) and underwent MCCE before and after 1-month combined treatment with WKC (0.9 g per time orally, 3 times per day). The gastrointestinal symptom score, gastric Lanza score, the duodenal, jejunal and ileal mucosal injury scores were used to evaluate the gastrointestinal injury before and after treatment. Adverse events including nausea, vomiting, abdominal pain, abdominal distension, abdominal discomfort, dizziness, or headache during MCCE and combined treatment were observed and recorded. Twenty-two patients (male/female, 13/9) taking enteric-coated aspirin aged 59.5 ± 11.3 years with a duration of aspirin use of 28.0 (1.0, 48.0) months were recruited. Compared with pre-treatment, the gastrointestinal symptom rating scale scores, gastric Lanza scores, and duodenal mucosal injury scores were significantly reduced after 1-month WKC treatment (P<0.05), and jejunal and ileal mucosal injury scores showed no obvious change. No adverse events occurred during the trial. WKC can alleviate gastrointestinal symptoms, as well as gastric and duodenal mucosal injuries, in patients taking enteric-coated aspirin; it does not aggravate jejunal or ileal mucosal injury, which may be an effective alternative for these patients (Clinical trial registry No. ChiCTR1900025451).

A New Intraepithelial \u03b3\u03b4 T-Lymphocyte Marker for Celiac Disease Classification in Formalin-Fixed Paraffin-Embedded (FFPE) Duodenal Biopsies

BackgroundThe histopathologic diagnosis of celiac disease (CD) may be challenging when the duodenal biopsies mucosal injury is limited. Intraepithelial T-lymphocytes (IELs) can be useful to characterize the degree of mucosal inflammation. A small fraction of IELs expresses the γδ T-cell receptor (named γδ-IELs), whose density, determined by flow cytometry or frozen section immunohistochemistry (IHC), is a specific marker for CD.AimTo establish a new IHC assay for γδ-IELs applicable to formalin-fixed paraffin-embedded (FFPE) duodenal biopsies.MethodsWe analyzed γδ-IELs using IHC in 138 duodenal biopsies using a standard IHC staining protocol with a new monoclonal antibody H-41. IELs were quantitated with digital image analysis.ResultsCompared to those in non-celiac controls (n = 51), γδ-IEL density was significantly increased in newly diagnosed celiac disease patients (n = 22, p < 0.0001). In ROC-curve analysis, the cutoff of 6.5 γδ-IELs/100 enterocytes distinguished optimally active CD patients from non-celiac controls (sensitivity 96%, specificity 95%). γδ-IEL density in CD patients on a gluten-free diet (n = 53) were also higher than in controls (p < 0.0001), but lower than those in newly diagnosed CD (p < 0.0001). The diagnostic value of γδ-IELs outperformed that of CD3 + IELs in both patient groups. γδ-IELs were better than CD3 + IELs distinguishing between celiac disease and conditions histologically mimicking celiac disease (n = 12).ConclusionsIntraepithelial γδ T-lymphocytes can be stained and quantitated reliably in FFPE duodenal biopsies. The results showed excellent specificity and sensitivity for celiac disease. The new IHC method of detection of γδ-IELs is a promising addition to the routine histopathologic assessment methodology of celiac disease.

Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge

Background & AimsGluten challenge studies are instrumental in understanding the pathophysiology of celiac disease. Our aims in this study were to reveal early gluten-induced transcriptomic changes in duodenal biopsies and to find tools for clinics.MethodsDuodenal biopsies were collected from 15 celiac disease patients on a strict long-term gluten-free diet (GFD) prior to and post a gluten challenge (PGC) and from 6 healthy control individuals (DC). Biopsy RNA was subjected to genome-wide 3’ RNA-Seq. Sequencing data was used to determine the differences between the three groups and was compared to sequencing data from the public repositories. The biopsies underwent morphometric analyses.ResultsIn DC vs. GFD group comparisons, 167 differentially expressed genes were identified with 117 genes downregulated and 50 genes upregulated. In PGC vs. GFD group comparisons, 417 differentially expressed genes were identified with 195 genes downregulated and 222 genes upregulated. Celiac disease patients on a GFD were not “healthy”. In particular, genes encoding proteins for transporting small molecules were expressed less. In addition to the activation of immune response genes, a gluten challenge induced hyperactive intestinal wnt-signaling and consequent immature crypt gene expression resulting in less differentiated epithelium. Biopsy gene expression in response to a gluten challenge correlated with the extent of the histological damage. Regression models using only four gene transcripts described 97.2% of the mucosal morphology and 98.0% of the inflammatory changes observed.ConclusionsOur gluten challenge trial design provided an opportunity to study the transition from health to disease. The results show that even on a strict GFD, despite being deemed healthy, patients reveal patterns of ongoing disease. Here, a transcriptomic regression model estimating the extent of gluten-induced duodenal mucosal injury is presented.

Sini San ameliorates duodenal mucosal barrier injury and low‑grade inflammation via the CRF pathway in a rat model of functional dyspepsia.

The gut-brain interaction is associated with impaired duodenal mucosal integrity and low-grade inflammation, which have been proven to be important pathological mechanisms of functional dyspepsia (FD). Sini San (SNS) is a classical Chinese medicine used to treat FD, but its underlying mechanisms are poorly understood. The aim of the present study was to evaluate the effects of SNS on duodenal mucosal barrier injury and low-grade inflammation with FD, and to assess its potential molecular mechanisms on the brain-gut axis. FD rats were established using the iodoacetamide and tail-squeezed methods. The expression of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF-R1) and CRF-R2, were determined by western blot analysis and/or immunohistochemistry (IHC). In addition, mast cell (MC) migration was assessed by IHC with an anti-tryptase antibody, and histamine concentration was quantified using ELISA. The mRNA expression levels of tryptase and protease-activated receptor 2 (PAR-2) were quantified using reverse transcription-quantitative PCR, and the protein expression levels of zona occludens protein 1 (ZO-1), junctional adhesion molecule 1 (JAM-1), β-catenin and E-cadherin were determined via western blot analysis. It was demonstrated that the expression level of CRF was downregulated in the central nervous system and duodenum following SNS treatment, and that SNS modulated the expression of both CRF-R1 and CRF-R2. In addition, SNS suppressed MC infiltration and the activity of the tryptase/PAR-2 pathway in the duodenum. Furthermore, treatment with SNS restored the normal expression levels of ZO-1, JAM-1 and β-catenin in FD rats. These findings suggested that the therapeutic effects of SNS on FD were achieved by restoring mucosal barrier integrity and suppressing low-grade inflammation in the duodenum, which was at least partially mediated via the CRF signaling pathway.

Tissue Transglutaminase Antibody and Its Association with Duodenal Biopsy in Diagnosis of Pediatric Celiac Disease.

PurposeThis study aimed to evaluate a possible association between the anti-tissue transglutaminase antibody (anti-tTG) titer and stage of duodenal mucosal damage and assess a possible cut-off value of anti-tTG at which celiac disease (CD) may be diagnosed in children in conjunction with clinical judgment.MethodsThis observational study was conducted at a gastroenterology clinic in a tertiary hospital from April 2012 to May 2013. Seventy children between 6-months and 18-years-old with suspected CD underwent celiac serology and duodenal biopsy. Statistical analyses were done using SPSS 16. Diagnostic test values were determined for comparing the anti-tTG titer with duodenal biopsy. An analysis of variance and Tukey-Kramer tests were performed for comparing the means between groups. A receiver operating characteristics curve was plotted to determine various cut-off values of anti-tTG.ResultsThe mean antibody titer increased with severity of Marsh staging (p<0.001). An immunoglobulin (Ig) A-tTG value at 115 AU/mL had 76% sensitivity and 100% specificity with a 100% positive predictive value (PPV) and 17% negative predictive value (NPV) for diagnosis of CD (p<0.001, 95% confidence interval [CI], 0.75–1).ConclusionThere is an association between the anti-tTG titer and stage of duodenal mucosal injury in children with CD. An anti-tTG value of 115 AU/mL (6.4 times the upper normal limit) had 76% sensitivity, 100% specificity, with a 100% PPV, and 17% NPV for diagnosing CD (95% CI, 0.75–1). This cut-off may be used in combination with clinical judgment to diagnose CD.

Effects of melatonin on acetylsalicylic acid induced gastroduodenal and jejunal mucosal injury

We evaluated the effects of melatonin on acetylsalicylic acid (ASA) induced gastroduodenal and jejunal mucosal injury. We used 40 postpubertal rats divided randomly into five groups of eight animals. The control group consisted of untreated animals. The Mel group was injected intraperitoneally (i.p.) with 5 mg/kg melatonin. The ASA group was injected i.p. with 200 mg/kg ASA. The ASA + Mel group was injected i.p. with 5 mg/kg melatonin 45 min after administering 200 mg/kg ASA i.p. The Mel + ASA group was injected i.p. with 5 mg/kg melatonin 45 min before administering 200 mg/kg ASA i.p. We found no statistically significant differences in mean histopathological scores in the ASA + Mel group compared to the ASA group. ASA caused shortened villi and loss of the apical villus in the duodenum. The histopathological score was increased and villus height was decreased in the ASA group compared to untreated controls. Treatment with melatonin attenuated the histological damage. In the ASA group, occasional areas showed erosion of villi in the jejunum; however, differences in mean histopathological score in ASA group compared to the other groups were not statistically significant. Malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) activities were measured in stomach, duodenal and jejunum tissue. We found increased MDA activity in both stomach and duodenal tissues in the ASA group compared to the control group (p < 0.05). We found no statistically significant changes in MDA levels in jejunal tissue in the ASA group compared to the control group. We found no change in SOD activity in either stomach or duodenal tissues in the ASA group compared to the control group. We observed decreased SOD activity in jejunal tissue in the ASA group compared to the control group (p < 0.05). We detected no change in GSH activity in stomach, duodenal or jejunal tissues in the ASA group compared to the control group. The stomach damage was less in melatonin treated groups, but the lesions were not completely eliminated. The jejunum in the ASA group retained a nearly normal appearance. We found that melatonin exhibited some healing effects on ASA induced duodenal mucosal injury.

FFA2 activation combined with ulcerogenic COX inhibition induces duodenal mucosal injury via the 5-HT pathway in rats

Serotonin (5-HT), predominantly synthesized and released by enterochromaffin cells, is implicated in gastrointestinal symptoms such as emesis, abdominal pain, and diarrhea. Because luminal short-chain fatty acids (SCFAs) release 5-HT from enterochromaffin cells, which express the SCFA receptor free fatty acid receptor 2 (FFA2) in rat duodenum, we examined the effects of the selective FFA2 agonist phenylacetamide-1 (PA1) on duodenal 5-HT release with consequent bicarbonate secretion [duodenal bicarbonate secretion (DBS)] and on indomethacin (IND)-induced enteropathy. Intestinal injury was induced by IND (10 mg/kg sc) with or without PA1. We measured DBS in vivo in a duodenal loop perfused with PA1 while measuring 5-HT released in the portal vein. Duodenal blood flow was measured by laser-Doppler flowmetry. IND induced small intestinal ulcers with duodenal sparing. PA1 given with IND (IND + PA1) dose dependently induced duodenal erosions. IND + PA1-induced duodenal lesions were inhibited by the FFA2 antagonist GLPG-0974, ondansetron, or omeprazole but not by RS-23597 or atropine. Luminal perfusion of PA1 augmented DBS accompanied by increased portal blood 5-HT concentrations with approximately eight times more release at 0.1 mM than at 1 µM, with the effects inhibited by coperfusion of GLPG-0974. Luminal PA1 at 1 µM increased, but at 0.1 mM diminished, duodenal blood flow. Cosuperfusion of PA1 (0.1 mM) decreased acid-induced hyperemia, further reduced by IND pretreatment but restored by ondansetron. These results suggest that, although FFA2 activation enhances duodenal mucosal defenses, FFA2 overactivation during ulcerogenic cyclooxygenase inhibition may increase the vulnerability of the duodenal mucosa to gastric acid via excessive 5-HT release and 5-HT3 receptor activation, implicated in foregut-related symptoms such as emesis and epigastralgia.NEW & NOTEWORTHY Luminal free fatty acid receptor 2 agonists stimulate enterochromaffin cells and release serotonin, which enhances mucosal defenses in rat duodenum. However, overdriving serotonin release with high luminal concentrations of free fatty acid 2 ligands such as short-chain fatty acids injures the mucosa by decreasing mucosal blood flow. These results are likely implicated in serotonin-related dyspeptic symptom generation because of small intestinal bacterial overgrowth, which is hypothesized to generate excess SCFAs in the foregut, overdriving serotonin release from enterochromaffin cells.

No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease

Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.

Upper gastrointestinal mucosal injury and symptoms in elderly low-dose aspirin users.

Background. We investigated the prevalence, symptoms, and QOL impact of esophageal (EI), gastric (GI), and duodenal mucosal injury (DI) individually between low-dose aspirin (LDA) users and nonusers to reveal the clinical features of LDA-related mucosal injury. Methods. Data were extracted from the records of subjects who underwent upper gastrointestinal endoscopy at our department between April 2008 and December 2013. Responses from 3162 elderly patients on Frequency Scale for Symptoms of GERD (FSSG) and SF-8 QOL questionnaires (SF-8) were analyzed. FSSG items were classified into total score (TS), reflux score (RS), and dyspepsia score (DS). The SF-8 questionnaire consisted of the physical component summary (PCS) and mental component summary (MCS). Results. Prevalence among LDA users and nonusers, respectively, was 9.6% and 10.0% (P = 0.83) for EI, 35.9% and 27.5% (P = 0.0027) for GI, 3.3% and 3.4% (P = 0.84) for DI, and 8.2% and 5.2% (P = 0.036) for mucosal injury in 2 or more organs. LDA users diagnosed with EI had significantly lower PCS, LDA users diagnosed with GI had significantly lower DS, and LDA users diagnosed with DI had significantly lower RS and significantly lower MCS. Conclusion. These results provide important clinical information indicating that symptom-based management is not appropriate in LDA users regarding upper gastrointestinal mucosal injury.

Sa1342 Modulation of Gluten-Induced Duodenal Mucosal Injury in Celiac Disease: Results of a Randomized Controlled Phase 2 Clinical Trial of Oral Administered Gluten-Specific Proteases in Seronegative Celiac Disease Patients (Clinicaltrials.Gov Nct01255696)

Sa1342 Modulation of Gluten-Induced Duodenal Mucosal Injury in Celiac Disease: Results of a Randomized Controlled Phase 2 Clinical Trial of Oral Administered Gluten-Specific Proteases in Seronegative Celiac Disease Patients (Clinicaltrials.Gov Nct01255696)

Sa1735 Prophylactic Effect of Gastromucoprotective Drugs on NSAIDs-Induced Esophageal, Gastric, Duodenal, and Small Intestinal Mucosal Injury in Healthy Subjects: A Prospective Randomized Study

Sa1735 Prophylactic Effect of Gastromucoprotective Drugs on NSAIDsInduced Esophageal, Gastric, Duodenal, and Small Intestinal Mucosal Injury in Healthy Subjects: A Prospective Randomized Study Eiji Umegaki*, Yuichi Kojima, Yukiko Yoda, Takanori Kuramoto, Sadaharu Nouda, Toshihisa Takeuchi, Kumi Ishida, Takuya Inoue, Satoshi Tokioka, Kazuhide Higuchi 2nd Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan Introduction: A variety of factors are involved in the formation of lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) in the small intestine, considered unaffected by acid, including intestinal flora, bile, and mucus, and as yet there are no established preventive or therapeutic measures. Gastromucoprotective agent such as geranylgeranylacetone (GGA), irsogladine (IG), and rebamipide (REB), is used in the treatment of gastritis and gastric ulcers, and prevented NSAID-induced small intestinal lesions in rats (Gastroenterology 2010;138:A-528). Recently there was the report that proton pump inhibitors exacerbate NSAID-induced small intestinal injury by iducing dysbiosis (Gastroenterology 2011;141:1314). In this study, we investigated whether gastromucoprotective agent monotherapy can protect against NSAIDinduced esophageal, gastric, duodenal, and small intestinal mucosal injury. Subjects and Methods: We randomly allocated healthy volunteers(each group: n 15), aged 20 years, to take (1) diclofenac 75mg plus famotidine 20mg daily or diclofenac 75mg plus GGA 150mg daily, (2) diclofenac 75mg plus omeprazole 10mg or diclofenac 75mg plus IG 4mg, (3) aspirin 100mg plus omeprazole 10mg, aspirin 100mg plus REB 300mg or aspirin 100mg plus REB 900mg. All subjects underwent upper gastrointestinal endoscopy and video capsule endoscopy(VCE) before and 2 weeks after the treatment period, and were evaluated for gastric and small intestinal lesions. Upper gastrointestinal mucosal injury was evaluated using the Modified Lanza Score(MLS), and small intestinal changes were scored for the number of 6 lesion types of: erythema, haemorrhage, erosions, ulcers, edema, and strictures. In addition, we measured fecal calprotectin levels, as a marker of digestive tract mucosal permeability. Results: 1)No significant differences were seen between gastromucoprotective agent groups and acid suppressive agent groups in the background of volunteers, and in the mean increase in esophageal, gastric and duodenal mucosal lesions. 2)When examining the total number of small intestinal mucosal injury, lesion development was suggested after administration in acid suppressive agent groups. However, there was no development in gastromucoprotective agent groups. 3)GGA/IG/REB significantly inhibited an increase in the fecal calprotectin level in comparison with acid suppressive agent in patients with NSAIDs-related digestive tract mucosal injury. Conclusions: A similar protective effect against NSAID-induced acute esophageal, gastric and duodenal mucosal injury was seen for gastromucoprotective agent and acid suppressive agent. The protective effect in the small intestine was clearly superior for gastromucoprotective agent, however, indicating that GGA/IG/REB monotherapy can protect against NSAID-induced acute mucosal injury to the esophagus, stomach, duodenum and small intestine.

Helicobacter pyloriVacuolating Cytotoxin Inhibits Duodenal Bicarbonate Secretion by a Histamine‐Dependent Mechanism in Mice

The pathogenic mechanisms involved in Helicobacter pylori-induced duodenal mucosal injury are incompletely understood. In the present study, we sought to investigate the effect of H. pylori vacuolating cytotoxin (VacA) on duodenal mucosal bicarbonate (HCO3-) secretion. Concentrated bacterial culture supernatants from an H. pylori wild-type strain producing VacA with s1/m1 genotypes (P12) and from an isogenic mutant lacking VacA (P12DeltavacA) were used. HCO3- secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. Duodenal mucosal histamine release was measured using enzyme-linked immunosorbent assay. The expression of histamine H2 receptor was examined by immunohistochemical analysis. In a dose-dependent manner, the VacA-positive supernatant P12 reduced prostaglandin E2 (PGE2)-stimulated duodenal mucosal HCO3- secretion to a maximum of 49% (P<.0001), whereas P12DeltavacA did not result in significant inhibition (P>.05). Purified VacA had a similar effect. Histamine H2 receptor antagonists attenuated the effect of P12 on PGE2-induced HCO3- secretion. P12 stimulated duodenal histamine release in a dose-dependent manner, and exogenous histamine inhibited PGE2-stimulated duodenal HCO3- secretion. H2 receptor expression was found in duodenal epithelial cells, the enteric nerve plexus, and lymphocytes in Peyer's patch. H. pylori VacA inhibits PGE2-stimulated duodenal epithelial HCO3- secretion by a histamine-dependent mechanism. This effect likely contributes to the damaging effect of H. pylori in the duodenal mucosa.

Pilot Evaulation of a Novel Combination Tablet (PN 100) Containing a Proton Pump Inhibitor and a Nonsteroidal Anti-Inflammatory Drug in Prevention of Upper Gastrointestinal Mucosal Injury

Purpose: To compare the incidence of gastric and duodenal mucosal injury with twice-daily administration of PN100, twice-daily enteric-coated naproxen, and twice-daily naproxen with delayed-release lansoprazole once daily. Methods: A single-center, randomized, parallel-group study enrolled 60 male and female volunteers aged 40–65 years. After normal baseline endoscopy (EGD), subjects received 14 days' treatment with either: (a) twice-daily PN100 (immediate-release lansoprazole 15mg and enteric-coated (EC) naproxen 500mg in a combination tablet), (b) twice-daily EC naproxen 500mg, or (c) delayed-release lansoprazole 15mg capsule each morning and twice-daily naproxen 500mg. The endoscopist was blinded to treatment assignment. EGD was performed at baseline and on days 8 and 14. Gastric pH monitoring (24 hour) and pharmacokinetic sampling were performed on days 1 and 7. Mucosal injury was assessed by the Lanza scale and enumeration of erosions and/or ulcers. Results: After two weeks, no ulcers were present in subjects receiving PN100 whereas 11% of subjects receiving EC naproxen had gastric ulcers. Subjects who received naproxen twice-daily with delayed-release lansoprazole each morning had an ulcer rate of 5%. The cumulative median numbers of gastric erosions at days 8 and 14 were: 5 for PN100; 14 for naproxen and lansoprazole; and 21 for EC naproxen (p = 0.02, Kruskal-Wallis test among 3 treatment groups). No mucosal lesions meeting criteria for Lanza Grade 4 were present at day 14 in subjects receiving PN100, whereas 53% of subjects receiving EC naproxen and 30% of subjects receiving naproxen and lansoprazole met criteria for Lanza Grade 4 injury (≥25 erosions or hemorrhages or any ulcer). Gastric pH monitoring suggested the possibility of better nocturnal acid suppression with use of twice-daily PN100 than with once-daily delayed-release lansoprazole and twice-daily naproxen. Conclusions: A combination tablet containing lansoprazole and EC naproxen was associated with the lowest incidence of upper gastrointestinal mucosal injury when compared with either EC naproxen alone or with naproxen administered with a morning dose of delayed-release lansoprazole. If these results are confirmed, clinical use of this novel formulation would ensure adherence with gastroprotective therapy when recommended for use with an NSAID.

The protective effect of vitamin C, vitamin E and selenium combination therapy on ethanol-induced duodenal mucosal injury.

In this study, the effect of a combination of vitamin C, vitamin E and selenium on ethanol-induced duodenal mucosal damage in rats was investigated morphologically and biochemically. The duodenal mucosal injury was produced by oral administration of 1 mL of absolute ethanol to each rat. Animals received vitamin C (250 mg/ kg), vitamin E (250 mg/kg) and selenium (0.5 mg/kg) for 3 days and absolute ethanol 1 hour after last antioxidant administration and were sacrificed 1 hour after absolute ethanol. Extreme degeneration in intestinal mucosa of rats given ethanol was observed morphologically. In addition, an increase in neuronal nitric oxide synthase immunoreactive areas was observed in the rats of the group given ethanol. On the other hand, a normal morphological appearance and a decrease in neuronal nitric oxide synthase immunoreactive areas were detected in the rats given ethanol+vitamin C+vitamin E+ selenium. In the group to which ethanol was administered, an increase in serum cholesterol and a decrease in serum albumin levels were determined. On the other hand, in the group to which ethanol+vitamin C+vitamin E+selenium were administered, serum cholesterol value decreased, and the serum albumin level increased. As a result, we can say that the combination of vitamin C, vitamin E and selenium has a protective effect on ethanol-induced duodenal mucosal injury.