Noriko Okaniwa

G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells.

Background:Short-chain fatty acids (SCFAs), which are produced by the fermentation of dietary fiber by intestinal microbiota, may positively influence immune responses and protect against gut inflammation. SCFAs bind to G protein-coupled receptor 43 (GPR43). Here, we show that SCFA–GPR43 interactions profoundly affect the gut inflammatory response. Methods:Colitis was induced by adding dextran sulfate sodium to the drinking water of GPR43 knockout (−/−) and wild-type mice. Results:Dextran sulfate sodium–treated GPR43−/− mice exhibited weight loss, increased disease activity index (a combined measure of weight loss, rectal bleeding, and stool consistency), decreased hematocrit, and colon shortening, resulting in significantly worse colonic inflammation than in wild-type mice. Tumor necrosis factor alpha and interleukin 17 protein levels in the colonic mucosa of GPR43−/− mice were significantly higher than in wild-type mice. Treatment of wild-type mice with 150 mM acetate in their drinking water markedly improved these disease indices, with an increase in colon length and decrease in the disease activity index; however, it had no effect on GPR43−/− mice. Mononuclear cell production of tumor necrosis factor alpha after lipopolysaccharide stimulation was suppressed by acetate. This effect was inhibited by anti-GPR43 antibody. Conclusions:SCFA–GPR43 interactions modulate colitis by regulating inflammatory cytokine production in mononuclear cells.

Predictive Factors for Intractability to Endoscopic Hemostasis in the Treatment of Bleeding Gastroduodenal Peptic Ulcers in Japanese Patients

Background/Aims Despite improvements in endoscopic hemostasis and pharmacological therapies, upper gastrointestinal (UGI) ulcers repeatedly bleed in 10% to 20% of patients, and those without early endoscopic reintervention or definitive surgery might be at a high risk for mortality. This study aimed to identify the risk factors for intractability to initial endoscopic hemostasis. Methods We analyzed intractability among 428 patients who underwent emergency endoscopy for bleeding UGI ulcers within 24 hours of arrival at the hospital. Results Durable hemostasis was achieved in 354 patients by using initial endoscopic procedures. Sixty-nine patients with Forrest types Ia, Ib, IIa, and IIb at the second-look endoscopy were considered intractable to the initial endoscopic hemostasis. Multivariate analysis indicated that age ≥70 years (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.07 to 4.03), shock on admission (OR, 5.26; 95% CI, 2.43 to 11.6), hemoglobin <8.0 mg/dL (OR, 2.80; 95% CI, 1.39 to 5.91), serum albumin <3.3 g/dL (OR, 2.23; 95% CI, 1.07 to 4.89), exposed vessels with a diameter of ≥2 mm on the bottom of ulcers (OR, 4.38; 95% CI, 1.25 to 7.01), and Forrest type Ia and Ib (OR, 2.21; 95% CI, 1.33 to 3.00) predicted intractable endoscopic hemostasis. Conclusions Various factors contribute to intractable endoscopic hemostasis. Careful observation after endoscopic hemostasis is important for patients at a high risk for incomplete hemostasis.

Nonsteroidal anti-inflammatory drug-induced visible and invisible small intestinal injury

Permeation of the small intestinal mucosa is a key mechanism in the induction of enteropathy. We investigated the effect of rebamipide in healthy subjects with diclofenac-induced small intestinal damage and permeability. In this crossover study, each treatment period was 1 week with a 4-week washout period. Diclofenac (75 mg/day) and omeprazole (20 mg/day) plus rebamipide (300 mg/day) or placebo were administered. Capsule endoscopy and a sugar permeability test were performed on days 1 and 7 in each period. Ten healthy subjects were enrolled. Small intestinal injuries were observed on day 7 in 6 of 10 subjects in both groups. Urinary excretion of administered lactulose increased from 0.30% to 0.50% of the initial dose during the first treatment period in the placebo group, and from 0.13% to 0.33% in the rebamipide group. Despite recovery from small-intestinal mucosal damage, the increased permeability in both groups resulted in sustained high levels of lactulose (0.50% to 1.06% in the placebo group and 0.33% to 1.12% in the rebamipide group) through the 4-week washout period. Diclofenac administration induced enteropathy and hyperpermeability of the small intestine. The sustained hyperpermeability during the washout period may indicate the presence of invisible fragility.

Serum-Derived Hyaluronan-Associated Protein Is a Novel Biomarker for Inflammatory Bowel Diseases

Background/Aims: We evaluated the role of serum-derived hyaluronan-associated protein (SHAP) in inflammatory bowel disease (IBD) pathogenesis and its potential as a novel IBD biomarker. Methods: We studied the SHAP expression in a mouse model of colitis and in human intestinal samples of IBD and compared serum concentrations with normal controls. Results: SHAP was expressed in the connective tissue derived from inflamed regions of the intestine. In mice, serum levels of SHAP-hyaluronic acid (SHAP-HA) were positively correlated with the histological damage of the colon (r = 0.566, p < 0.001). Serum concentration of SHAP-HA complex was significantly higher in patients with active ulcerative colitis than in those in remission, and this value was positively correlated with the erythrocyte sedimentation rate, serum level of tumor necrosis factor (TNF)-α, and endoscopic damage (r = 0.568, p < 0.001; r = 0.521, p < 0.001, and r = 0.641, p < 0.001). In patients with Crohns disease, the serum SHAP-HA level correlated only with TNF-α (r = 0.630, p = 0.002). Conclusion: SHAP is a novel IBD biomarker that is related to disease activity in certain types of colitis, and it may affect disease pathogenesis. Future studies are needed to evaluate the therapeutic potential of this complex.

Risk factors for bleeding evaluated using the Forrest classification in Japanese patients after endoscopic submucosal dissection for early gastric neoplasm.

Background/aims Bleeding remains a serious complication after endoscopic submucosal dissection (ESD). Second-look endoscopy for hemostasis helps prevent post-ESD bleeding. We investigated the relationships between patient characteristics, tumor characteristics, and the Forrest classification for exposed vessels on artificial ulcers after ESD and evaluated whether hemostasis during second-look endoscopy was useful for preventing post-ESD bleeding. Patients and methods We analyzed 250 patients (265 lesions) who underwent ESD for gastric neoplasms. Vessels classified by Forrest classifications during scheduled second-look endoscopy were analyzed for associations with patient characteristics, tumor characteristics, and recurrent bleeding. Results Two of 250 patients (0.8%) underwent emergency hemostatic endoscopy before scheduled second-look endoscopy. The remaining 248 patients (99.2%) underwent scheduled second-look endoscopy on the day after ESD. Patients with Forrest classification Ia, Ib, or IIa vessels had a significantly higher risk for recurrent bleeding after scheduled second-look endoscopy compared with patients with IIb or III vessels according to univariate analysis (P<0.05) and multivariate logistic regression analysis (odds ratio: 3.45; 95% confidence interval: 1.04–11.41; P=0.042). Univariate analysis indicated that hemodialysis correlated significantly with the presence of Ia, Ib, or IIa vessels compared with that of IIb or III vessels found during second-look endoscopy (P<0.05). Multivariate analysis indicated a significant relationship between hemodialysis and recurrent bleeding after second-look endoscopy (odds ratio: 10.05; 95% confidence interval: 1.97–51.26; P=0.006). Conclusion Hemodialysis is a risk factor for post-ESD bleeding. Proper classification of exposed vessels within post-ESD ulcers according to the Forrest classification using second-look endoscopy might help predict or prevent recurrent bleeding.

eNOS plays an important role in the regulation of colonic inflammation: A novel therapeutic target and a predictive marker for the prognosis of ulcerative colitis

Abstract Background. We reported that deficiency of the eNOS protein exacerbates colitis induced by dextran sodium sulfate (DSS-induced colitis). However, the role of eNOS in colitis remains controversial. Therefore, we studied how over-expression of eNOS affected this inflammatory condition, using vascular endothelial cells and mice as in vitro and in vivo models, respectively. Furthermore, we investigated the influence of a polymorphism in the eNOS gene on the clinical features of ulcerative colitis (UC). Methods. We examined the effect of eNOS overexpression on the expression of adhesion molecules in the endothelium and assessed the degree of DSS-induced colitis in eNOS transgenic (eNOS-Tg) mice. We also investigated the relationship between a polymorphism in the eNOS gene and clinical features of patients with UC. Results. The expression of adhesion molecules, under inflammatory conditions, was attenuated in eNOS gene-transfected vascular endothelial cells, as measured by western blot analysis. Symptoms of DSS-induced colitis were likewise attenuated in eNOS-Tg mice, which exhibited lower weight loss, mortality, histological damage (by inflammation score and crypt damage score), and colonic myeloperoxidase activity, tumor necrosis factor-α expression, and MAdCAM-1 expression than in wild-type mice. Furthermore, there was a significant relationship between intractable cases of UC and a polymorphism in the eNOS gene promoter (c.-786 T > C) that decreases eNOS expression. Conclusion. The eNOS gene plays an important role in the regulation of colonic inflammation. The level of eNOS expression may be a predictive marker for prognosis of UC, and eNOS expression may be a novel therapeutic target.

Effect of aspirin cessation before endoscopy in Japanese patients with low-dose-aspirin-associated gastroduodenal mucosal injury

Background The incidence of upper gastrointestinal injury by low-dose aspirin (LDA) has increased. Objective We aimed to clarify the risk factors and prevention strategies associated with LDA-induced gastroduodenal ulcer in Japanese patients. Methods A retrospective study involving 284 LDA users who underwent oesophagogastroduodenoscopy between January and December 2010 were included. We investigated the patients’ clinical characteristics and endoscopic findings. Results Of 284 patients, 29 (10.2%) had gastro and/or duodenal ulcers. Male gender, peptic ulcer history, abdominal symptoms, half-dose proton pump inhibitors (PPIs), complete-dose PPIs, and nonsteroidal anti-inflammatory drugs were significantly associated with LDA-induced gastro and/or duodenal ulcers: odds ratio (95% confidence interval) 3.62 (1.06–12.27), 6.60 (1.84–23.62), 3.06 (1.12–8.40), 0.16 (0.03–0.94), 0.07 (0.01–0.61), and 9.68 (1.64–57.18), respectively. PPI significantly reduced gastric ulcers and/or duodenal ulcers (p = 0.03). The modified Lanza score for gastric mucosal lesion in the LDA cessation group was significantly lower than in the LDA noncessation group (0.53 vs. 1.02; p = 0.008). Conclusions Half-dose PPIs as well as complete-dose PPIs were effective for preventing LDA-induced gastric and/or duodenal ulcers. The cessation of LDA before endoscopy may lead to an underestimation of LDA-induced gastric injury.

Treatment Adherence in Patients with Ulcerative Colitis Is Dependent on the Formulation of 5-Aminosalicylic Acid

Background/Aims: It is unclear whether 5-aminosalicylic acid (5-ASA) formulation is associated with treatment adherence in ulcerative colitis (UC). Thus, we aimed to investigate the adherence rate after switching from 5-ASA tablets to granules. Methods: This prospective study included 121 UC outpatients treated using 5-ASA tablets. They were grouped based on choice: Group 1 (continued with tablets) and Group 2 (switched to granules without regimen change). Group 2 was further divided into Group 3 (returned to tablets) and Group 4 (continued with granules). The patients completed a self-administered questionnaire regarding the treatment. The primary endpoint was change in adherence after switching to granules. Results: Seventy-nine patients continued with tablets, while 42 patients switched to granules. The adherence rate to the tablet was not significantly different between Group 1 and 2 before switching. In Group 2, switching to granules did not affect adherence. However, in Group 4, adherence significantly improved after switching to granules. Group 3 showed no significant change in adherence before and after switching from tablets. Full-time work and difficulty taking tablets were significant predictors of continuing with granules in Group 4. Conclusion: Patients who continued with 5-ASA granules showed significantly increased adherence, suggesting that patient-tailored drug formulations improved treatment adherence.

Edema of the interarytenoid mucosa seen on endoscopy is related to endoscopic-positive esophagitis (EE) and is an independent predictor of EE

Laryngopharyngeal reflux (LPR) is defined as the retrograde flow of gastric contents up through the esophagus to the larynx and hypopharynx; this is an extra‐esophageal manifestation of gastroesophageal reflux disease (GERD). Although both LPR and GERD are caused by reflux of stomach contents, their clinical presentations and treatments differ.