Akihito Iida

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.

Transglucosidase improves the gut microbiota profile of type 2 diabetes mellitus patients: a randomized double-blind, placebo-controlled study

BackgroundRecently, the relationship between gut microbiota and obesity has been highlighted. The present randomized, double-blind, placebo-controlled study aimed to evaluate the efficacy of transglucosidase (TGD) in modulating blood glucose levels and body weight gain in patients with type 2 diabetes mellitus (T2DM) and to clarify the underlying mechanism by analyzing the gut microbiota of T2DM patients.MethodsThis study included 60 patients who received placebo or TGD orally (300 or 900 mg/day) for 12 weeks, and blood and fecal samples were collected before and after 12 weeks. Comparisons of fecal bacterial communities were performed before and after the TGD treatment and were performed between T2DM patients and 10 healthy individuals, using the terminal-restriction fragment length polymorphism analysis.ResultsThe Clostridium cluster IV and subcluster XIVa components were significantly decreased, whereas the Lactobacillales and Bifidobacterium populations significantly increased in the T2DM patients compared with the healthy individuals. By dendrogram analysis, most of the healthy individuals (6/10) and T2DM patients (45/60) were classified into cluster I, indicating no significant difference in fecal bacterial communities between the healthy individuals and the T2DM patients. In the placebo and TGD groups, the bacterial communities were generally similar before and after the treatment. However, after 12 weeks of TGD therapy, the Bacteroidetes-to-Firmicutes ratio in the TGD groups significantly increased and was significantly higher compared with that in the placebo group, indicating that TGD improved the growth of the fecal bacterial communities in the T2DM patients.ConclusionsTherefore, TGD treatment decreased blood glucose levels and prevented body weight gain in the T2DM patients by inducing the production of oligosaccharides in the alimentary tract and modulating gut microbiota composition.Trial registrationUMIN-CTR UMIN000010318

Pathophysiology of functional heartburn based on Rome III criteria in Japanese patients

AIM To investigate the pathophysiology of functional heartburn (FH) in Japanese patients. METHODS A total of 111 patients with proton pump inhibitor (PPI)-refractory non-erosive gastroesophageal reflux disease underwent intraesophageal pressure testing and 24-h multichannel intraluminal impedance-pH (24MII-pH) testing. The patients also completed several questionnaires while they were receiving the PPI treatment, including the questionnaire for the diagnosis of reflux disease (QUEST), the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), the gastrointestinal symptoms rating scale (GSRS), SF-36, and the Cornell Medical Index (CMI). The subjects were classified into FH and endoscopy-negative reflux disease (ENRD) groups based on the Rome III criteria. RESULTS Thirty-three patients with esophageal motility disorder were excluded from this study, while 22 patients with abnormal esophageal acid exposure time (pH-POS) and 34 with hypersensitive esophagus (HE) were included in the ENRD group. The FH group included 22 patients with no reflux involvement. Sex, age, and body mass index did not differ significantly between the groups. The mean SF-36 values were < 50 (normal) for all scales in these groups, with no significant differences. The GSRS scores in these groups were not different and showed overlap with other gastrointestinal symptoms. The QUEST and the FSSG scores did not differ significantly between the groups. Neuroticism was diagnosed using the CMI questionnaire in 17 of the 78 included subjects within the pH-POS (n = 4), HE (n = 8), and FH (n = 5) groups, with no significant differences. CONCLUSION Clinical characteristics of the FH and PPI-refractory ENRD groups were similar. Therefore, esophageal function should be examined via manometry and 24MII-pH testing to differentiate between them.

ENDOSCOPIC SUBMUCOSAL DISSECTION WITH SHEATH-ASSISTED COUNTER TRACTION FOR EARLY GASTRIC CANCERS

Aim:  Endoscopic submucosal dissection (ESD) is associated with frequent complications, such as bleeding and perforation. The procedure is technically difficult, requires considerable skill and is longer than conventional endoscopic mucosal resection (EMR). Thus, non‐invasive tools and methods are needed to facilitate direct visualization of the submucosal layer during ESD.

The Role of Gastroesophageal Reflux in Relation to Symptom Onset in Patients with Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease Accompanied by an Underlying Esophageal Motor Disorder

Background: The symptom improvement rate is low with proton pump inhibitors (PPIs) in nonerosive reflux disease (NERD). The underlying pathogenic mechanism is complex. Esophageal motility disorders (EMDs) are thought to be a factor, but their prevalence, type, symptoms and the role played by gastroesophageal reflux (GER) in symptom onset have not been fully investigated. Aim: To investigate the role of GER in symptom onset in PPI-refractory NERD patients with EMDs. Methods: This study comprised 76 patients with PPI-refractory NERD. Manometry was performed during PPI treatment and patients were divided into an EMD group and normal motility (non-EMD) group. Then, multichannel intraluminal impedance-pH monitoring was performed and medical interviews were conducted. Results: Nineteen patients (25%) had an EMD. Data were compared between 17 patients, excluding 2 with achalasia and 57 non-EMD patients. No significant differences were observed between groups in 24-hour intraesophageal pH <4 holding time (HT), mean number of GER episodes or mean number of proximal reflux episodes. The reflux-related symptom index (≥50%) showed a relationship between reflux and symptoms in 70.5% of EMD patients and 75% of non-EMD patients. In the EMD group, the score for FSSG (Frequency Scale for the Symptoms of GERD) question (Q)10 was significantly correlated with the number of GER episodes (r = 0.58, p = 0.02) and the number of proximal reflux episodes (r = 0.63, p = 0.02). In addition, the score for Q9 tended to be correlated with the number of GER episodes (r = 0.44, p = 0.06). Conclusion: Our results suggest that some PPI-refractory NERD patients have EMDs, and that GER plays a role in symptom onset.

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.

How to interpret a functional or motility test - slow nutrient drinking test.

The gastric barostat study is the gold standard method for evaluating gastric perception and accommodation. This technique has serious drawbacks, such as expense and invasiveness. Several drinking tests have been developed as noninvasive methods. Such tests are easily performed without special instruments and are well tolerated. We have reported that (1) a threshold volume inducing mild bloating in the slow nutrient drinking test might be an alternative parameter of gastric accommodation volume as determined by the barostat method and (2) the maximum satiety volume in the drinking test correlated positively with the pressure to induce severe discomfort in healthy volunteers, indicating that the slow nutrient drinking test may be useful for evaluating accommodation volume and the threshold to induce severe discomfort. However, the correlation between the maximum satiety drinking volume and accommodation volume as measured by the barostat study has been controversial. Therefore, validation of a certain nutrient drink test for measuring gastroduodenal function might be recommended in each institution.

Usefulness of a Slow Nutrient Drinking Test for Evaluating Gastric Perception and Accommodation

Background/Aim: An implication of the drinking test for gastric function is controversial. We evaluated the usefulness of a nutrient drinking test for examining gastric function by comparing it with a gastric barostat study. Methods: We investigated perceived pressure of an intragastric bag with stepwise distension and postprandial peak gastric volume (accommodation volume) with a consistent pressure after drinking a liquid meal (200 ml, 300 kcal) in 18 volunteers. Drinking a similar liquid meal on a different day at a continual rate of 15 ml/min was performed to score satiety and bloated sensations at 5-min intervals. An additional 10 volunteers performed the drinking test before and after administration of mosapride citrate or a placebo in a double-blind crossover study. Results: Pressure to induce severe discomfort correlated positively with maximum satiety volume in the drinking test (r = 0.60, p = 0.02). Accommodation volume in the barostat study showed a significant correlation (r = 0.59, p = 0.03) with threshold volume to induce bloating in the drinking test. Mosapride tended to increase the volume inducing the first bloated sensation as compared to the placebo. Conclusion: The present drinking test may be useful for evaluating the threshold to induce severe discomfort and accommodation volume.

Effects of transglucosidase on diabetes, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes: a 12‐week, randomized, double‐blind, placebo‐controlled trial

In this 12‐week, randomized, double‐blind, placebo‐controlled trial, the efficacy and safety of transglucosidase (TGD) were compared with placebo in patients with type 2 diabetes mellitus (T2DM). At 12 weeks, TGD 300 mg/day and TGD 900 mg/day significantly reduced HbA1c (0.18 and 0.21%) and insulin concentration (19.4 and 25.0 pmol/l), respectively, vs. placebo. TGD 300 mg/day and TGD 900 mg/day also significantly reduced low‐density lipoprotein cholesterol (0.22 and 0.17 mmol/l, respectively). TGD 900 mg/day significantly reduced triglyceride by 0.24 mmol/l and diastolic blood pressure by 8 mmHg. Placebo was associated with a significant increase from baseline in body mass index, alanine aminotransferase and aspartate aminotransferase (0.17 kg/m2, 3 and 2 U/l, respectively), whereas TGD was not. TGD 300 mg/day significantly increased high‐molecular‐weight adiponectin by 0.6 µg/ml. Adverse events did not differ significantly between the groups. TGD resulted in lowering of HbA1c and blood insulin level and improvements in metabolic and cardiovascular risk factors in T2DM.

A Patient with Vigorous Achalasia and Rapid Enlargement of an Epiphrenic Esophageal Diverticulum.

A 47-year-old man was found to have a 3-cm epiphrenic esophageal diverticulum on an upper gastrointestinal (UGI) barium study. He developed the symptoms of heartburn approximately 12 months later. UGI endoscopy indicated non-erosive gastroesophageal reflux disease (NERD) and an epiphrenic esophageal diverticulum. A proton pump inhibitor (PPI) did not relieve the symptoms. An UGI barium study at that time showed that the epiphrenic esophageal diverticulum had enlarged to 7 cm, and esophageal manometry showed findings of achalasia and diffuse esophageal spasm (DES), thus vigorous achalasia was diagnosed. Resection of the epiphrenic esophageal diverticulum, myotomy, and fundoplication (the Heller-Dor procedure) were successfully performed and no postoperative symptoms were encountered.