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Background Functional dyspepsia (FD) is a disorder that presents with chronic dyspepsia, which is not only very common but also highly affects quality of life of the patients. In Japan, FD became a disease name for national insurance in 2013, and has been gradually recognized, though still not satisfactory. Following the revision policy of Japanese Society of Gastroenterology (JSGE), the first version of FD guideline was revised this time. Method Like previously, the guideline was created by the GRADE (grading of recommendations assessment, development and evaluation) system, but this time, the questions were classified to background questions (BQs, 24 already clarified issues), future research questions (FRQs, 9 issues cannot be addressed with insufficient evidence), and 7 clinical questions that are mainly associated with treatment. Results and Conclusion These revised guidelines have two major features. The first is the new position of endoscopy in the flow of FD diagnosis. While endoscopy was required to all cases for diagnosis of FD, the revised guidelines specify the necessity of endoscopy only in cases where organic disease is suspected. The second feature is that the drug treatment options have been changed to reflect the latest evidence. The first-line treatment includes gastric acid-secretion inhibitors, acetylcholinesterase (AChE) inhibitors (acotiamide, a prokinetic agent), and Japanese herbal medicine (rikkunshito). The second-line treatment includes anxiolytics /antidepressant, prokinetics other than acotiamide (dopamine receptor antagonists, 5-HT4 receptor agonists), and Japanese herbal medicines other than rikkunshito. The patients not responding to these treatment regimens are regarded as refractory FD.

BACKGROUND Potential etiological mechanisms of irritable bowel syndrome (IBS) have been reported, and emerging data suggest that immune activation is present in a major subset of IBS, especially in those with diarrhea. Intestinal mucosal mast cell and intraepithelial lymphocyte (IEL) infiltration and related factors were examined in patients with IBS. In addition, the correlations of symptoms and micro-inflammation were assessed. METHODS Intestinal biopsy specimens were obtained from patients with IBS and controls. Mast cells and IELs were stained with specific antibodies. The mRNA levels of cytokines and chemokines were assessed by quantitative reverse transcription polymerase chain reaction. RESULTS Infiltration of mast cells in the duodenum was significantly higher in IBS patients than in control subjects. The infiltration of IELs was higher in the duodenum and terminal ileum of IBS patients compared to the control subjects. The numbers of duodenal and ileal IELs were significantly correlated. The number of IELs but not mast cells in the duodenum and terminal ileum was significantly correlated with diarrhea frequency in control subjects and IBS patients. The expression level of the chemotactic chemokine CXCL11 was significantly higher in the duodenum of IBS patients. CONCLUSION Duodenal mast cells and IELs were increased in IBS patients. In addition, a positive correlation was found between the number of duodenal and ileal IELs and the frequency of diarrhea. Given that the present study was strictly observational, further studies are needed to clarify the pathophysiological functions associated with micro-inflammation in IBS.

Clostridium difficile infection (CDI) is a cause of increased morbidity and health care costs among hospitalized patients. Proton pump inhibitors (PPIs) are mainly used for the treatment of acid-related upper gastrointestinal diseases. The aim of the study was to assess the risks associated with initial and recurrent CDI in adult and pediatric patients treated with PPIs.A systematic search was performed using PubMed (Medline), Embase, and Web of Science with the following search terms: ("proton pump inhibitor," "PPI," or "acid suppression") AND ("infection," "diarrhea," "diarrhoea," "colitis," or "disease") AND ("Clostridium difficile"). Meta-analysis was performed using Revman5.3 software. Pooled odds ratios (ORs) presented as standard plots with 95% confidence intervals (CIs) were determined.Sixty-seven eligible studies were selected. PPI use was significantly associated with risk of CDI (OR 2.34, 95% CI 1.94-2.82; P 0.00001). Pooled data from twelve studies demonstrated a significant association between PPI use and recurrent CDI (OR 1.73, 95% CI 1.39-2.15; P = 0.02). Subgroup analysis revealed significant associations between PPI use and an increased incidence of CDI among adult (OR 2.30, 95% CI 1.89-2.80; P 0.00001) and pediatric (OR 3.00, 95% CI 1.44-6.23; P 0.00001) patients.PPI use was associated with CDI in adult and pediatric patients, and with recurrent CDI. Although many risk factors are associated with the occurrence and recurrence of CDI, consideration should be given to not administering PPIs at any age if they are unnecessary.

Patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have unmet clinical needs. Recently, we reported that esophageal prostaglandin E2 (PGE2) plays a crucial role in the generation of heartburn. In the present study, we focused on the PGE2 receptor, EP1, and investigated the effects of ONO-8539, a novel EP1 receptor antagonist, on heartburn symptoms in healthy male volunteers. This prospective, double-blind, placebo-controlled, two-period crossover study was performed in 20 healthy male subjects. The novel prostanoid EP1 receptor antagonist, ONO-8539 (450 mg), was administered once 4 h prior to acid perfusion test. During the test, hydrochloric acid (0.15 mol l−1) was perfused into the lower esophagus for 30 min. Acid perception threshold was quantified by the time to first sensation of heartburn and intensity of GI symptoms determined using a validated categorical rating scale, and the area under the curve (AUC) as the total symptom score. ONO-8539 significantly reduced a total heartburn symptom score, not other upper GI symptom scores, during acid perfusion compared with placebo (AUC for heartburn, 85.0 ± 10.6 for placebo and 56.5 ± 7.2 for ONO-8539; P < 0.01), and significantly extended the time to first sensation of heartburn compared with placebo (5.7 ± 4.3 min for placebo and 9.7 ± 7.2 min for ONO-8539; P

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

The gastrointestinal mucosal barrier plays an essential role in the separation of the inside of the body from the outside environment. Tight junctions (TJs) are the most important component for construction of a constitutive barrier of epithelial cells, and they regulate the permeability of the barrier by tightly sealing the cell-cell junctions. TJ proteins are represented by claudins, occludin, junctional adhesion molecules, and scaffold protein zonula occludens. Among these TJ proteins, claudins are the major components of TJs and are responsible for the barrier and the polarity of the epithelial cells. Gastrointestinal diseases including reflux esophagitis, inflammatory bowel disease, functional gastrointestinal disorders, and cancers may be regulated by these molecules, and disruption of their functions leads to chronic inflammatory conditions and chronic or progressive disease. Therefore, regulation of the barrier function of epithelial cells by regulating the expression and localization of TJ proteins is a potential new target for the treatment of these diseases. Treatment strategies for these diseases might thus be largely altered if symptom generation and/or immune dysfunction could be regulated through improvement of mucosal barrier function. Since TJ proteins may also modify tumor infiltration and metastasis, other important goals include finding a good TJ biomarker of cancer progression and patient prognosis, and developing TJ protein-targeted therapies that can modify patient prognosis. This review summarizes current understanding of gastrointestinal barrier function, TJ protein expression, and the mechanisms underlying epithelial barrier dysregulation in gastrointestinal diseases.

Over almost 30 years since functional dyspepsia (FD) was defined, researchers have endeavored to elucidate the pathophysiology of functional gastrointestinal disorders. Now a consensus is emerging that the gastric symptoms of FD are caused mainly by gastric motility abnormalities and gastric hypersensitivity. The involvement of other causative factors including acid, Helicobacter pylori, psychological factors, and diet has been debated, but how they are involved in the manifestation of dyspeptic symptoms remains unclear. We believe that most of those factors cause FD symptoms by inducing gastric motility abnormalities and gastric hypersensitivity via the duodenum. Here, we discuss 2 possible reasons why patients with FD experience chronic upper abdominal symptoms: (1) the possibility that the contents of the duodenum of patients with FD differ from those of healthy persons and the different contents stimulate the duodenum, and (2) the possibility that the duodenum of patients with FD is more sensitive to noxious stimuli because of low-grade inflammation and increased mucosal permeability.

The prevalence of gastroesophageal reflux disease (GERD) has been increasing worldwide over recent decades. A previous study demonstrated that gastric acid secretion, thought to be an important factor in the increase in the rate of GERD, in Japanese individuals increased in the era from the 1970s to the 1990s. The aim of this study was to evaluate whether gastric acid secretion has altered over the past two decades with and without the influence of Helicobacter pylori infection in nonelderly and elderly Japanese. Gastric acid secretion, the concentrations of serum gastrin, pepsinogen I, and pepsinogen II, and H. pylori infection were determined in 78 healthy Japanese subjects. The findings were compared with data obtained in the 1990s. Basal acid output (BAO) and maximal acid output (MAO) gradually decreased with age in H. pylori-negative subjects. In addition, those with H. pylori infection tended to show decreased gastric acid secretion as compared with those without infection, particularly in the elderly group. MAO decreased gradually with age in males, whereas it remained unchanged with age in females. MAO in H. pylori-negative subjects has not changed over the past two decades (17.7 mEq/h vs 17.6 mEq/h in nonelderly subjects, and 15.2 mEq/h vs 12.7 mEq/h in elderly subjects). In contrast to the increased prevalence of GERD, gastric acid secretion has not increased over the past two decades in Japanese. However, secretion has decreased with age in males but not in females, which may partly explain the sex difference in the age-related GERD prevalence.

Functional dyspepsia (FD) is a heterogeneous disorder, and it is not clear whether childhood abuse influences the severity of dyspeptic symptoms and the type of dyspepsia. Accordingly, we administered a questionnaire survey to evaluate the association of abuse history in the development of dyspepsia. Study subjects were selected from among a panel of volunteers, to make equal distribution of age, sex, and residential area. A Web-based questionnaire was administered to uninvestigated dyspepsia subjects who had obtained a consultation at a medical institute, dyspepsia subjects who had not, and healthy control subjects. Dyspepsia was categorized into epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) using the Rome III adult FGID questionnaire. Physical, sexual, and psychological abuse history and severity of dyspeptic symptoms were assessed by a questionnaire. Each type of abuse was significantly prevalent in uninvestigated dyspepsia subjects. Childhood abuse history was significantly prevalent in dyspepsia. However, these abuse histories were not associated with consultation behavior. Childhood abuse was more prevalent in subjects with dyspepsia and in females. Severity of dyspeptic symptoms was significantly greater in dyspepsia subjects with a history of abuse. Childhood abuse was more prevalent in dyspepsia subjects with the overlap of EPS and PDS and in those who also had irritable bowel syndrome (IBS). Childhood abuse history was associated with the development of dyspepsia especially in the overlapping diagnoses of EPS and PDS, and overlapping with IBS but not with consultation behavior. Abuse history should be assessed in the care of patients with dyspepsia.

The present study sought to establish a standard third-line eradication regimen for Helicobacter pylori in Japan.Subjects were 204 patients with H. pylori infection in whom the standard Japanese first- and second-line eradication therapies had proven unsuccessful. Patients were randomly assigned to one of the following third-line eradication therapy groups: (1) LA group: lansoprazole (LPZ) 30 mg 4 times a day (qid) + amoxicillin (AMPC) 500 mg qid for two weeks; (2) LAL group: LPZ 30 mg twice a day (bid) + AMPC 750 mg bid + levofloxacin (LVFX) 300 mg bid for one week; (3) LAS group: LPZ 30 mg bid + AMPC 750 mg bid + sitafloxacin (STFX) 100 mg bid for one week. Patients for whom these therapies failed underwent a crossover fourth-line eradication regimen. Drug sensitivity was also tested for AMPC, clarithromycin (CAM), MNZ, LVFX, and STFX.Drug resistance rates prior to third-line eradication therapy were 86.4 % for CAM, 71.3 % for MNZ, 57.0 % for LVFX, 8.2 % for AMPC, and 7.7 % for STFX. Intention-to-treat analysis of third-line eradication therapy eradication rates showed a significantly higher rate in the LAS group (70.0 %) compared with the LA group (54.3 %; p0.05) and the LAL group (43.1 %; p0.001). The significantly lower rate in the LAL group than the LAS group was caused by bacterial resistance to LVFX.The findings suggest that triple therapy with PPI, AMPC, and STFX for one week would be an effective standard third-line eradication regimen for H. pylori in Japan.

Acotiamide is widely used to improve symptoms in patients with functional dyspepsia (FD) in multiple large-scale clinical studies, but there are few reports about the drug’s mechanism of action. The aim of this study was to assess the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms, and health-related quality of life (HR-QOL) in a placebo-controlled study. We conducted a randomized, double-blind placebo-controlled study. Fifty Japanese FD patients were randomly assigned to either placebo (n = 25) or acotiamide 100 mg × 3/day for 2 weeks (n = 25). At baseline and at 2 weeks of treatment, we evaluated the patients’ gastric motility using scintigraphy to determine the accommodation and emptying values, gastrointestinal symptom rating scale (GSRS), HR-QOL (SF-8), and anxiety and depression scale (HADS). Four patients failed to complete the medication regimen and were omitted from analysis; data from 24 placebo patients and 22 acotiamide patients were analyzed. Acotiamide significantly increased gastric accommodation compared to the placebo (p = 0.04 vs. p = 0.08; respectively). Acotiamide significantly accelerated gastric emptying (50 % half-emptying time) (p = 0.02 vs. p = 0.59). Acotiamide significantly improved the total GSRS scores compared to placebo (p = 0.0007 vs. p = 0.14). HR-QOL did not differ significantly between the two groups, but acotiamide significantly improved the HADS anxiety score compared to placebo (p = 0.04 vs. p = 0.20). Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients’ dyspeptic symptoms and anxiety score. Clinical Trials Registry no: UMIN000013544.

The aim of this study was to examine the impact of age on esophageal sensation, and to determine whether esophageal mechanosensitivity and chemosensitivity are correlated in healthy Japanese subjects. To evaluate chemosensitivity, a catheter was inserted and placed 10 cm above the upper border of the lower esophageal sphincter (LES), which was determined with an esophageal manometric catheter. After saline had been infused into the esophagus at a rate of 10 mL/min for 2 min, 0.1 N hydrochloric acid, instead of saline–without the subjects’ knowledge–was infused for 10 min at the same rate. The acid perfusion sensitivity score (APSS) was assessed. To evaluate mechanosensitivity, a barostat test was performed, with a balloon being placed 10 cm above the upper border of the LES. The initial perception threshold (IPT), pain threshold (PT), and maximal pain were quantified. The APSS was significantly inversely correlated with age. IPT, PT, and mean maximal pain were significantly correlated with age. Body mass index, drinking, and smoking habits were not correlated with the esophageal perception threshold. The correlation of chemosensitivity and mechanosensitivity was also assessed, and the APSS was inversely correlated with IPT, PT, and maximal pain. The thresholds of esophageal visceral chemosensitivity and mechanosensitivity in same individuals were significantly correlated and both of these thresholds were inversely correlated with age.

The endoscopic characteristics of gastric ulcers in patients who were using non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA) and were infected with Helicobacter pylori remain unclear. We elucidated the endoscopic characteristics of gastric ulcers that occurred in the presence or absence of H. pylori infection and were associated with the use of these drugs.A total of 379 patients with active-stage gastric ulcer were divided into three groups: H. pylori-positive patients using neither NSAIDs nor LDA (control group, n = 216), H. pylori-positive or -negative patients using NSAIDs (NSAIDs group, n = 100), and H. pylori-positive or -negative patients using LDA (LDA group, n = 63). The differences among these groups in endoscopic characteristics of the ulcers (site, multiplicity, and morphology) were determined. The influence of an antacid drug, i.e., a proton pump inhibitor (PPI) or a histamine H(2) receptor antagonist (H(2)RA), was also investigated.The NSAIDs group, regardless of H. pylori infection status, had higher incidences of antral, multiple, and irregularly shaped ulcers. The LDA group had a higher incidence of antral ulcers in H. pylori-negative patients and, regardless of H. pylori infection status, a higher incidence of multiple ulcers. However, the incidence of irregularly shaped ulcers in the LDA group did not differ from that in the control group. Neither the concomitant use of an antacid nor the dosing period of NSAIDs affected the results.Our study elucidated the morphological characteristics of gastric ulcers in persons taking NSAIDs or LDA in the presence and absence of H. pylori infection. Our results may be clinically useful for inferring the causes of ulcers from their morphological characteristics.

Gastroesophageal reflux is the most favored etiology for globus; however, recent studies suggest that a cervical inlet patch (heterotopic gastric mucosa in the cervical esophagus) involves globus. This study aimed to reveal whether these two conditions were associated with globus.A prospective cross-sectional survey was conducted for 2116 consecutive patients who underwent esophagogastroduodenoscopy in our hospital. Patients were interviewed about globus sensations and reflux symptoms prior to endoscopy. Non-erosive reflux disease was considered with reflux symptoms without reflux esophagitis. Inlet patch was detected using narrow-band imaging.Sixty-three patients were excluded, and of the remaining 2053 patients (1117 male, 61 years old on average), 120 (5.8%) and 284 (13.8%) had globus and inlet patch, respectively. Multivariate analysis (n = 1584) following the exclusion of proton pump inhibitor users revealed that female gender, younger age (60), inlet patch, and reflux symptoms were independent risk factors for the development of globus; however, reflux esophagitis was an independent factor for reducing the development of globus. In a reanalysis of non-erosive reflux disease instead of reflux symptoms, inlet patch and non-erosive reflux disease were independent risk factors for the development of globus (odds ratio, 2.9 and 12.1, respectively).Non-erosive reflux disease was more closely associated with globus than an inlet patch. Our controversial results indicating a strong association of globus with non-erosive reflux disease and an inverse association of globus with reflux esophagitis may suggest that mechanisms other than gastroesophageal reflux as the etiology, such as an esophageal visceral hypersensitivity, involve globus.

A traditional Japanese medicine, rikkunshito, has been reported to relieve dyspepsia symptoms. We investigated the effect of rikkunshito on RE-induced abdominal dyspepsia, and performed experiments to elucidate the mechanism of that effect.RE model rats were prepared using 8-week-old male Wistar rats, and rikkunshito was administered in drinking water. Voluntary movement was used as an index of RE-induced abdominal dyspepsia, which was monitored by an infrared sensor. On the tenth day after surgery, the total area of esophageal erosion was measured, and samples of nonerosive mucosa were collected. Using those samples, intercellular spaces of epithelial mucosa were examined by transmission electron microscopy, and the NP-40-soluble and -insoluble levels of the tight junction proteins claudin-1, -3 and -4 and their mRNAs were determined.Rikkunshito did not reduce the average total area of erosive lesions in the esophageal mucosa of RE model rats. On day 10, voluntary movement was significantly decreased in the RE model rats and rikkunshito significantly increased it. Nonerosive esophageal mucosa from RE rats showed dilation of intercellular spaces in epithelium, and significantly decreased claudin-3 mRNA and protein levels. Rikkunshito significantly suppressed intercellular space dilation and significantly increased the level of NP-40-insoluble claudin-3, but it did not affect the mRNA level, suggesting that it promoted tight junction formation by facilitating the translocation of proteins.Rikkunshito increased voluntary movement in RE model rats. This may have been because rikkunshito ameliorated the symptoms of RE by improving the barrier function of esophageal mucosa.

N-methyl-D-aspartate (NMDA) receptor is the major excitatory neurotransmitter receptor in the central nervous system. Recent evidence has pointed to expression of NMDA receptor in peripheral non-neuronal tissues and organs; however, little is known about the expression of the receptor in the stomach. The present study identified what types of NMDA receptor subunits are expressed in the rat stomach and examined whether vagotomy affects their expression.To see the expression and distribution of the mRNAs and proteins for the NMDA receptor subunits, real-time reverse transcription-polymerase chain reaction, Western blotting, in situ hybridization, and immunohistochemistry were carried out on rat stomach with and without vagotomy.Of the NMDA receptor subunits, NR1, NR2 (2A, 2B, 2C, 2D), and NR3 (3A, 3B), all NR subunit mRNAs except for the NR2B subunit mRNA were expressed in the intact rat stomach, with huge expression of NR2D mRNA. Expression of NR2D subunit mRNA and protein significantly increased after vagotomy. Increased expression was found in mucosal cells, the myenteric plexus, and the outer membrane of the stomach with vagotomy.Vagotomy upregulates expression of the NR2D subunit in the stomach and therefore, the NR2D subunit may be implicated in gastric motility.

Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways. Normal primary human esophageal epithelial cells were cultured with use of an air–liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT7) was assessed by Western blotting. The involvement of 5-HT7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers. Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK. Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.

General interest in functional gastrointestinal disorders is increasing among Japanese doctors as well as patients. This increase can be attributed to a number of factors, including recent increased interest in quality of life and advances in our understanding of the pathophysiology of gastrointestinal disease. Japan recently became the world’s first country to list “functional dyspepsia” as a disease name for national insurance billing purposes. However, recognition and understanding of functional dyspepsia (FD) remain poor, and no standard treatment strategy has yet been established. Accordingly, the Japanese Society of Gastroenterology (JSGE) developed an evidence-based clinical practice guideline for FD, consisting of five sections: concept, definition, and epidemiology; pathophysiology; diagnosis; treatment; and prognosis and complications. This article summarizes the Japanese guideline, with particular focus on the treatment section. Once a patient is diagnosed with FD, the doctor should carefully explain the pathophysiology and benign nature of this condition, establish a good doctor–patient relationship, and then provide advice for daily living (diet and lifestyle modifications, explanations, and reassurance). The proposed pharmacological treatment is divided into two steps: initial treatment including an acid inhibitory drug (H2RA or PPI) or prokinetics, (strong recommendation); second-line treatment including anxiolytics, antidepressants, and Japanese traditional medicine (weak recommendation). H. pylori eradication, strongly recommended with a high evidence level, is positioned separately from other treatment flows. Conditions that do not respond to these treatment regimens are regarded as refractory FD. Patients will be further examined for other organic disorders or will be referred to specialists using other approaches such as psychosomatic treatment.

IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE).IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used.IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA.Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.

Epithelial-mesenchymal interactions are important for maintenance of the gastrointestinal tract mucosa. Moreover, diffusible factors from the underlying mesenchyme control the proliferation and differentiation of the epithelial cells. However, the details of the associated signaling remain unknown.Two novel cell lines, designated MSE1 (mouse stomach epithelium) and MSMF1 (mouse stomach myofibroblast) cells, were established from mouse glandular stomach and cocultured in three-dimensional collagen gels in vitro.MSE1 cells formed dramatic branching tubular structures upon coculture with MSMF1 cells. In contrast, they formed spherical cyst structures in the absence of fibroblast support or the presence of Swiss 3T3 cells. Since bone morphogenetic protein 2 (BMP2) was expressed by MSMF1 cells but not Swiss 3T3 cells, we investigated whether it induced the morphological differentiation. Addition of BMP2 to MSE1 cells induced the formation of branching tubular structures, even in the absence of MSMF1 cells. Noggin, a BMP2 antagonist, blocked the MSMF1-induced tubular branch formation by MSE1 cells. MSE1 cells were induced to express mRNA of MUC5AC, an important marker for gastric superficial epithelium in the upper part of pits, upon branching tubule formation after BMP2 addition. Coculture with MSMF1 cells or BMP2 addition induced Smad1 phosphorylation in MSE1 cells. Furthermore, BMP2 inhibited MSE1 cell proliferation in MTS assays and suppressed AKT phosphorylation.BMP2 stimulated MSE1 cells to form branching duct-like structures and differentiate toward superficial epithelium in three-dimensional cocultures in vitro, suggesting that it may act as a morphogen and differentiation inducer in epithelial-mesenchymal interactions of gastric mucosa.