Immunotherapy Targeting CCR8+ Regulatory T Cells Induces Antitumor Effects via Dramatic Changes to the Intratumor CD8+ T Cell Profile.

Regulatory T cells (Tregs) contribute to the formation of a tumor-immunosuppressive microenvironment. CCR8 is reportedly selectively expressed in tumor Tregs, and an anti-CCR8 Ab can exert potent antitumor effects by eliminating intratumor Tregs in murine tumor models. In this study, we analyzed changes to intratumor immunity after anti-CCR8 Ab administration, especially in CD8+ T cells, which are involved in cancer cell killing, using the CT26 colorectal carcinoma mouse model. Immunophenotyping of tumor-infiltrating cells by mass cytometry after Ab administration on day 5 of tumor inoculation revealed that CD8+ T cell subsets were dramatically altered in the CCR8 Ab-treated group, with an increase in naive cells and nonexhausted effector cells and a decrease in exhausted cells with high expression levels of TOX. These results were corroborated with flow cytometry analysis. Delayed administration of the anti-CCR8 Ab on day 9 or 12, when the amount of CCR8+ Tregs and CD8+ T cell exhaustion were more progressed, also resulted in a decrease in exhausted CD8+ T cells, leading to tumor regression. Finally, we confirmed that high CCR8+ Treg infiltration was associated with high TOX expression in CD8+ T cells in human cancer patients. In conclusion, administration of an anti-CCR8 Ab can dramatically alter the activation and exhaustion state of intratumor CD8+ T cells, resulting in strong antitumor effects. In cancer patients with an advanced tumor-immunosuppressive environment, CD8+ T cell exhaustion has progressed along with CCR8+ Treg induction. Therefore, targeted depletion of CCR8+ Tregs is expected to be effective in these patients.

Health Care Cost Analysis of PPI or P-CAB-First Treatment in Patients With Gastroesophageal Reflux Disease.

GOALS: The aim was to examine actual health care cost in patients with gastroesophageal reflux disease (GERD) who were initiated on proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) as first-line therapy in Japanese real-world clinical settings. BACKGROUND: To date, cost-utility evaluation of acid-suppressants treatment in Japan has only been conducted by model analysis. STUDY: A cost utilization analysis was performed using a Japanese nationwide hospital-based claim database by extracting patients with GERD initiated on either PPI or P-CAB (242,102 pairs) and esomeprazole (EPZ) or P-CAB (241,825 pairs). Health care costs were compared in each comparison cohort with propensity-score matched pairs. The switching rates of initial acid-suppressants were also examined. RESULTS: Baseline characteristics were well-balanced after matching. The 3-year mean cumulative GERD-related and hospitalization costs per patient were ¥142,620 and ¥122,444 in PPI-first and P-CAB-first treatment groups, and ¥105,263 and ¥121,958 in EPZ-first and P-CAB-first treatment groups, respectively. Most hospitalization costs were non-GERD related in all the groups. The switching rates of PPI to P-CAB and P-CAB to PPI in 12 months were 7.5% and 20.2%, respectively. CONCLUSIONS: In this propensity-score matched analysis, health care cost was higher in patients with GERD initiated on PPI than in those initiated on P-CAB mainly owing to non-GERD-related hospitalization cost, whereas it was lower in those initiated on EPZ than in those initiated on P-CAB. When considering health care costs except hospitalization costs, PPI-first treatment was less expensive than P-CAB-first treatment. Low switching rate from PPI to P-CAB in the real-world practice may partially explain the discrepancy.

Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction.

OBJECTIVE: An international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ. DESIGN: Clinical questions relevant to the afore-mentioned major issues were drafted for which expert panels formulated relevant statements and textural explanations.A Delphi method using an anonymous system was employed to develop the consensus, the level of which was predefined as ≥80% of agreement. Two rounds of voting and amendments were completed before the meeting at which clinical questions and consensus were finalised. RESULTS: Twenty eight clinical questions and statements were finalised after extensive amendments. Critical consensus was achieved: (1) definition for the GOJ, (2) definition of the GOJZ spanning 1 cm proximal and distal to the GOJ as defined by the end of palisade vessels was accepted based on the anatomical distribution of cardiac type gland, (3) chemical and bacterial (Helicobacter pylori) factors as the primary causes of inflammation, metaplasia and neoplasia occurring in the GOJZ, (4) a new definition of Barrett's oesophagus (BO). CONCLUSIONS: This international consensus on the new definitions of BO, GOJ and the GOJZ will be instrumental in future studies aiming to resolve many issues on this important anatomic area and hopefully will lead to better classification and management of the diseases surrounding the GOJ.

Treatment Satisfaction With Current Medications for Chronic Constipation: An Internet Survey of Japanese Patients.

GOALS: This survey aims to determine relevant patient characteristics, treatment satisfaction, and bothersome symptoms in Japanese patients with chronic constipation (CC) treated at medical institutions. BACKGROUND: Epidemiological surveys of Japanese patients with CC are limited. STUDY: This internet survey, conducted in 2017, included 500 adults (selected from 589 respondents to match age composition ratio in Japan) who experienced constipation-like symptoms for ≥6 months, were treated at medical institutions for symptoms, and were taking any prescribed medication. RESULTS: Of 500 patients, 65.6% were female and 62.6% had experienced constipation for >10 years. Abdominal bloating, infrequent bowel movement, hard consistency of stool, and difficulty of defecation were the most frequently reported and most bothersome symptoms in males and females. Overall, 29% of patients were satisfied with treatment (36% of males, 26% of females); the individual major CC symptom with the highest level of treatment satisfaction was infrequent bowel movement (31% of total, 45% of males, 26% of females). The level of treatment satisfaction for most individual major CC symptoms was lower in females than in males, and overall treatment satisfaction by therapeutic categories ranged from 16% to 46%. Mean overall treatment satisfaction, as well as mean treatment satisfaction for each major symptom, decreased with increasing number of treatments. CONCLUSIONS: The survey results suggest that conventional treatment options were not effective enough to improve bothersome symptoms or treatment satisfaction. Treatment selection that is tailored to individual symptoms and takes patient characteristics into consideration may be key to improving patients' treatment satisfaction.

Pretreatment risk factors for endoscopic noncurative resection of gastric cancers with undifferentiated-type components.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is recommended for the treatment of early gastric cancers with an undifferentiated-type component, clinically diagnosed as intramucosal lesions ≤ 2 cm, without ulceration. In the JCOG1009/1010 trial, ESD could be performed with stomach preservation in 70% of such patients whose pathological findings met the curative resection criteria. However, additional gastrectomy was required for the remaining 30%. We identified the pretreatment risk factors for noncurative resection. METHODS: Post-hoc analysis indicated that 336 patients were identified in the JCOG1009/1010 trial; among them, 243 and 93 patients were categorized into the curative or noncurative resection groups, respectively, based on the pathological findings of the resected specimens. We explored the pretreatment risk factors for noncurative resection and investigated their associated pathological findings. RESULTS: Multivariable analysis revealed that a pretreatment tumor size > 1 cm was an independent risk factor for noncurative resection (odds ratio, 3.538; 95% confidence interval, 2.020-6.198, P < 0.0001). Patients with a pretreatment tumor size > 1 cm (n = 172) had a histological tumor size > 2 cm (22.1% vs 4.3%, odds ratio, 6.313; 95% confidence interval, 2.73-14.599, P < 0.0001) and submucosal invasion (17.4% vs 9.1%, odds ratio, 2.000; 95% confidence interval, 1.032-3.877, P = 0.040) more frequently as noncurative resection findings compared with those with a tumor size < 1 cm (n = 164). CONCLUSIONS: Because pretreatment tumor size > 1 cm is an independent risk factor for noncurative resection, endoscopists should be aware that noncurative resection is not uncommon in ESD and fully explain the potential necessity for additional gastrectomy to patients before the procedure.

Acid increases PGE2 in the duodenal mucosa in rats.

Attention has recently been paid to the duodenum as the pathophysiologic center of functional dyspepsia. However, the precise mechanisms of symptom generation remain unknown. We here investigated the effect of acid on duodenal prostaglandin E2 and localization of prostaglandin E2 related receptors. Sprague-Dawley rats were used for this study. Hydrochloric acid was administered in the duodenum, then prostaglandin E2 levels in the duodenum were measured using the ELISA. The expression and localization of prostaglandin receptors (EP1-4) and the mRNAs of prostaglandin synthases were investigated using in situ hybridization histochemistry in duodenal tissue. After acid perfusion, prostaglandin E2 levels in the duodenum significantly increased. EP3 was expressed mainly at the myenteric plexus in the duodenal mucosa, and EP4 at both the epithelial surface and myenteric plexus. Contrary, EP2 was sparsely distributed in the villi and EP1 were not clearly seen on in situ hybridization histochemistry. Prostaglandin-synthetic enzymes were also distributed in the duodenal mucosa. The prostaglandin E2 levels in the duodenum increased after acidification. Prostaglandin E2 receptors and prostaglandin E2-producing enzymes were both observed in rat duodenum. These observations suggest that duodenal prostaglandin E2 possibly play a role in the symptom generation of functional dyspepsia.

Transnasal transplantation of human induced pluripotent stem cell-derived microglia to the brain of immunocompetent mice.

Microglia are the resident immune cells of the brain, and play essential roles in neuronal development, homeostatic function, and neurodegenerative disease. Human microglia are relatively different from mouse microglia. However, most research on human microglia is performed in vitro, which does not accurately represent microglia characteristics under in vivo conditions. To elucidate the in vivo characteristics of human microglia, methods have been developed to generate and transplant induced pluripotent or embryonic stem cell-derived human microglia into neonatal or adult mouse brains. However, its widespread use remains limited by the technical difficulties of generating human microglia, as well as the need to use immune-deficient mice and conduct invasive surgeries. To address these issues, we developed a simplified method to generate induced pluripotent stem cell-derived human microglia and transplant them into the brain via a transnasal route in immunocompetent mice, in combination with a colony stimulating factor 1 receptor antagonist. We found that human microglia were able to migrate through the cribriform plate to different regions of the brain, proliferate, and become the dominant microglia in a region-specific manner by occupying the vacant niche when exogenous human cytokine is administered, for at least 60 days.

Eosinophil-associated microinflammation in the gastroduodenal tract contributes to gastric hypersensitivity in a rat model of early-life adversity.

Gastric hypersensitivity is a major pathophysiological feature of functional dyspepsia (FD). Recent clinical studies have shown that a large number of patients with FD present with gastroduodenal microinflammation, which may be involved in the pathophysiology of FD. However, no animal model reflecting this clinical characteristic has been established. The underlying mechanism between microinflammation and FD remains unknown. In this study, using a maternal separation (MS)-induced FD model, we aimed to reproduce the gastroduodenal microinflammation and reveal the interaction between gastroduodenal microinflammation and gastric hypersensitivity. The MS model was established by separating newborn Sprague-Dawley rats for 2 h a day from postnatal day 1 to day 10. At 7-8 wk of age, electromyography was used to determine the visceromotor response to gastric distention (GD) and immunohistochemistry was performed to detect distension-associated neuronal activation as well as immunohistological changes. Our results demonstrated that MS-induced FD rats underwent gastric hypersensitivity with GD at 60 and 80 mmHg, which are related to increased p-ERK1/2 expression in the dorsal horn of T9-T10 spinal cords. Eosinophils, but not mast cells, were significantly increased in the gastroduodenal tract, and the coexpression rate of CD11b and major basic protein significantly increased in MS rats. Treatment with dexamethasone reversed gastric hypersensitivity in MS-induced FD rats by inhibiting eosinophil infiltration. These findings indicated that neonatal MS stress induces eosinophil-associated gastroduodenal microinflammation and gastric hypersensitivity in adulthood in rats. Microinflammation contributes to gastric hypersensitivity; therefore, anti-inflammatory therapy may be effective in treating patients with FD with gastroduodenal microinflammation.NEW & NOTEWORTHY We showed for the first time that neonatal MS stress-induced FD rats undergo gastroduodenal eosinophil-associated microinflammation in adulthood. Suppression of microinflammation attenuated gastric hypersensitivity in MS rats. These findings established a functional link between microinflammation and gastric hypersensitivity, which may provide a potential clue for the clinical treatment of FD.

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial.

BACKGROUND & AIMS: Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited-new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan. METHODS: We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded. RESULTS: The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P = .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups-especially in the 12 mg and 40 mg groups (P = .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively). CONCLUSIONS: In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

Meta-Analysis: Placebo Response and Its Determinants in Functional Dyspepsia.

INTRODUCTION: Placebo response rates are relatively higher in clinical trials of disorders of brain-gut interaction. However, placebo response in functional dyspepsia (FD) has not been well described. Minimizing placebo response is important in drug development. We therefore conducted a meta-analysis to determine placebo response in trials for FD and to identify factors affecting placebo response rates. METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify double-blinded randomized controlled trials (RCTs) comparing medication with placebo in patients with FD. Both symptom improvement and complete relief were considered as separate primary endpoints in the analysis. Proportions of placebo patients experiencing any symptom improvement or complete relief were calculated. Dropouts after randomization for any reason were assumed to represent treatment failure for data extraction and analysis. Placebo response was pooled by a random-effects model, and effects of trial characteristics on the magnitude of placebo response were evaluated. RESULTS: In 58 eligible placebo-controlled RCTs of FD from 52 selected citations, 6,732 of 17,890 participants in all trials received placebo. Pooled placebo response rates for symptom improvement and complete relief were 44.3% and 15.6%, respectively. The placebo response rate was lower when improvements were assessed for ≥8 weeks. Trials assessing complete symptom relief showed lower placebo response rates even in trials for <8 weeks. DISCUSSION: Our systematic review and meta-analysis showed that pooled placebo response rates in double-blinded RCTs of FD depended on efficacy criteria. Trials assessing complete symptom relief showed stable low placebo response rates in short-term trials.

Senna Versus Magnesium Oxide for the Treatment of Chronic Constipation: A Randomized, Placebo-Controlled Trial.

INTRODUCTION: This is the first prospective, double-blinded, randomized, placebo-controlled trial to evaluate the safety and efficacy of a stimulant laxative compared with an osmotic agent for the treatment of chronic idiopathic constipation. METHODS: Patients were randomly administered stimulant laxative (senna, 1.0 g), osmotic agent (magnesium oxide [MgO], 1.5 g), or placebo for 28 consecutive days. The primary endpoint was overall symptom improvement. Secondary endpoints were spontaneous bowel movement (SBM), complete SBM, and patient assessment of constipation quality of life (QOL). RESULTS: Ninety patients (mean age, 42 years; 93% women; mean duration of symptoms, 9.9 years) were enrolled; all completed the study. The response rate for overall improvement was 11.7% in the placebo group, 69.2% in the senna group, and 68.3% in the MgO group (P < 0.0001). Change in SBM was significantly greater in the senna and MgO groups than that in the placebo group (P < 0.001). Similarly, change in complete SBM was significantly greater in the senna and MgO groups than that in the placebo group (P < 0.01). On the patient assessment of constipation QOL, significant improvements were seen in the senna and MgO groups compared with those in the placebo group (senna, P < 0.05; MgO, P < 0.001). The frequency of severe treatment-related adverse events was 0%. DISCUSSION: Senna and MgO significantly improved the frequency of bowel movements and QOL score and seem to be effective in the treatment of constipation.

Evidence-based clinical practice guidelines for liver cirrhosis 2020.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020.

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.

Impact of chronic constipation on health-related quality of life and work productivity in Japan.

BACKGROUND AND AIM: The impact of chronic constipation on health-related quality of life (HRQoL), work productivity, and healthcare resource use in Japan is not well understood. This study aimed to evaluate and compare the humanistic burden of respondents with chronic constipation to respondents without chronic constipation and to respondents with type 2 diabetes mellitus (T2DM), irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD), respectively. METHODS: This cross-sectional study collected demographic and general health data and HRQoL data as measured by the Short Form 12-Item (Version 2) Health Survey and EuroQol 5-dimension health surveys. Health impacts on employment-related activities and indirect costs were measured using the Work Productivity and Activity Impairment questionnaire. Propensity score matching was used to identify a control group without chronic constipation. Multivariate generalized linear models were used to identify potential factors that may impact the outcomes of respondents. RESULTS: A total of 30 001 individuals responded to the Japan National Health and Wellness Survey 2017, whereof 3373 (11.2%) reported having chronic constipation; 963 were physician diagnosed. Compared with matched controls, patients with physician-diagnosed chronic constipation had lower mean HRQoL scores and higher mean absenteeism, presenteeism, total Work Productivity and Activity Impairment, and indirect costs. Physician-diagnosed chronic constipation was associated with a higher health burden than T2DM, IBS, and GERD. CONCLUSIONS: Chronic constipation is associated with a considerable health burden, which is higher compared with T2DM, IBS, and GERD. These results suggest an urgent need for effective treatment of Japanese patients with chronic constipation to improve their quality of life.

Vitamin D receptor is overexpressed in the duodenum of patients with irritable bowel syndrome.

BACKGROUND AND AIM: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, and bile acids are thought to be associated with the pathogenesis of IBS. Bile acid receptors are expressed on intestinal epithelial cells. However, no study has assessed bile acid receptor proteins in IBS. Therefore, we examined the intestinal mucosal expression of bile acid receptors in patients with IBS. METHODS: Intestinal biopsies were performed in patients with IBS and controls. Mast cells, vitamin D receptor (VDR), and somatostatin were stained with specific antibodies. Levels of VDR, farnesoid X receptor (FXR), takeda-G-protein-receptor-5 (TGR5), claudins, and transient-receptor-potential-cation-channel-subfamily-V-member 6 (TRPV6) were assessed by western blotting. RESULTS: 3Mast cell counts in the second part of the duodenum were significantly higher in patients with IBS than in controls. VDR protein levels were significantly elevated in the duodenum and terminal ileum of patients with IBS compared with controls, although this difference was not seen in the cecum or rectum. FXR and TGR5 protein levels did not differ in any part of the intestine. VDR-positive cryptal epithelia in IBS were distributed not only at basal crypt but also along the upper part of the basal crypt epithelial cells. In contrast, the pattern of gut somatostatin-positive cells, claudins, and TRPV6 levels did not differ. CONCLUSIONS: The number of mast cells in the duodenum was significantly increased, and the protein expression levels of VDR, but not those of FXR or TGR5, were elevated in the duodenal epithelial crypt in patients with IBS.

Impacts of the COVID-19 pandemic on functional dyspepsia and irritable bowel syndrome: A population-based survey.

BACKGROUND AND AIM: Functional gastrointestinal disorders are a group of stress-sensitive gut-brain disorders. The COVID-19 outbreak has caused immense stress and anxiety among the general public. Strict measures to counter COVID-19 emergency, including physical distancing, have also taken a toll on physical and mental health. We investigated the impact of the COVID-19 pandemic on the gastrointestinal and psychological symptoms of functional dyspepsia (FD) and irritable bowel syndrome (IBS). METHODS: An online survey was conducted in Japan for a group of randomly assigned panelists from May 26 to 27, 2020. Each respondent answered a questionnaire on stress, physical distancing, and worries about COVID-19. Gastrointestinal symptoms were assessed to diagnose FD and IBS (Rome III), and psychological symptoms were assessed using the Hospital Anxiety and Depression Scale. RESULTS: A total of 5157 subjects were finally enrolled, with FD in 8.5%, IBS in 16.6%, and FD-IBS overlap in 4.0%. For both gastrointestinal and psychological symptoms, respondents with FD-IBS overlap showed the worst scores, followed by IBS-alone, then FD-alone respondents. During the COVID-19 pandemic, 11.9% of respondents reported deterioration and 2.8% reported improvement of gastrointestinal symptoms. FD-IBS overlap, psychological disease comorbidity, and stress at work/school were significantly associated with symptom deterioration. Younger age, commuting by public transport, and work/study from home were associated with symptom improvement. CONCLUSIONS: The COVID-19 pandemic negatively affected FD/IBS subjects, with respondents showing FD-IBS overlap syndrome as the most important independent factor associated with deterioration in gastrointestinal symptoms. Physicians need to take extra care of FD/IBS patients in the post-COVID period.

Impact of the coronavirus disease 2019 pandemic on irritable bowel syndrome.

BACKGROUND AND AIM: Gastrointestinal manifestations of the coronavirus disease 2019 (COVID-19) pandemic may mimic irritable bowel syndrome (IBS), and social distancing measures may affect IBS patients negatively. We aimed to study the impact of COVID-19 on respondents with self-reported IBS. METHODS: We conducted an anonymized survey from May to June 2020 in 33 countries. Knowledge, attitudes, and practices on personal hygiene and social distancing as well as psychological impact of COVID-19 were assessed. Statistical analysis was performed to determine differences in well-being and compliance to social distancing measures between respondents with and without self-reported IBS. Factors associated with improvement or worsening of IBS symptoms were evaluated. RESULTS: Out of 2704 respondents, 2024 (74.9%) did not have IBS, 305 (11.3%) had self-reported IBS, and 374 (13.8%) did not know what IBS was. Self-reported IBS respondents reported significantly worse emotional, social, and psychological well-being compared with non-IBS respondents and were less compliant to social distancing measures (28.2% vs 35.3%, P = 0.029); 61.6% reported no change, 26.6% reported improvement, and 11.8% reported worsening IBS symptoms. Higher proportion of respondents with no change in IBS symptoms were willing to practice social distancing indefinitely versus those who deteriorated (74.9% vs 51.4%, P = 0.016). In multivariate analysis, willingness to continue social distancing for another 2-3 weeks (vs longer period) was significantly associated with higher odds of worsening IBS. CONCLUSION: Our study showed that self-reported IBS respondents had worse well-being and compliance to social distancing measures than non-IBS respondents. Future research will focus on occupational stress and dietary changes during COVID-19 that may influence IBS.

Glutamine Blocks Interleukin-13-Induced Intestinal Epithelial Barrier Dysfunction.

INTRODUCTION: Impaired intestinal epithelial barrier function is a hallmark of a variety of pathological conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). IBD patients with IBS-like symptoms show higher interleukin-13 (IL-13) serum levels and poor psychological well-being. Supplementary glutamine reduced the daily bowel movement frequency, improved the stool form, and normalized intestinal hyperpermeability. This study was aimed at assessing the effects of IL-13 and supplementary glutamine on human intestinal epithelial function in vitro. METHODS: Caco-2 cells were grown on TranswellTM inserts. -IL-13 was added to the basolateral compartment, and transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) labeled-dextran permeability measured. Effects of glutamine or the phosphatidylinositol-3-kinase inhibitor LY294002 were assessed. Involvement of tight junction proteins was assessed using Western blotting and immunofluorescence staining. RESULTS: IL-13 significantly decreased TEER and increased FITC labeled-dextran epithelial permeability. IL-13 stimulation decreased the claudin-1 expression and increased the claudin-2 expression. Glutamine alleviated IL-13-induced decrease of TEER and increase of FITC labeled-dextran permeability. Further, the phosphatidylinositol-3-kinase inhibitor showed this alleviating effect while the signal transducer and activator of transcription 6 inhibitor did not. CONCLUSIONS: IL-13 induced barrier integrity impairment by decreasing claudin-1 and increasing claudin-2. Glutamine alleviated IL-13-induced barrier dysfunction by increasing claudin-1 expression, via disruption of the phosphatidylinositol-3-kinase/Akt signaling pathway.

A case of ectopic pancreas of the stomach accompanied by intraductal papillary mucinous neoplasm with GNAS mutation.

BACKGROUND: Ectopic pancreas is basically a benign disease and is not always necessary to be removed. However, all types of neoplasms occurring in the normal pancreas such as ductal adenocarcinomas and intraductal papillary mucinous neoplasms (IPMNs) may develop even within ectopic pancreas. We recently encountered an extremely rare case of ectopic pancreas in the gastric antrum associated with IPMN possessing a GNAS mutation. CASE PRESENTATION: A 71-year-old Japanese woman complained of epigastric pain. Computed tomography and upper gastrointestinal endoscopy showed an intramural cystic mass in the antrum of the stomach. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy did not give a definitive diagnosis, and the patient underwent resection of the lesion. Histology of the resected specimen showed that the gastric intramural lesion was ectopic pancreas. Moreover, the lesion contained dilated duct components with tubulo-villous epithelial proliferation consistent with pancreatic IPMN. Since the covering epithelial cells had highly atypical nuclei, the lesion was diagnosed as IPMN with high grade dysplasia. Immunohistochemistry showed that the IPMN component showed to be MUC2-, MUC5AC-, and CDX2-positive but MUC1- and MUC6-negative. Mutational analyses using genomic DNA revealed that the IPMN component had a mutation of GNAS at exon 8 (Arg201Cys). CONCLUSION: We finally diagnosed this case as gastric ectopic pancreas accompanied by intestinal type IPMN with high grade dysplasia possessing GNAS mutation. Although there were 17 cases of ectopic pancreas with IPMN including 6 cases of gastric ones reported in the English literature, this is the first case of ectopic pancreas with IPMN which was proved to have GNAS mutation. Intimate preoperative examinations including imaging analyses and EUS-FNA biopsy/cytology are recommended to decide whether the lesion has to be resected or not even if they are not effective for getting the right diagnosis.

The Potential Role of REG Family Proteins in Inflammatory and Inflammation-Associated Diseases of the Gastrointestinal Tract.

Regenerating gene (REG) family proteins serve as multifunctional secretory molecules with trophic, antiapoptotic, anti-inflammatory, antimicrobial and probably immuno-regulatory effects. Since their discovery, accumulating evidence has clarified the potential roles of the REG family in the occurrence, progression and development of a wide range of inflammatory and inflammation-associated diseases of the gastrointestinal (GI) tract. However, significant gaps still exist due to the undefined nature of certain receptors, regulatory signaling pathways and possible interactions among distinct Reg members. In this narrative review, we first describe the structural features, distribution pattern and purported regulatory mechanisms of REG family proteins. Furthermore, we summarize the established and proposed roles of REG proteins in the pathogenesis of various inflammation-associated pathologies of the GI tract and the body as a whole, focusing particularly on carcinogenesis in the ulcerative colitis-colitic cancer sequence and gastric cancer. Finally, the clinical relevance of REG products in the context of diagnosis, treatment and prognostication are also discussed in detail. The current evidence suggests a need to better understanding the versatile roles of Reg family proteins in the pathogenesis of inflammatory-associated diseases, and their broadened future usage as therapeutic targets and prognostic biomarkers is anticipated.