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Patients with inflammatory bowel disease (IBD) are recommended to receive the coronavirus disease 2019 (COVID-19) vaccine. However, a recent survey showed that patients with IBD are more hesitant to receive the vaccine than the general population. Detailed information on the side effects of the COVID-19 vaccine is necessary to encourage vaccination among patients with IBD.To investigate the frequency of side effects following COVID-19 vaccination in patients with IBD in Japan.a cross-sectional survey was conducted using a questionnaire administered to adult patients with IBD in a tertiary medical facility.Among the participants who answered the questionnaire, 92.6%, 91.5%, and 41.5% of the participants had received their first, second, and third doses of the COVID-19 vaccine, respectively. Of the vaccinated participants, 88.3%, 86.3%, and 89.0% experienced side effects after receiving the first, second, and third doses of the vaccine, respectively. The incidences of fever, chills, and headaches were significantly higher among female participants than among male participants (p 0.05). However, the frequencies of most side effects were comparable between the BNT162b2 mRNA and mRNA-1273 vaccines.The findings of our survey can help encourage patients with IBD to receive the COVID-19 vaccine.

Resistant starch (RS) has been reported to improve steatosis as well as obesity. Type 4 resistant starch (RS4), a chemically modified starch, is particularly hard to digest and suggesting higher efficacy. However, because the effects of RS4 on steatosis are not yet fully understood, the effects of RS4 on steatosis were examined using a murine high-fat diet model. Seven-week-old male mice were divided into three groups and fed a normal diet, a high-fat diet (HFD), or a high-fat diet with added RS (HFD + RS). Amylofiber SH® produced from acid-treated corn starch was used as the dietary RS. At 22 weeks old, hepatic steatosis and short chain fatty acid (SCFA) content and gut microbiota in cecum stool samples were analyzed. The ratio of body weight to 7 weeks was significantly suppressed in the HFD + RS group compared to the HFD group (132.2 ± 1.4% vs. 167.2 ± 3.9%, p = 0.0076). Macroscopic and microscopic steatosis was also suppressed in the HFD + RS group. Analysis of cecum stool samples revealed elevated SCFA levels in the HFD + RS group compared with the HFD group. Metagenome analysis revealed that Bifidobacterium (17.9 ± 1.9% vs. 3.6 ± 0.7%, p = 0.0019) and Lactobacillus (14.8 ± 3.4% vs. 0.72 ± 0.23%, p = 0.0045), which degrade RS to SCFA, were more prevalent in the HFD + RS group than the HFD group. In conclusion, RS4 suppressed steatosis, and increased Bifidobacterium and Lactobacillus, and SCFAs. RS4 may prevent steatosis by modulating the intestinal environment.

Objective: G protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using ApcMin/+, a murine model of intestinal tumors. Materials and Methods: Using GPR43−/− ApcMin/+ and GPR43+/− ApcMin/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways. Results: Our results revealed that GPR43 deficiency resulted in increased tumor numbers in ApcMin/+ mice. Ki67 was highly expressed in GPR43−/− mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088). Conclusion: Collectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway.

The human gut harbors a complex microbial community that performs a range of metabolic, physiological, and immunological functions. The host and its inhabiting microorganisms are often referred to as a "superorganism." Dysbiosis of gut microflora has been associated with the pathogenesis of intestinal disorders including inflammatory bowel disease, colorectal cancer, and extra-intestinal disorders such as cardiovascular disease. Therefore, gut microbiome interventions are important for the prevention and treatment of diseases. However, ethical, economic, scientific, and time constraints limit the outcome of human intervention or animal studies targeting gut microbiota. We recently developed an in vitro batch fermentation model (the Kobe University Human Intestinal Microbiota Model, KUHIMM) that is capable of hosting a majority of gut microbial species in humans and also detects the metabolites produced by microorganisms in real time. In this mini review, we elucidated the characteristics of the KUHIMM and its applicability in analyzing the effect of diet, drugs, probiotics, and prebiotics on intestinal bacteria. In addition, we introduce as examples its application to disease models, such as ulcerative colitis, in which intestinal bacteria are intricately involved in the process of pathogenesis. We also discuss the potential of the KUHIMM in precision medicine. KEY POINTS: • In vitro gut fermentation model to simulate human colonic microbiota • Screening of potential prebiotics and probiotic candidates in healthy model • Construction of disease models of ulcerative colitis and coronary artery disease.

Background: Colorectal cancer (CRC) is a major cause of cancer-related deaths in Japan and worldwide. Since CRC has been reported to have close relationship with diet, it seems significant to identify dietary constituents that might suppress occurrence of CRC. Recently, an epidemiological investigation for cancer incidence in Japan revealed that consumptions of black soybeans seem to reduce incidence of several cancers, especially colorectal cancer. Black soybeans coat extract (BE) is known to contain rich procyanidins which have many beneficial physiological activities such as anticancer effects. Therefore, we hypothesized that BE may have inhibitory effects to intestinal tumorigenesis and investigated using APCmin/+ mice models. Materials and Methods: APCmin/+ male mice in the C57BL/6 genetic background were obtained from Jackson Laboratories. APCmin/+ genotypes of each mouse were confirmed by polymerase chain reaction analysis (PCR) using DNA extracted from the tip of mouse tails. Mice were weighed weekly once and monitored regularly for any signs of weight loss. APC min/+ mice at 4 weeks of age were randomly divided into three groups with 5 mice, and fed by either AIN-76A diet, AIN-76A diet containing 0.05% or 0.05% BE for 8 weeks. At 12 weeks of age, intestines were removed from each mouse and then sliced longitudinally. The small intestine was cut into three equally parts: proximal, middle, and distal. Numbers and sizes of intestinal polyps in each portion were evaluated under Video-Zoom-microscope XV-440. Intestinal polyps were categorized by size into 1-2 mm, 2-3 mm and >3 mm. Other parts of the intestines were placed in 10% phosphate-buffered formalin for histopathology and immunohistochemical (PCNA, β-catenin, and MUC2) analyses. Results: Numbers of polyps in mice fed with containing 0.05% or 0.5% BE diet were significantly smaller than in mice fed without BE (P < 0.05). As for size of polyps, the number of polyps of 1 to 3 mm in size was decreased in mice with BE, however, there were no significant difference for numbers of polyps more than 3 mm in size regarding diets with or without BE. With 0.05% BE diet, reduction rates for occurrence of polyps were 81% for proximal, 48% for middle, and 47% for distal positions, while in with 0.5% BE diet, those reduction rates were 71% for proximal, 59% for middle, and 58% for distal positions, respectively. From these results, the BE, either 0.05% or 0.05% concentration, showed inhibitory effects for tumorigeneses in the small intestine of APC min/+ mice. In histological analyses, the BE was induced higher expression of MUC2-positive cells in normal intestinal lesions and lower expression of β-catenin in tumor sites Conclusions: The BE showed inhibitory effects in occurrence and growth of intestinal polyps in APCmin/+ mice models. With further evaluation of mechanisms, the BE could be a promising nutrition for prevention of CRC in human. Citation Format: Yasuyuki Shimizu, Shunta Hirano, Yoko Yamashita, Tsuyoshi Fukumoto, Naritoshi Mukumoto, Ai Nakaoka, Namiko Hoshi, Takeaki Ishihara, Daisuke Miyawaki, Ashida Hitoshi, Ryohei Sasaki. Black soybean seed coat extract suppress intestinal tumorigenesis in APCmin mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4244.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.

The aim of this study was to clarify the effect of the spore-forming and lactic acid-producing probiotic strain, Bacillus coagulans SANK 70258, on human colonic microbiota of healthy subjects and ulcerative colitis patients. A model culture system was employed to construct the in vitro human colonic microbiota, to retain the bacterial species richness and simulate the patient’s disordered composition, from the fecal inoculum. Bacterial 16S rRNA gene sequencing confirmed that administration of B. coagulans SANK 70258 (at an initial concentration of 4 × 107-total cells/mL) suppressed bacteria related to the family Enterobacteriaceae in the microbiota models for both healthy subjects (P = 0.016) and ulcerative colitis patients (P = 0.023). In addition, administration of B. coagulans SANK 70258 increased bacteria related to the family Lachnospiraceae (P = 0.031), thereby enhancing butyrate production (P = 0.031) in the microbiota models of healthy subjects. However, these changes were not observed in the microbiota models of ulcerative colitis patients, likely owing to the low abundance of Lachnospiraceae species. This study demonstrates the potential of B. coagulans SANK 70258 to exhibit antimicrobial activity against harmful organisms in patients with ulcerative colitis, while improving the intestinal microenvironment by increasing butyrogenesis in healthy persons. • B. coagulans SANK 70258 treatment reduced colonic Enterobacteriaceae species. • B. coagulans SANK 70258 treatment enhanced butyrogenesis in healthy individuals. • B. coagulans SANK 70258 treatment increased Lachnospiraceae in healthy persons. • B. coagulans SANK 70258 improves the colonic microenvironment in ulcerative colitis.

Background Behçet’s disease (BD) is a recurrent multisystem inflammatory disease. Anti-tumor necrosis factor (TNF) α agents have been used to treat patients with intestinal BD with severe disease activity or those who are resistant to conventional treatments; however, the long-term efficacy of anti-TNFα agents in intestinal BD remains unclear. In the present study, we investigated the clinical outcomes and predictors of discontinuation of anti-TNFα agents in patients with intestinal BD. Methods We reviewed the medical records of patients with intestinal BD who received first-line anti-TNFα agents between January 2009 and June 2020. The primary outcome was the percentage of patients who continued anti-TNFα therapy for 48 weeks. Secondary outcomes included the percentage of patients who achieved marked improvement, complete remission, and mucosal healing, as well as predictors of discontinuation of anti-TNFα agents. Results A total of 29 patients were included in the study. Twenty-two (75.9%) patients continued anti-TNFα therapy for 48 weeks. The percentage of patients who achieved marked improvement, complete remission, and mucosal healing at week 48 was 48.3%, 37.9%, and 48.3%, respectively. At week 96, 11 (37.9%) patients achieved marked improvement, complete remission, and mucosal healing. A higher C-reactive protein level (CRP; ≥ 1 mg/dL) at baseline was a predictor of discontinuation of anti-TNFα agents. Conclusions The 48-week continuation rate of anti-TNFα agents was 75.9% in bio-naïve patients with intestinal BD. However, a higher baseline CRP level (≥ 1 mg/dL) was associated with discontinuation of anti-TNFα agents.

Background and aim One of the main concerns related to peroral endoscopic myotomy (POEM) is postoperative gastroesophageal reflux (GER). The two penetrating vessels (TPVs) that are found at the boundary between the circular and oblique muscles in the posterior cardia wall have been suggested to be a good indicator of the optimal distal extent of POEM. However, the effect of performing myotomy using the TPVs as an anatomical reference on the frequency of post-POEM GER has not been studied. Methods This study involved consecutive patients who underwent POEM for the treatment of achalasia between April 2015 and June 2017. All enrolled patients underwent POEM in the 5 o'clock position and were divided into two groups: the conventional line group (CL group, n = 31), in which the TPVs were not exposed during submucosal tunnel dissection in the cardia, and the TPVs line group (TPVs group, n = 83), in which the TPVs were exposed and gastric myotomy was performed along the right side of the TPVs to preserve the oblique muscle. Examinations for post-POEM GER were conducted 3 months after the POEM. Results The frequency of grade B or higher reflex esophagitis was 26/83 (31.3%) in the TPVs group and 18/31 (58.1%) in the CL group (P = 0.017). Nine of 83 patients (10.8%) had GER symptoms in the TPVs group, and six of 31 (19.4%) had GER symptoms in the CL group (P = 0.23). Conclusions The novel myotomy method preserving oblique muscle using TPVs as anatomical landmarks significantly reduced the frequency of post-POEM GER.

Background and study aims Patients who have undergone colorectal surgery for resection of cancer and benign lesions are at risk for recurrent, residual, or metachronous lesions at the anastomosis site. Surgical resection of such lesions is difficult because of adhesions, and a stoma may be required as there are risks for leakage after resection. The feasibility and safety of endoscopic submucosal dissection (ESD) for these lesions remain unknown. Therefore, this case series aimed to examine the feasibility and safety of ESD by evaluating the clinical outcomes. Patients and methods We retrospectively investigated five patients who underwent ESD by a single expert for superficial neoplastic lesions at the anastomosis site after previous colorectal surgery. Results R0 resections were achieved for all lesions. Mean procedure time was 160.6 minutes. Mean dimensions of the resected specimen and tumor were 52.4 mm and 31.8mm, respectively. None of the patients had complications or recurrence after surveillance colonoscopy 1-year post-resection. Conclusions In an expert’s hands, ESD at the anastomosis site might be feasible minimally invasive treatment for superficial neoplastic lesions.

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), which is triggered spontaneously by unknown mechanisms and manifests as chronic and relapsing inflammatory conditions in the colon. Eosinophil infiltration is often observed in the colonic tissue of ulcerative colitis patients. However, the role of eosinophils in the disease has not been well defined. The aim of this study is to investigate the role of eosinophils in colonic inflammation using the murine model of spontaneous colitis. CC chemokine receptor type 3 (CCR3) and interleukin (IL)-10 double knockout mice (CCR3−/−;IL-10−/−) were utilized to evaluate the function of eosinophils in colitis. The levels of colitis were evaluated by colonoscopy, histology, and real-time PCR measurements to determine expression levels of inflammatory cytokines in the colonic tissue. The levels of cytokines produced by T cells in mesenteric lymph nodes were evaluated by ELISA. There was no significant difference in endoscopic and histological scores between the groups of CCR3−/−;IL-10−/− mice and control CCR3+/−;IL-10−/− mice. There was also no significant difference in the expression levels of pro-inflammatory cytokines in the intestinal tissue between the two groups. Similar results were found for IL-17A and interferon gamma (IFN-γ) production from mesenteric lymph node-derived T cells. Our data indicate that eosinophils do not play a significant role in the immunopathology of colitis in IL-10−/− mice.

Daikenchuto (TU-100) is herbal medicine which predominantly contains ginger, Japanese pepper, and ginseng. We investigated whether TU-100 can affect the composition of gut flora and intestinal tumor development using Apc(Min/+) mice, a murine model of intestinal tumor. Bacterial 16S rRNA sequencing and short-chain fatty acid analysis were performed on faecal samples. Tumor number and size were analysed. Any change in gene expression of the tumor tissues was assessed by real-time PCR. Principal coordinate analysis (PCoA) showed that the faecal microbiota cluster of TU-100-fed mice was different from the microbiota of control mice. However, no significant difference was observed in the concentration of short-chain fatty acids, tumor number, and gene expression levels between the two groups. Our data showed that TU-100 can affect the intestinal environment; however, it does not contribute in tumor progression or inhibition in our setting.

W27 monoclonal immunoglobulin A (IgA) suppresses pathogenic Escherichia coli cell growth; however its effect on the human intestine remains unclear. We thus aimed to determine how W27 IgA affects the human colonic microbiota using the in vitro microbiota model. This model was established using fecal samples collected from 12 healthy volunteers; after anaerobic cultivation, each model was found to retain the genera found in the original human fecal samples. After pre-incubating W27 IgA with the respective fecal sample in aerobic condition, the mixture of W27 IgA (final concentration, 0.5 µg/mL) and each fecal sample was added to the in vitro microbiota model and cultured under anaerobic condition,. Next-generation sequencing of the bacterial 16S rRNA gene revealed that W27 IgA addition significantly decreased the relative abundance of bacteria related to the genus Escherichia in the model. Additionally, at a final concentration of 5 µg/mL, W27 IgA delayed growth in pure culture of Escherichia coli isolated from human fecal samples. Our study thus revealed the suppressive effect of W27 IgA on the genus Escherichia at relatively low-concentrations and the usefulness of an in vitro microbiota model to evaluate the effect of IgA as a gut microbiota regulator.

OBJECTIVE: G protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using ApcMin/+, a murine model of intestinal tumors. MATERIALS AND METHODS: Using GPR43−/− ApcMin/+ and GPR43+/− ApcMin/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways. RESULTS: Our results revealed that GPR43 deficiency resulted in increased tumor numbers in ApcMin/+ mice. Ki67 was highly expressed in GPR43−/− mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088). CONCLUSION: Collectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway.

Background: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. Methods: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Results: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei . Conclusions: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. Clinical Trial Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

Background and study aims In order to perform peroral endoscopic myotomy (POEM) safely, retained liquid and food debris must be removed before the procedure is started. We developed a novel technique using a super-slim gastroscope, and a gastric tube to remove retained food debris in achalasia patients. In this study, the safety and efficacy of this novel technique were investigated Patients and methods Eleven patients with achalasia were enrolled in this study and underwent this novel method for esophageal clearance. Results All patients had complete clearance of the retained food debris using this method. The median procedure time (range) was 13 (6 – 30) minutes. There were no serious adverse events (AEs) and one minor AE of mucosal erythema due to mucosal suctioning. Conclusion This novel method for esophageal clearance is safe and effective in achalasia patients with large amounts of retained food debris.

Due to the heterogeneous pathology of traumatic brain injury (TBI), the exact mechanism of how initial brain damage leads to chronic inflammation and its effects on the whole brain remain unclear. Here, we report on long-term neuroinflammation, remote from the initial injury site, even after subsiding of the original inflammatory response, in a focal TBI mouse model. The use of translocator protein-positron emission tomography in conjunction with specialised magnetic resonance imaging modalities enabled us to visualize “previously undetected areas” of spreading inflammation after focal cortical injury. These clinically available modalities further revealed the pathophysiology of thalamic neuronal degeneration occurring as resident microglia sense damage to corticothalamic neuronal tracts and become activated. The resulting microglial activation plays a major role in prolonged inflammatory processes, which are deleterious to the thalamic network. In light of the association of this mechanism with neuronal tracts, we propose it can be termed “brain injury related inflammatory projection”. Our findings on multiple spatial and temporal scales provide insight into the chronic inflammation present in neurodegenerative diseases after TBI., Graphical abstract TSPO-PET detects two types of distinct inflammation occur after focal cortical injury: 1) cortical lesions respecting stable lesion boundaries, complete scars and rapid neuronal loss of injured tracts, and 2) thalamic lesions exhibiting delayed inflammatory response and long-term neuronal degeneration of uninjured tractsUnlabelled Image, Highlights • TSPO-PET tomography enables the assessment of longitudinal neuronal inflammation • Inflammatory responses at the cortical injury site diminish after about 1 week • The ipsilateral thalamus exhibits remote neuroinflammation for up to 14 weeks • Microglial activation is associated with remote chronic degeneration • Inflammation expands to remote sites via damaged cortico-thalamic projections

AIM To investigated the hemostatic ability of the S and F1-10 methods in clinical and ex vivo studies. METHODS The hemostatic abilities of the two methods were analyzed retrospectively in all six gastric endoscopic submucosal dissection cases. The treated vessel diameter, compressed vessel frequency, and bleeding frequency after cutting the vessels were noted by the recorded videos. The coagulation mechanism of the two power settings was evaluated using the data recording program and histological examination on macro- and microscopic levels in the ex vivo experiments using porcine tissues. RESULTS F1-10 method showed a significantly better hemostatic ability for vessels ≥ 2 mm in diameter and a trend of overall better coagulation effect, evaluated by the bleeding rate after cutting the vessels. F1-10 method could sustain electrical current longer and effectively coagulate the tissue wider and deeper than the S method in the porcine model. CONCLUSION F1-10 method is suggested to achieve a stronger hemostatic effect than the S method in clinical procedures and ex vivo models.

Background and study aims Peroral endoscopic myotomy (POEM) is an evolving new treatment strategy for achalasia. Although several kinds of electrosurgical knives have been used in performing POEM, the best device has yet to be determined. The FlushKnife BT is a waterjet-emitting short needle-knife with a small ball tip (BT) that offers the potential to perform all aspects of POEM with a single device. In this study, we evaluated the safety and efficiency of the FlushKnife BT for POEM. Patients and methods A total of 54 consecutive patients with achalasia and other spastic esophageal motility disorders, such as jackhammer esophagus or distal esophageal spasm, who underwent POEM between January 2016 and August 2016, were included in this retrospective study. Results The median operation time was 73.0 minutes (range 39 – 184 minutes). All procedures were completed using only the FlushKnife BT without changing to any other electrosurgical instrument. The median number of additional submucosal injections with an injection needle was 0 (range 0 – 1). Endoscopic vessel sealing was performed a mean of 3 times (range 0 – 7). The median number of bleeding episodes requiring treatment with hemostatic forceps was 0 (range 0 – 5). There were no significant adverse events. Seven of 52 patients (13.5 %) reported symptoms of gastroesophageal reflux disease such as heartburn or acid reflux at 3 month follow-up. Conclusions The FlushKnife BT enabled POEM to be performed with very few device exchanges, either for re-injection or to control intraoperative bleeding. In this uncontrolled case series, the ability of the FlushKnife BT to perform nearly all aspects of the POEM procedure seems to make it particularly well suited to this procedure.

A 66-year-old man was diagnosed with a gastric submucosal tumor. Endoscopic ultrasound (EUS) revealed an iso/hypoechoic mass in the third layer. No malignant cells were detected in a histological examination. Yearly follow-up endoscopy and EUS showed the slow growth of the tumor. Endoscopic submucosal dissection (ESD) was performed and a glistening tumor was resected. The lesion showed a multinodular plexiform growth pattern consisting of spindle cells with an abundant fibromyxoid stroma that was rich in small vessels. The tumor was diagnosed as plexiform fibromyxoma (PF) by immunohistochemistry. Although difficulties are associated with reaching a diagnosis preoperatively, chronological changes on EUS may contribute to the diagnosis of PF. ESD may also be useful in the diagnosis and treatment of PF.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1β.

Background and Aim Currently, endoscopic submucosal dissection (ESD) is a widely accepted standard treatment for early gastric cancer, but one challenging aspect of ESD is hemostasis. We developed a new hemostatic forceps (FD-Y0007) with the aim of achieving more effective hemostasis and investigated the hemostatic ability of the FD-Y0007 during gastric ESD in humans. Methods This study was a prospective randomized controlled trial, which was conducted at a cancer referral center. Sixty-six patients who were scheduled to undergo ESD were enrolled and randomly assigned to either the Coagrasper or the FD-Y0007, which was used for hemostasis throughout the case. The primary end point was the time required to obtain hemostasis, which was measured for the first episode of bleeding during each case. Results Hemostasis time for the first bleeding episode during ESD was 73.0 s for the Coagrasper and 21.5 s for the FD-Y0007 (P

AIM To investigated the usefulness of a novel slim type balltipped FlushKnife (FlushKnife-BTS) over ball-tipped FlushKnife (FlushKnife-BT) in functional experiments and clinical practice. METHODS In order to evaluate the functionality of FlushKnife-BTS, water aspiration speed, resistance to knife insertion through the scope, and waterjet flushing speed were compared between FlushKnife-BTS and BT. In clinical practice, esophageal endoscopic submucosal dissection (ESD) performed using FlushKnife-BTS or BT by an experienced endoscopist between October 2015 and January 2016 were retrospectively reviewed. The treatment speed and frequency of removing and reinserting the knife to aspirate fluid and air during ESD sessions were analyzed. RESULTS Functional experiments revealed that water aspiration speed by the endoscope equipped with a 2.8-mm working channel with FlushKnife-BTS was 7.7-fold faster than that with conventional FlushKnife-BT. Resistance to knife insertion inside the scope with a 2.8-mm working channel was reduced by 40% with FlushKnife-BTS. The waterjet flushing speed was faster with the use of FlushKnife-BT. In clinical practice, a comparison of 6 and 7 ESD using FlushKnife-BT and BTS, respectively, revealed that the median treatment speed was 25.5 mm(2)/min (range 19.6-30.3) in the BT group and 44.2 mm(2)/min (range 15.5-55.4) in the BTS group (P = 0.0633). However, the median treatment speed was significantly faster with FlushKnife-BTS when the resection size was larger than 1000 m(2) (n = 4, median 24.2 mm(2)/min, range 19.6-27.7 vs n = 4, median 47.4 mm(2)/min, range 44.2-55.4, P = 0.0209). The frequency of knife replacement was less in the BTS group (median 1.76 times in one hour, range 0-5.45) than in the BT group (7.02 times in one hour, range 4.23-15) (P = 0.0065). CONCLUSION Our results indicate that FlushKnife-BTS enhances the performance of ESD, particularly for large lesions, by improving air and fluid aspiration and knife insertion during ESD and reducing the frequency of knife removal and reinsertion.

Background: Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. Methods: A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. Results: IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. Conclusions: Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions).

BACKGROUND/AIMS: While some studies have shown that IFX and TAC exhibit similar efficacy against UC in the short-term, it is unclear which drug produces better long-term outcomes. In this study, we compared the long-term efficacy of IFX and TAC in patients with moderate to severe UC. METHODS: This retrospective study was conducted from 2009 to 2017. It included patients with no history of IFX or TAC treatment. We analyzed the clinical response and remission rates at 12 and 52 weeks, and colectomy-free and relapse-free survival were evaluated until the end of the study. RESULTS: At 12 weeks, 94.4% and 77.8% of the patients in the IFX group (n = 18) had demonstrated clinical responses and clinical remission, respectively, whereas 72.7% of the patients in the TAC group (n = 11) exhibited clinical responses and clinical remission. The clinical response, clinical remission, and colectomy-free rates did not differ significantly between the groups. At 52 weeks, clinical responses and clinical remission had been achieved in 76.5% and 70.6% of the patients both in the IFX group, respectively. In the TAC group, clinical responses and clinical remission were achieved in 50.0% of patients. Relapse-free and colectomy-free survival were estimated significantly better in IFX group evaluated by Kaplan-Meier curves. CONCLUSION: This study indicates that IFX and TAC produce similar short-term outcomes in UC patients, but IFX produces better long-term outcomes than TAC especially with avoidance of colectomy. Our data suggest that IFX therapy may be prioritized over TAC for the treatment of moderate to severe UC.

Postoperative abdominal adhesions are one of the most common post-laparotomy complications observed. Several types of adhesion preventative agents are available and their effectiveness and adverse impact have been clinically evaluated in previous studies. However, few basic studies have tested whether those agents do not trigger any unwanted xenobiotic reaction, which makes some surgeons hesitant to use them. To clarify this point, we investigated whether the adhesion preventative agent Seprafilm® (KAKEN PHARMACEUTICAL CO., LTD., Tokyo, Japan), one of the most widely used hyaluronate-based bioresorbable membrane (HBBM), can trigger an inflammatory response in normal abdominal tissue and delay the healing process. The rat underwent laparotomy and a HBBM was placed directly below the incision. Tissue samples at the incision and away from the incision (normal tissue) were harvested and inflammatory response and fibrosis were evaluated using quantitative PCR and histological scoring. We found that HBBM did not induce inflammatory cytokine expression at mRNA level in the peritoneal wall tissue or modify the fibrosis process in the abdominal cavity. These findings confirm the safety of using HBBM for the prevention of adhesion development post-laparotomy.

Endoscopic submucosal dissection (ESD) has been applied to treat early colorectal cancers. The aim of this study was to clarify the clinical course of ESD for lesions involving the ileocecal valve (ICV) by evaluating the successful resection rates, and the risk and frequency of adverse events.The outcome of ESD on 38 ICV lesions was compared with the outcome of 132 cecal lesions that did not involve the ICV or appendiceal orifice during the same study period. The factors related to longer procedure time, postoperative stricture development, and tumor recurrence were investigated for ESD of ICV lesions.There was no significant difference between the ICV and non-ICV groups in the en block resection rates. The median procedure time was significantly longer in the ICV group than in the non-ICV group, with a point estimate of the difference of 37 minutes (95 % confidence interval [CI] 20.00 to 56.00; P 0.01). None of the patients developed symptomatic post-ESD stricture or tumor recurrence. ESD procedure duration was ≥ 120 minutes in 16 lesions and 120 minutes in 22 lesions of the ICV group. A specimen diameter of ≥ 40 mm and tumor extension into terminal ileum were factors related to a longer procedure time (odds ratio [OR] 8.40, 95 %CI 1.53 to 46.10, P = 0.01; OR 10.60, 95 %CI 2.17 to 51.40, P 0.01, respectively).ICV lesions can be resected by ESD without major adverse events or causing symptomatic stricture development. However, ESD for ICV lesions should be performed only by expert endoscopists, as the procedure requires accomplished endoscopic skill and experience.

Compositional alteration of the gut microbiota is associated with ulcerative colitis (UC). Here, a model culture system is established for the in vitro human colonic microbiota of UC, which will be helpful for determining medical interventions. 16S ribosomal RNA sequencing confirms that UC models are successfully developed from fecal inoculum and retain the bacterial species biodiversity of UC feces. The UC models closely reproduce the microbial components and successfully preserve distinct clusters from the healthy subjects (HS), as observed in the feces. The relative abundance of bacteria belonging to the family Lachnospiraceae significantly decreases in the UC models compared to that in HS, as observed in the feces. The system detects significantly lower butyrogenesis in the UC models than that in HS, correlating with the decreased abundance of Lachnospiraceae. Interestingly, the relative abundance of Lachnospiraceae does not correlate with disease activity (defined as partial Mayo score), suggesting that Lachnospiraceae persists in UC patients at a decreased level, irrespective of the alteration in disease activity. Moreover, the system shows that administration of Clostridium butyricum MIYAIRI restores butyrogenesis in the UC model. Hence, the model detects deregulation in the intestinal environment in UC patients and may be useful for simulating the effect of probiotics.

A 73-year-old female with a 6-month history of progressive dysphagia and chest pain was referred to our hospital. She underwent esophagogastroduodenoscopy, which revealed abnormally strong contractions in the distal esophagus. Esophageal biopsy specimens showed massive eosinophil infiltration into the epithelium, and high-resolution manometry (HRM) also demonstrated abnormally strong contractions in the distal esophagus. Based on these results, she was diagnosed with Jackhammer esophagus (JHE) due to eosinophilic esophagitis (EoE). Treatment was started with 5 mg/day of prednisolone (PSL), and the number of peripheral blood eosinophils quickly decreased without any improvement in the patient’s dysphagia. Esophageal biopsy specimens obtained after the PSL treatment showed the disappearance of eosinophils from the epithelium. However, abnormally strong contractions were still detected on HRM. Per-oral endoscopic myotomy (POEM) was performed to treat the JHE. Interestingly, the intraoperative esophageal muscle biopsy sample demonstrated massive eosinophil infiltration into the muscle layer. After the POEM, the patient’s symptoms improved, and abnormal contractions were no longer detected on HRM. The current case suggests that when EoE combined with an esophageal motility disorder are refractory to steroid therapy, clinicians should be aware that motility disorders can develop due to eosinophil infiltration deep into the esophageal muscularis propria.

Recently, endoscopic submucosal dissection (ESD) has been applied for superficial colorectal neoplasms and the number of publications about it has been increasing, but little is known about the outcomes of colorectal ESD for the lesions50 mm. In this study, we evaluated the feasibility and safety of colorectal ESD for the lesions50 mm compared with the lesions50 mm.A total of 674 superficial colorectal neoplasms in 629 patients treated by ESD at Kobe University Hospital from July 2008 to July 2013 were included in the analysis.The median operation time (range) in the large lesion group (≥ 5 cm) was 109 (37 to 596) minutes, and it was 55 (6 to 248) minutes in the small lesion group (5 cm). Median procedure speed (range) in the large lesion group was 0.28 (0.06 to 0.83) cm2/min, and it was 0.19 (0.04 to 0.83) cm2/min in the small lesion group. The en bloc resection rate and the curative resection rate in the small lesion group was 98.7% and 96.0%, and those were 95.7% and 91.4% in the large lesion group, respectively. In terms of adverse events, perforation, muscle damage, and postoperative bleeding occurred at similar frequency in both groups.ESD on colorectal lesions50 mm takes longer operation time; however, it is resected time effectively without increasing the risk of adverse events compared with smaller lesions by ESD.

Helicobacter (H.) suis is capable of infecting various animals including humans, and H. suis infections can lead to gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Recently, we reported that interferon-γ (IFN-γ) was highly expressed in the stomachs of H. suis-infected mice, but the direct relationship between the upregulation of IFN-γ expression and the formation of gastric lymphoid follicles after H. suis infection remains unclear. Here, we demonstrated that the IFN-γ produced by B cells plays an important role in the formation of gastric lymphoid follicles after H. suis infection. In addition, IFN-γ-producing B cells evoked gastric lymphoid follicle formation independent of T-cell help, suggesting that they are crucial for the development of gastric MALT induced by Helicobacter infection.

Afferent loop obstruction caused by cancer recurrence after pancreaticoduodenectomy (PD) can be managed by either surgical or nonsurgical treatment. The general condition of patients with recurrent pancreaticobiliary cancer is often not good enough for them to undergo surgery, so less invasive nonsurgical treatment is desirable. We report a case of a 66-year-old male who had undergone PD for pancreatic head adenocarcinoma 10 months previously and who presented at our hospital with fever and jaundice due to afferent loop obstruction caused by pancreatic cancer recurrence. An endoscopic self-expandable metal stent (SEMS) was placed for afferent loop obstruction without any complications. He quickly recovered after SEMS placement. He retained a good quality of life by receiving chemotherapy until his death due to cancer progression. Our case indicates that this method could be an easy, effective, safe, and less invasive treatment, which may confer a better quality of life for patients with afferent loop obstruction due to cancer recurrence after PD.

OBJECTIVE The standard treatment for submucosal esophageal cancer is esophagectomy or chemoradiotherapy (CRT). However, these treatment modalities could deteriorate the general condition and quality of life of the patients who are intolerant to invasive therapy. It is therefore important and beneficial to develop less invasive treatment protocols for these patients. METHODS The study included 43 patients who were clinically suspected of mucosa or submucosal esophageal cancer but underwent endoscopic submucosal dissection (ESD) as a primary treatment, due to the patients' poor performance statuses and/or preferences for less invasive therapy. According to the pathological findings and patient's general condition, whether the patient underwent additional treatments or remained hospitalized without additional treatments was thereafter decided for each patient. We retrospectively analyzed the outcomes of these patients. RESULTS Fifteen patients underwent additional surgery, 11 patients underwent CRT/radiation therapy (RT) and 17 patients were followed without additional treatments. During the 3-year follow-up period, the relapse-free survival rates in the patients who received or did not receive additional treatments were 88% and 64%, respectively (95% confidence interval, 0.45-0.76, p=0.04). The relapse-free and overall survival rates in the patients with additional treatments were equivalent or superior to those described in previous reports of the standard treatments. Preceding ESD contributed to reduce the local relapse significantly to approximately 3.5% and additional CRT-related toxicities. CONCLUSION Preceding ESD is very effective for the local control of cancer, and useful for histologically confirming the high-risk factors of relapse, such as ≥submucosal layer 2 (SM2) invasion and lymphovascular involvements. ESD with additional therapy may be a promising strategy for optimizing the selection of therapy depending on the patient's general condition.

Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it. Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration. Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution. Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.

Background and aim One of the challenges during peroral endoscopic myotomy (POEM) is ensuring the appropriate length of myotomy on the gastric side. To determine the appropriate distal end of the gastric myotomy, we focused on the two penetrating vessels (TPVs) found in the gastric cardia during POEM. In the present study, we evaluated whether the TPVs could serve as an accurate indicator of the appropriate distal end of the gastric myotomy. Methods All patients who underwent POEM between March and August 2016 were included for this study. When making the submucosal tunnel in the 5 o'clock direction into the stomach, two vessels penetrating through the circular muscle along the edge of oblique muscle in the cardia can be exposed. We designated these two vessels as TPVs. The myotomy was extended until the second TPVs was exposed. The anal end of the submucosal tunnel was confirmed by the double-scope POEM technique, and the length from the gastroesophageal junction to the anal side end of the myotomy was measured by the scale on the endoscope. Results Among 37 patients who underwent myotomy in the 5 o'clock position, TPVs were found in 34 patients (91.2%). Sufficient submucosal tunneling on the gastric side was confirmed by the double-scope POEM technique in these 34 patients. Median length of the gastric myotomy was 3.0 cm (range 2-4 cm). Conclusion TPVs appears to be a simple and reliable indicator to determine the appropriate distal end of myotomy.

Background Inflammation-induced carcinogenesis in pancreatic ductal adenocarcinoma (PDAC) has been reported; however, its involvement in PDAC with intraductal papillary mucinous neoplasm (IPMN) remains unclear. We herein investigated the relationship between pancreatic atrophy and inflammation and the incidence of PDAC concomitant with IPMN. Methods This study included 178 consecutive patients who underwent surgical resection for PDAC with IPMN (N = 21) and IPMN (N = 157) between April 2001 and October 2016. A multivariable logistic regression analysis was conducted to assess the relationship between pancreatic inflammation and atrophy and the incidence of PDAC concomitant with IPMN, with adjustments for clinical characteristics and imaging features. Pathological pancreatic inflammation and atrophy were evaluated in resected specimens. Results High degrees of pancreatic inflammation and atrophy were not associated with the incidence of PDAC with IPMN (multivariable odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.07 to 3.33, P = .52, adjusted by clinical characteristics, OR = 0.9, 95% CI = 0.10 to 5.86, P = .91, adjusted by imaging studies; OR = 0.2, 95% CI = 0.009 to 1.31, P = .10, adjusted by clinical characteristics, OR = 0.2, 95% CI = 0.01 to 1.43, P = .12, adjusted by imaging studies, respectively). Conclusions Pancreatic inflammation and atrophy were not associated with pancreatic cancer concomitant with IPMN.

Aims: To investigate the utility of ozone nanobubble water (NBW3) for the treatment of Helicobacter pylori in the stomach, we tested the influence of pepsin concentrations and pH levels on the disinfective activity of NBW3, and the cytotoxicity of NBW3 against mammalian cells and mucosa. Methods: Different concentrations of pepsin were dissolved in NBW3, and the bactericidal activity was tested on H. pylori. NBW3 was adjusted to different pH levels (2.0-7.4) and the bactericidal activity on H. pylori was also tested. To examine the cytotoxicity of NBW3, AGS cells, human gastric epithelial cells, were treated with NBW3 and the viability of the cells was evaluated in vitro. Furthermore, NBW3 was administered to mice and gastric mucosal damage was evaluated by histology. Results: Pepsin reduced the disinfective activity of NBW3 on H. pylori in a pepsin concentration-dependent manner. NBW3 showed stable disinfective activity at all pH levels examined. Cytotoxicity of NBW3 against human gastric epithelial cells and gastric mucosa was not observed in our experimental setting. Conclusions: NBW3 can sustain its disinfective activity in wide range of pH levels and show no cytotoxicity on mammalian cells and tissue. Pepsin can inhibit NBW3 activity in a dose-dependent manner.