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Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy, the mechanism of which is involved in oxidative stress, can be lethal due to hemorrhage. Thus, we aimed to investigate the effect of hydrogen-rich water (HRW), in terms of oxidative stress, on intestinal mucosal damage as well as changes in the gut microbiome and the short-chain fatty acids (SCFAs) content in feces.Hydrogen-rich water was orally administered for 5 days to investigate the effectiveness of indomethacin-induced enteropathy in mice. Small intestinal damage and luminal reactive oxygen species (ROS) were evaluated to investigate the ameliorating effects of hydrogen. Then, components of the gut microbiome were analyzed; fecal microbiota transplantation (FMT) was performed using the cecal contents obtained from mice drinking HRW. The cecal contents were analyzed for the SCFAs content. Finally, cells from the macrophage cell line RAW264 were co-cultured with the supernatants of cecal contents.Hydrogen-rich water significantly ameliorated IND-induced enteropathy histologically and reduced the expression of IND-induced inflammatory cytokines. Microscopic evaluation revealed that luminal ROS was significantly reduced and that HRW did not change the gut microbiota; however, FMT from HRW-treated animals ameliorated IND-induced enteropathy. The SCFA content in the cecal contents of HRW-treated animals was significantly higher than that in control animals. The supernatant had significantly increased interleukin-10 expression in RAW264 cells in vitro.Hydrogen-rich water ameliorated NSAID-induced enteropathy, not only via direct antioxidant effects but also via anti-inflammatory effects by increasing luminal SCFAs. These results suggest that hydrogen may have therapeutic potential in small intestinal inflammatory diseases.

The functions of basophils have not been elucidated until recently because of their rarity. However, with recent developments in basophil-specific antibodies and basophil-deficient animals, the roles of basophils in various diseases related to chronic inflammation have been clarified. In this study, we aimed to investigate the roles of basophils in human ulcerative colitis (UC) and oxazolone (OXA) colitis using genetically engineered Mcpt8Immunohistochemical staining of human colon specimens was performed to examine the involvement of basophils in the pathogenesis of UC. We examined the correlation between the number of infiltrating basophils and the UC endoscopic index of severity (UCEIS), Mayo score, and Matts score. We also examined the correlation between eosinophil count and basophil infiltration. In murine experiments, we examined whether basophil infiltration was involved in OXA-induced colitis and whether basophil depletion improved inflammation in Mcpt8Colonic basophil infiltration was significantly increased in patients with UC. There were significant correlations between UCEIS, Mayo score, Matts score, and the number of infiltrating basophils. In murine OXA-induced colitis, a significant increase in basophil infiltration was observed. When basophils were depleted by diphtheria toxin in Mcpt8Basophil infiltration correlated with endoscopic, clinical, and pathological scores in human UC independently of eosinophil infiltration, and depletion of basophils ameliorated mucosal inflammation in murine OXA-induced colitis, collectively suggesting that basophils exert a proinflammatory role in chronic intestinal inflammation such as UC.

Takayasu arteritis (TA) sometimes presents with colitis, which may be diagnosed as inflammatory bowel disease unclassified (IBDU) because of atypical or mixed findings of ulcerative colitis (UC) and Crohn's disease. We herein report an 18-year-old girl presenting with colitis with an occasional high fever eventually diagnosed as TA with IBDU. Colonic inflammation was initially discontinuous and stronger in the proximal colon, atypical of UC. However, over 10-year observation, the distribution of colonic inflammation varied and became UC-like. Variations in TA-related colonic inflammations over time have been unclear. Our long-term observation might help clarify the details of TA-related colonic inflammation.

The study of the impact of environmental factors during pregnancy on fetal development has so far been focused primarily on those negatively affecting human health; however, little is known about the effects of probiotic treatment during pregnancy on inflammatory bowel diseases (IBD). In this study, we investigated whether oral administration of heat-killed probiotics isolated from fermented foods decreased the vulnerability of offspring to IBD.Probiotics were administered to the pregnant mice until the birth of pups, after which the parent mice were maintained with autoclaved water. Partial pups were evaluated for dextran sodium sulfate-induced colitis. The influence of CD11cOral administration of heat-killed probiotics to pregnant dams significantly decreased inflammation induced by dextran sodium sulfate in pups. Probiotic treatment increased the number of CD103Oral administration of probiotics during gestation induced transgenerational immunomodulatory effects on the gut-associated immune system and resilience to experimental colitis in the offspring. Our results suggest that consumption of fermented foods during pregnancy can be effective in preventing inflammatory diseases such as IBD beyond generation.

BACKGROUND AND AIM The artificial sweetener acesulfame potassium (ACK) is officially approved as safe for intake and has been used in processed foods. However, ACKs have been reported to induce metabolic syndrome, along with alteration of the gut microbiota in mice. In recent years, studies have suggested that this artificial sweetener promotes myeloperoxidase reactivity in Crohn's disease-like ileitis. We aimed to investigate the effect of ACK on the intestinal mucosa and gut microbiota of normal mice. METHODS Acesulfame potassium was administered to C57BL/6J mice (8 weeks old) via free drinking. Intestinal damage was evaluated histologically, and messenger RNA (mRNA) levels of TNF-α, IFN-γ, IL1-β, MAdCAM-1, GLP1R, and GLP2R were determined with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed to examine the expression of MAdCAM-1 in the small intestine. The composition of gut microbiota was assessed using high-throughput sequencing. We performed intravital microscopic observation to examine if ACK altered lymphocyte migration to the intestinal microvessels. RESULTS Acesulfame potassium increased the expression of proinflammatory cytokines, decreased the expression of GLP-1R and GLP-2R, and induced small intestinal injury with an increase in intestinal permeability, and ACK treatment induced microbial changes, but the transfer of feces alone from ACK mice did not reproduce intestinal damage in recipient mice. ACK treatment significantly increased the migration of lymphocytes to intestinal microvessels. CONCLUSION Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa. Massive use of non-caloric artificial sweeteners may not be as safe as we think.

Background The small intestine plays a central role in gut immunity, and enhanced lymphocyte migration is involved in the pathophysiology of various enteropathy. Bile acid (BA) is closely related to lipid metabolism and gut microbiota, and essential for gut homeostasis. However, the effects of BA on gut immunity have not been studied in detail, especially on the small intestine and lymphocyte migration. Therefore, we aimed to investigate the effect of BA on small intestinal lymphocyte microcirculation. Methods The effect of deoxycholic acid (DCA), taurocholic acid (tCA) or cholic acid (CA) on the indomethacin (IND)-induced small intestinal enteropathy in mice was investigated. Lymphocyte movements were evaluated after exposure to BA using intravital microscopy. The effects of BA on surface expression of adhesion molecules on the vascular endothelium and lymphocytes through BA receptors were examined in vitro. Results IND-induced small intestinal enteropathy was histologically aggravated by DCA treatment alone. The expression of adhesion molecules ICAM-1 and VCAM-1 were significantly enhanced by DCA. Exposure to DCA increased lymphocyte adhesion in the microvessels of the ileum, which was partially blocked by anti-α4β1 integrin antibody in vivo. The expression of ICAM-1 and VCAM-1 were significantly enhanced by DCA in vitro, which was partially suppressed by the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist. The S1PR2 antagonist significantly ameliorated IND-induced and DCA-exaggerated small intestinal injury. Conclusion DCA exacerbated IND-induced small intestinal enteropathy. DCA directly acts on the vascular endothelium and enhances the expression levels of adhesion molecules partially via S1PR2 leading to enhanced small intestinal lymphocyte migration.

Background Non-Helicobacter pylori Helicobacter (NHPH) is not widely recognized as a cause of acute gastric mucosal lesions (AGML), as only a few cases of AGML caused by NHPH have been reported. We present here one case and examine the species and eradication of NHPH together with the three previously reported cases. Case presentation A 52-year-old woman presented with a two-day history of severe epigastric pain, nausea, and vomiting. An esophagogastroduodenoscopy showed mucosal edema, multiple erosions, and ulcerations in the antrum. Biopsy specimens taken from the antrum revealed long spiral-shaped organisms, suggesting NHPH. As both serum anti-Helicobacter pylori (H. pylori) antibody and H. pylori stool antigen test were negative, this case was diagnosed as AGML caused by NHPH. After the administration of esomeprazole 20 mg for 14 days and the interval of the following 12 days, AGML was deemed to have been cured endoscopically. In addition, microscopic examination and PCR analysis confirmed the success of NHPH eradication. Conclusions NHPH should be considered a probable cause of AGML in cases that are not attributed to the other causes already recognized. Taking probability of spontaneous eradication into consideration, it is appropriate to start eradication therapy after confirming the chronicity of NHPH infection.

We herein present the case of an immunocompetent 63-year-old man who had previously undergone resection of Crohn's disease (CD)-related small intestinal obstruction more than 30 years ago. He had not been receiving any medication for many years, but had recently started to suffer from ileus. A stenosed site of ileo-cecal anastomosis was identified and therefore was surgically resected, which was diagnosed as CD with small intestinal extramedullary plasmacytoma (EMP). The subsequent progression of CD was successfully controlled by anti-TNFα agents without any recurrence of EMP for over 3 years, implying the clinical benefit and safety of the biological therapy. This was the first known case of a patient who received anti-TNFα agents after a resection of small intestinal EMP accompanied with CD.

Background/Aims: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. Methods: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. Results: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. Conclusions: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS. (Gut Liver 2019;13:325-332)

We herein report a 44-year-old man suffering from systemic edema due to protein-losing enteropathy (PLE) with superior mesenteric vein (SMV) obstruction and development of collateral veins, which subsequently proved to be a chronic result of thrombosis and a complication of Crohn's disease (CD). PLE was supposedly induced by both intestinal erosion and thrombosis-related lymphangiectasia, which was histologically proven in his surgically-resected ileal stenosis. Elemental diet and anti-TNFα agent improved his hypoalbuminemia after surgery. The rarity of the simultaneous coexistence of SMV obstruction and PLE and the precedence of these complications over typical abdominal symptoms of CD made the clinical course complex.

Background and aim There are only a few reports of non-Helicobacter pylori Helicobacter (NHPH) gastritis in Japanese patients. We aimed to examine its prevalence, clinical features, and esophagogastroduodenoscopy (EGD) findings based on 50 patients encountered in one facility. Materials and methods Subjects were all patients who had undergone gastric mucosal biopsy endoscopically at Kenwakai Hospital for approximately 10 years. NHPH infection was diagnosed by microscopic findings of Giemsa staining performed on all specimens. PCR analysis of urease genes was performed to detect and identify NHPH, when informed consent was obtained. Helicobacter pylori-diagnostic tests were also performed. NHPH-infected patients were questioned about symptoms and animal contact. Results NHPH gastritis was found in 50 of 3847 patients (1.30%). The percentage increased to 3.35% (30 of 896 patients) in the latter 2 years and 4 months with increasing recognition of its characteristic endoscopic findings by endoscopists. PCR analysis, performed in 30 patients, detected NHPH in 28 patients: 26 as Helicobacter suis and 2 as Helicobacter heilmanii/Helicobacter ailurogastricus. Helicobacter pylori-diagnostic tests were almost negative. However, anti-H. pylori antibody showed high-negative titer (3.0-9.9 U/ml) in 12. Of 50 patients (consisting of 49 men and 1 woman), almost all were asymptomatic, and 25 were keeping pets. Regarding EGD findings, in all 50 patients, "crack-like mucosa" and/or nodular gastritis was noted in gastric antrum, and regular arrangement of collecting venules (RAC) was noted in gastric corpus. None of the patients infected with NHPH were co-infected with H. pylori. Conclusions The prevalence was finally estimated to be approximately 3.35%. Helicobacter suis was the most common NHPH species. "Crack-like mucosa" and/or nodular gastritis in gastric antrum, RAC in gastric corpus, and H. pylori-negativity by H. pylori-diagnostic tests especially containing a high-negative titer of anti-H. pylori antibody may indicate NHPH infection.

Yeasts are a type of fungi thought to have probiotic functions. In this study, we isolated a novel probiotic yeast (Zygosaccharomyces sapae strain I-6) from Miso (a traditional Japanese fermented food). We examined its effects on phenotypic changes in intestinal dendritic cells (DCs), and evaluated its anti-inflammatory effects in dextran sulfate sodium (DSS)-induced colitis. A single colony was selected from homogenized Miso, based on its ability to produce interleukin (IL)-10 in CD11c+ bone marrow DCs (BMDCs) in vitro. The anti-inflammatory effects of strain I-6 on CD11c+ BMDCs and CD11c+ CD103+ DCs were analyzed in mouse mesenteric lymph nodes in vitro and in a DSS mouse model. The IL-10 concentrations in the co-culture BMDC supernatants treated with I-6 were dramatically higher than in those treated with Saccharomyces cerevisiae (Sc). IL-10 production is mediated by both TLR2 and Dectin-1. β-Glucan extracted from I-6 also induced higher levels of IL-10 production in BMDCs than β-glucan from Sc. The number of mesenteric lymph node CD11c+ CD103+ DCs was significantly increased by I-6 administration, compared with Sc administration. Strain I-6 showed strong anti-inflammatory effects on DSS-induced colitis compared to Sc. Moreover, the adoptive transfer of I-6-treated BMDCs showed anti-inflammatory effects on DSS-induced colitis in mice without oral administration of I-6 cells. Strain I-6 induced phenotypic changes in intestinal CD11c+ DCs characterized by high IL-10 production and exerted strong anti-inflammatory effects on DSS-induced colitis. Traditional Japanese fermented foods may be a valuable source of probiotic yeasts for effective IBD therapy and treatment.

Background: Although the infection rate of Helicobacter suis is significantly lower than that of Helicobacter pylori, the H. suis infection is associated with a high rate of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In addition, in vitro cultivation of H. suis remains difficult, and some H. suis-infected patients show negative results on the urea breath test (UBT). Materials and Methods: Female C57BL/6J mice were orally inoculated with mouse gastric mucosal homogenates containing H. suis strains TKY or SNTW101 isolated from a cynomolgus monkey or a patient suffering from nodular gastritis, respectively. The high-purity chromosomal DNA samples of H. suis strains TKY and SNTW101 were prepared from the infected mouse gastric mucosa. The SOLiD sequencing of two H. suis genomes enabled comparative genomics of 20 Helicobacter and 11 Campylobacter strains for the identification of the H. suis-specific nucleotide sequences. Results: Oral inoculation with mouse gastric mucosal homogenates containing H. suis strains TKY and SNTW101 induced gastric MALT lymphoma and the formation of gastric lymphoid follicles, respectively, in C57BL/6J mice. Two conserved nucleotide sequences among six H. suis strains were identified and were used to design diagnostic PCR primers for the detection of H. suis. Conclusions: There was a strong association between the H. suis infection and gastric diseases in the C57BL/6 mouse model. PCR diagnosis using an H. suis-specific primer pair is a valuable method for detecting H. suis in gastric biopsy specimens.

Background Non-Helicobacter pylori helicobacters (NHPHs) besides H. pylori infect human stomachs and cause chronic gastritis and mucosa-associated lymphoid tissue lymphoma. Cholesteryl-α-glucosides have been identified as unique glycolipids present in H. pylori and some Helicobacter species. Cholesterol-α-glucosyltransferase (αCgT), a key enzyme for the biosynthesis of cholesteryl-α-glucosides, plays crucial roles in the pathogenicity of H. pylori. Therefore, it is important to examine αCgTs of NHPHs. Materials and Methods Six gastric NHPHs were isolated from Japanese patients and maintained in mouse stomachs. The αCgT genes were amplified by PCR and inverse PCR. We retrieved the αCgT genes of other Helicobacter species by BLAST searches in GenBank. Results αCgT genes were present in most Helicobacter species and in all Japanese isolates examined. However, we could find no candidate gene for αCgT in the whole genome of Helicobacter cinaedi and several enterohepatic species. Phylogenic analysis demonstrated that the αCgT genes of all Japanese isolates show high similarities to that of a zoonotic group of gastric NHPHs including Helicobacter suis, Helicobacter heilmannii, and Helicobacter ailurogastricus. Of 6 Japanese isolates, the αCgT genes of 4 isolates were identical to that of H. suis, and that of another 2 isolates were similar to that of H. heilmannii and H. ailurogastricus. Conclusions All gastric NHPHs examined showed presence of αCgT genes, indicating that αCgT may be beneficial for these helicobacters to infect human and possibly animal stomachs. Our study indicated that NHPHs could be classified into 2 groups, NHPHs with αCgT genes and NHPHs without αCgT genes.