Search

Background: Mild blast‐induced traumatic brain injury (bTBI) induces various gut symptoms resembling human irritable bowel syndrome (IBS) as one of mental and behavioral disorders. However, the underlying mechanisms remain unclear. We investigated whether the extremely localized brain impact extracranially induced by laser‐induced shock wave (LISW) evoked IBS‐like phenomenon including visceral hypersensitivity and intestinal hyperpermeability in rats. Methods: The rats were subjected to LISW on the scalp to shock the entire brain. Visceral hypersensitivity was evaluated by the threshold pressure of abdominal withdrawal reflex (AWR) using a colorectal distension test. Permeability was evaluated by the concentration of penetrating FITC‐dextran from intestine and the mRNA expression levels of tight junction family proteins. Involvement of corticotropin‐releasing factor receptor (CRFR) 1 and 2 was examined by evaluating mRNA expression and modulating CRFR function with agonist, recombinant CRF (10 μg/kg), and antagonist, astressin (33 μg/kg). High‐throughput sequencing of the gut microbiota was performed by MiSeqIII instrument and QIIME tool. Key Results: The thresholds of the AWR were significantly lowered after LISW. Permeability was increased in small intestine by LISW along with decreased expression of tight junction ZO‐1. LISW significantly increased CRFR1 expression and decreased CRFR2 expression. Visceral hypersensitivity was significantly aggravated by CRFR agonist and suppressed by CRFR antagonist. The α‐ and β‐diversity of the fecal microbiota was altered after LISW. Conclusions and Inferences: LISW provoked visceral hypersensitivity, small intestinal hyperpermeability, altered expression of CRFRs and changes in the microbiota, suggesting that genuine bTBI caused by LISW can induce a pathophysiology comparable to that of human IBS. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: The specific etiopathogenesis of inflammatory bowel disease (IBD) is still unknown. Although the conventional anti-inflammatory or immunomodulatory drugs relatively nonspecific to pathogenesis have been quite useful in many cases, elucidating the pathogenesis has gradually facilitated developments of disease-specific therapies for refractory cases in the last 2 decades. Summary: With a greater understanding of the multiple overactive signaling pathways of the gut mucosal immune response and enhanced leukocyte trafficking, several biological agents or small molecule drugs following the first novel biologic, anti-tumor necrosis factor α (anti-TNFα), have been developed against several modes of action including adhesion molecules, sphingosine-1-phospate receptors, cytokines (IL-12/23, TL1A, and IL-36), Janus kinase (JAK), and phosphodiesterase. Although preceding biological agents have dramatically changed the IBD treatment strategy, many patients still require alternative therapies due to failure or side effects. Newer treatments are now expected to be provided for better efficacy with an improved adverse event profile. In addition, translational studies have highlighted the new therapeutic concepts' potential, including modulation of host-microbiome interactions, stem therapy for perianal fistula, regulation of fibrosis, regulation of the gut-brain axis, and control of previously less targeted immune cells (B cells and innate lymphoid cells). This paper comprehensively reviewed not only the latest already or shortly available therapies but also emerging promising treatments that will be hopefully established in the future for IBD. Key Messages: Many kinds of new treatments are available, and promising treatments with new perspectives are expected to emerge for refractory IBD in the future. [ABSTRACT FROM AUTHOR]

Background and Aim: 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 Mcpt8DTRmice. Methods: Immunohistochemical 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 Mcpt8DTRmice. Results: Colonic 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 Mcpt8DTRmice, inflammation improved significantly and mRNA expression of some proinflammatory cytokines, including Tnf‐α and Ifn‐γ decreased significantly. Conclusion: Basophil 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. [ABSTRACT FROM AUTHOR]

Background: Uric acid (UA) has anti- and pro-inflammatory properties. We previously revealed that elevated serum UA levels provide protection against murine small intestinal injury probably via luminal UA secreted in the small intestine. Luminal UA may act as an antioxidant, preventing microbiota vulnerability to oxidative stress. However, whether luminal UA is increased under hyperuricemia and plays a protective role in a dose-dependent manner as well as the mechanism by which luminal UA exerts its protective effects on enteropathy remains unknown. Methods: Inosinic acid (IMP) (1000 mg/kg, i.p.) was administered to obtain high serum UA (HUA) and moderate serum UA (500 mg/kg IMP, i.p.) mice. UA concentrations and levels of oxidative stress markers in the serum and intestine were measured. Mice received indomethacin (20 mg/kg, i.p.) to evaluate the effects of UA on indomethacin-induced enteropathy. Reactive oxygen species (ROS) on the ileal mucosa were analyzed. The fecal microbiota of HUA mice was transplanted to investigate its effect on indomethacin-induced enteropathy. Results: IMP increased luminal UA dose-dependently, with higher levels of luminal antioxidant markers. Indomethacin-induced enteropathy was significantly ameliorated in both UA-elevated groups, with decreased indomethacin-induced luminal ROS. The microbiota of HUA mice showed a significant increase in α-diversity and a significant difference in β-diversity from the control. Fecal microbiota transplantation from HUA mice ameliorated indomethacin-induced enteropathy. Conclusions: The protective role of luminal UA in intestinal injury is likely exerted via oxidative stress elimination and microbiota composition modulation, preferably for gut immunity. Therefore, enhancing anaerobic conditions using antioxidants is a potential therapeutic target. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aim: 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 was 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 was 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. [ABSTRACT FROM AUTHOR]

Introduction: Innate lymphoid cells (ILCs) are abundant in the intestinal mucosa, forming boundaries externally. Herein, ILCs were directly obtained from intestinal lymph using a lymph fistula rat model and analyzed under physiological and pathological conditions. Methods: Thoracic duct (TD) lymphocytes were collected by cannulation with/without preceded mesenteric lymphadenectomy, which were comparable to lymphocytes flowing through mesenteric lymphatic vessels (MLVs) or TD, respectively. The collected ILCs were classified according to gene transcription factors and analyzed by flow cytometry. The effect of IL‐25 or indomethacin was studied. Results: The proportion of total ILCs in the MLVs (MLV‐ILCs) was significantly higher than that in TD (TD‐ILCs, 0.01% vs. 0.003%, respectively). Physiologically, there were several significant differences in the MLV‐ILCs compared with TD‐ILCs, including the proportion of ILC2 (42.3% vs. 70.9%) and ILC3 (33.3% vs. 13.8%), and the proportion of α4‐integrin‐positive cells (36.8% vs. 0.3%). IL‐25 significantly increased the proportion of MLV‐ILC2 after 3 days. Indomethacin‐induced intestinal injury increased the proportion of MLV‐ILC3 in the early phase within 12 h. Conclusion: Intestinal ILCs were found to migrate through MLVs. The altered mobilization of MLV‐ILCs after stimuli suggests that ILCs play an important role in regulating the immune responses at the secondary lymph nodes. [ABSTRACT FROM AUTHOR]

Background and Aim: Worldwide increasing aging societies have many elderlies with intractable diseases including ulcerative colitis (UC). Reportedly, each patients' frailty as well as chronological age is a clinical risk factor of elderly‐onset UC (EOUC). Because malnutrition is one of the major manifestations of frailty, we aimed to investigate the effect of malnutrition on the prognosis of EOUC with geriatric nutritional risk index (GNRI), a prognostic tool for several diseases in the elderly to estimate malnutrition, and to evaluate clinical risks among EOUC patients in Japan, the world‐leading aging society. Methods: The EOUC patients (≥ 65 years at diagnosis, n = 2778) in the previous nationwide survey were classified by age and GNRI, and odds ratios (ORs) of hospitalization and UC‐related surgery were determined to evaluate the effects of malnutrition on the EOUC patients as well as aging. Results: The risks of hospitalization and surgery were elevated as age advanced. The value of GNRI, negatively correlated with disease activity (r = −0.53), could distinguish severe activity (cutoff ≤ 86.82, sensitivity = 0.79, and specificity = 0.77) and discriminate the EOUC patients suffering from surgery and hospitalization. In a multivariate analysis, GNRI ≤ 86.82 was a higher risk of hospitalization (OR: 4.0, 95% CI, 2.5–6.5) and surgery (OR: 2.7, 95% CI, 0.98–7.4) than cutoff age ≥ 75 years old (OR of hospitalization and surgery were 1.4 [95% CI, 0.99–2.0] and 2.3 [95% CI, 0.8–6.3], respectively). Conclusion: Malnutrition estimated by GNRI was significantly related with poor clinical courses of the EOUC patients, suggesting that evaluation of nutritional status at the onset might be useful for predicting risks of clinical courses. [ABSTRACT FROM AUTHOR]

Background and Aim: Dietary emulsifiers are widely used in processed foods and officially approved as safe for intake. However, recent studies have demonstrated that some emulsifiers alter the colonic microbiota, leading to colonic low‐grade inflammation, in mice. The effect of dietary emulsifiers on small‐intestinal microbiota, which is important for gut immunity, has not been studied. We aimed to investigate the effect of a representative dietary emulsifier, polysorbate‐80 (P80), on the small‐intestinal microbiota in normal mice. Methods: Some mice were pretreated with P80 for 8 weeks with or without indomethacin administration on the last 2 days, and intestinal damage was evaluated histologically. The ileal and colonic microbiota composition was assessed using 16S rRNA polymerase chain reaction. Results: Polysorbate‐80 increased the Gammaproteobacteria abundance and decreased the α‐diversity in the small intestine. No decrease in α‐diversity was observed in the colon. P80 pretreatment exacerbated the indomethacin‐induced small‐intestinal lesions and significantly increased the interleukin‐1β expression. Culture of ileal content on deoxycholate hydrogen sulfide lactose agar showed that P80 significantly increased the colonies of the sulfide‐producing bacteria Proteus spp. (genetically identified as Proteus mirabilis). Antibiotic pretreatment abolished the P80‐induced aggravation of indomethacin‐induced ileitis. Motility assay in semisolid agar showed that adding 0.02% P80 to the agar significantly increased the diameter of P. mirabilis colonies but not that of Escherichia coli colonies. Conclusions: Polysorbate‐80 enhances the vulnerability of the small intestine to indomethacin‐induced injury by inducing ileal dysbiosis. Direct enhancement of the motility of specific flagellated microbiota by P80 might be related to dysbiosis and intestinal injury. [ABSTRACT FROM AUTHOR]

Aim: Chitinase 3‐like 1 (CHI3L1), an 18‐glycosyl hydrolase‐related molecule, is a member of the enzymatically inactive chitinase‐like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. Methods: Chitinase 3‐like 1‐deficient (Chi3l1−/−) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline‐deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. Results: In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1−/− mice compared to that in wild‐type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1−/− mice compared to that in wild‐type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1−/− mice. Chitinase 3‐like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. Conclusions: Chitinase 3‐like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

We herein present a unique and extremely rare fulminant case of Edwardsiella tarda infection-related necrotizing fasciitis. The patient had alcoholic cirrhosis and preferred to consume raw fish. He experienced painful swelling of the right forearm one day after he got a minor injury when falling from the ladder, and visited our hospital. His accompanied symptoms were diarrhea and general fatigue. His consciousness got deteriorated after the admission. The lesion of the right forearm had spread and the color had deteriorated with epidermolysis in a few hours. Necrotizing soft-tissue infection was suspected, and emergency debridement of the swollen forearm was performed 4 hours after the admission. However, unfortunately, he died of sepsis approximately 5 hours later. Histological examination of the biopsy specimen revealed features consistent with those of necrotizing fasciitis. The bacterial cultures of blood and the wound identified E. tarda. Since this microorganism is usually isolated from aquatic environments and can cause intestinal infection, sometimes followed by bacteremia especially in immunocompromised hosts, two possible infection routes were suspected. One route was from the skin injury, leading to bacteremia. Another possible route was per oral: orally taken E. tarda invaded deeper tissues from the intestine and reach the bloodstream, leading to extraintestinal infections, although direct evidence remains elusive. Raw fish eaten 1 week prior is considered to be the most possible contaminated food. Overall mortality rate of E. tarda bacteremia is very high and the clinician should pay attention on characteristic clinical findings of E. tarda infection on cirrhotic patients. [ABSTRACT FROM AUTHOR]

Japan has the largest aging society, where many elderly people have intractable diseases including ulcerative colitis (UC). Along with the increasing total number of UC patients, the number of elderly UC patients has also been increasing and will continue to do so in the future. Although the clinical features and natural history of UC in the elderly have many similarities with UC in the non-elderly population, age-specific concerns including comorbidities, immunological dysfunction, and polypharmacy make the diagnosis and management of elderly UC challenging compared to UC in non-elderly patients. Based on increasing data related to elderly UC patients from Japan, as well as other countries, we reviewed the epidemiology, clinical course, differential diagnosis, management of comorbidities, surveillance, medical therapy, and surgery of UC in the elderly. [ABSTRACT FROM AUTHOR]

Background and Aim: Studies on the characteristics of elderly‐onset ulcerative colitis (EOUC) and non‐elderly‐onset ulcerative colitis (NEOUC) have reported conflicting findings. The aim of this study was to compare disease characteristics of EOUC and NEOUC by analyzing the database of the Japanese nationwide inflammatory bowel disease (IBD) registry. Methods: We analyzed the age of disease onset, sex, disease severity, and disease extent in patients with ulcerative colitis that were newly diagnosed and registered within 1 year between 2004 and 2009 (n = 28 179). We also analyzed the medical treatment, rate of IBD‐related surgery, and postoperative complications. We compared them between younger than 65 years old (NEOUC group) and 65 years old or older (EOUC group) patients. Results: A total of 25 401 (90.1%) and 2778 (9.9%) patients were included in the NEOUC and EOUC groups, respectively. In the EOUC group, disease activity was significantly higher, and extent of pathological changes in the colon more extended significantly. Laboratory findings showed that inflammatory markers were elevated significantly in the EOUC group. The proportion of those with IBD‐related hospitalization was significantly higher in the EOUC group (54.2% vs 35.7%, P < 0.001). The proportion of patients who were treated with corticosteroids was significantly higher in the EOUC group (36.7% vs 30.8%, P < 0.001). Significantly more number of patients underwent IBD‐related surgery in the EOUC group (0.68% vs 0.27%, P < 0.001). Conclusion: Elderly patients show higher disease activity, with a higher proportion requiring IBD‐related hospitalization and IBD‐related surgery, according to the nationwide registry in Japan. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Sphingosine‐1‐phosphate (S1P) receptor 1, a therapeutic target of the S1P1 agonist FTY720, plays a crucial role in lymphocyte migration and is expressed in several cells including naïve T lymphocytes and endothelial cells. 2‐Acetyl‐4‐tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase, exhibits immunomodulatory activity through increasing the S1P concentration in the secondary lymphoid organs, but its effects on colitis remain unclear. This study aimed to clarify how THI affects colitis and migration of naïve T lymphocytes in Peyer's patches (PPs). Methods: The effect of THI on gut immunity was investigated by analyzing the dextran sulfate sodium (DSS)‐induced murine colitis model, lymphocyte components in thoracic duct lymphocytes (TDLs), and microscopic movement of TDLs in PPs. Results: 2‐Acetyl‐4‐tetrahydroxybutyl imidazole ameliorated DSS‐induced colitis histologically by causing a significant decrease in colonic lymphocyte infiltration and expression of mucosal pro‐inflammatory cytokines. THI suppressed the inflow of naïve T lymphocytes into the thoracic duct. Microscopic observation of PPs in control animals revealed that many TDLs egressed to the stroma and migrated to lymph capillaries after attaching to the high endothelial venules (HEVs). THI or FTY720 treatment in recipient animals blocked lymphocyte egression from the HEVs to the stroma. Conclusions: This is the first study to clarify the ameliorating effects of THI on DSS‐induced colitis. Microscopic observations demonstrated the involvement of HEVs in the egression of S1P‐dependent gut‐tropic T lymphocytes to lymph capillaries. This S1P lyase inhibitor might become a novel immunosuppressant for inflammatory bowel disease therapy by blocking infiltration of lymphocytes through HEVs into the stroma in PPs. [ABSTRACT FROM AUTHOR]

Background and Aim Few drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs ( NSAIDs)-induced enteropathy. Toll-like receptor ( TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan ( LAM) or lipoteichoic acid ( LTA), TLR2 agonists, attenuated indomethacin ( IND)-induced intestinal damage. Methods LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence-labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P-selectin, MAdCAM-1, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide ( LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-α, and interleukin-12p40 were measured. Results Pretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80+ macrophages, the level of P-selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner. Conclusion TLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages. [ABSTRACT FROM AUTHOR]

Background and Aim: Thrombomodulin (TM) is an anticoagulant cofactor protein. We hypothesized that its recombinant soluble TM (rhTM) form, widely used to treat disseminated intravascular coagulation, might have anti-inflammatory action in inflammatory bowel disease (IBD), possibly through its inhibition of high-mobility group box 1 protein (HMGB1). Methods: We investigated inflammatory effects of HMGB1 and anti-inflammatory effect of rhTM in dextran sulfate sodium (DSS)-treated mice, some cell lines and ulcerative colitis (UC) patients, particularly focusing on changes of vascular endothelial adhesion molecules. Results: Treatments with rhTM significantly attenuated DSS-treated mice clinically and histologically. The mRNA levels of proinflammatory cytokines and adhesion molecules were decreased by rhTM. Increased inflammatory cells in the colonic mucosa strongly expressed HMGB1 in the cytoplasm in the DSS-treated mice and UC patients' colonic mucosa, which were significantly decreased by rhTM in mice. In in vitro experiments, rhTM significantly decreased the mRNA levels of tumor necrosis factor-alpha (TNF-α) and adhesion molecules increased by endotoxin exposures in RAW 264.7 (macrophage cell line) and bEND.3 cells (endothelial cell line), suggesting the proinflammatory role of HMGB1 in TNF-α production from macrophages. Conclusions: These findings suggest that rhTM may be useful for the treatment of IBD by attenuating inflammatory cytokine production and adhesion molecule expression, partly because of its inhibition of HMGB1. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Backgrounds and Aims: We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury. Methods: Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. l-Alanine ( l-Ala) and inosine 5′-monophosphate (IMP) were co-administered ig after the treatment. Results: Indomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or l-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and l-Ala + IMP further accelerated intestinal ulcer healing. Conclusion: DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers. [ABSTRACT FROM AUTHOR]

Background. Neutrophil migration, one of the major factors predisposing to nonsteroidal anti-inflammatory drugs (NSAIDs)-induced intestinal lesions, consists of several steps, including interaction with P-selectin from platelets. Cilostazol, a specific phosphodiesterase (PDE)-3 inhibitor, suppresses the expression of P-selectin from platelets and reduces interaction between platelets and leukocytes, leading to inflammatory amelioration in several disease models. We tried to clarify the therapeutic effectiveness of cilostazol for NSAID-induced small intestinal lesions. Subjects and methods. 1) Anti-PSGL-1 antibody (2 mg/kg) or cilostazol (100 mg/kg) was administered to mice one hour before Indomethacin (IND, 2.5 mg/kg) administration for 4 days to evaluate small intestinal lesions. 2) IND-induced migratory behaviors of neutrophils and platelets were evaluated in intestinal vessels by an intravital microscopy. Results. i) IND induced small intestinal lesions with an increase in MPO activity. Anti-PSGL-1 antibody and cilostazol ameliorated intestinal lesions along with suppression of MPO activity. ii) Intravital microscopy revealed that administration of IND increased migration of platelet-bearing neutrophils. Cilostazol treatment ameliorated neutrophil migration by blocking interaction between platelets and neutrophils. Conclusion. Our results suggest that enhanced platelets-bearing neutrophil migration is critically involved in the pathogenesis of IND-induced small intestinal lesions and suggest a potential application of cilostazol for prevention of NSAID-induced small intestinal lesions. [ABSTRACT FROM AUTHOR]

We report a case of epidural abscess caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 in a previously healthy 25-year-old American woman who lived in Japan for more than 1 year. She started to complain of severe headache that continued for about 10 days after improvement of subcutaneous abscesses caused by MRSA. Computed tomography (CT) and magnetic resonance imaging (MRI) showed epidural abscess. As epidural abscess was not improved by treatment with vancomycin and ceftriaxone, craniotomy and drainage were performed, and the severe headache disappeared. Characteristics of the MRSA strain isolated from the abscess were identical to those of strain USA300; multilocus sequence typing sequence type 8, staphylococcal cassette chromosome mec type IVa, Panton-Valentine leukocidin positive, arginine catabolic mobile element positive, and pulsed-field gel electrophoresis type USA300. This may be the first report of epidural abscess caused by USA300 strain in Japan. Because CA-MRSA strains, including USA300, have begun to spread in Japan, epidural abscess should be taken into account in the diagnosis of previously healthy patients with persistent headache accompanied by skin lesions. [ABSTRACT FROM AUTHOR]

Background: Although platelets or monocytes are thought to be involved in intestinal inflammation, there has been no report on whether platelets can modulate monocyte recruitment in intestinal microvessels. The objective of this study was to determine whether blockade of platelet adhesion attenuates monocyte recruitment in inflamed murine intestinal microvessels. Methods: Monocytes and platelet-rich plasma were obtained from C57B6/J mice. Interaction of monocytes and platelets with intestinal microvessels was observed under an intravital microscope. Lipopolysaccharide (LPS) was administered intraperitoneally. The effects of anti-P-selectin or anti-platelets antibody treatments or phosphodiesterase (PDE) inhibitors (PDE-3 and PDE-2/4 inhibitor) treatments were also studied. Results: LPS-treatment increased the rolling and adhesion of both platelets and monocytes. Pretreatment with an anti-P-selectin antibody inhibited the increased platelet adhesion to venular walls and also attenuated the monocyte adhesion. A PDE-2/4 inhibitor (ibuzilast) also ameliorated both platelet and monocyte adhesion. A PDE-3 inhibitor (cilostazol) ameliorated only monocyte adhesion without directly affecting the adhesion of platelets to microvessels. Conclusions: We observed inhibition of platelets adhesion attenuated monocytes recruitment in intestinal microvessels. Attenuation of LPS induced monocyte adhesion by a specific PDE-3 inhibitor suggests that P-selectin on activated platelets may play an important role through monocyte and platelet interaction. [ABSTRACT FROM AUTHOR]

Management of elderly ulcerative colitis in Japan. [ABSTRACT FROM AUTHOR]

Background and Aim Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. Methods A mouse model of NSAID-induced enteropathy was generated by administering indomethacin intraperitoneally to 8-week-old male C57BL/6 mice, and then vehicle or uric acid was administered orally. A group of mice treated with indomethacin was also concurrently administered inosinic acid, a uric acid precursor, and potassium oxonate, an inhibitor of uric acid metabolism, intraperitoneally. For in vitro analysis, Caco-2 cells treated with indomethacin were incubated in the presence or absence of uric acid. Results Oral administration of uric acid ameliorated NSAID-induced enteropathy in mice even though serum uric acid levels did not increase. Intraperitoneal administration of inosinic acid and potassium oxonate significantly elevated serum uric acid levels and ameliorated NSAID-induced enteropathy in mice. Both oral uric acid treatment and intraperitoneal treatment with inosinic acid and potassium oxonate significantly decreased lipid peroxidation in the ileum of mice with NSAID-induced enteropathy. Treatment with uric acid protected Caco-2 cells from indomethacin-induced oxidative stress, lipid peroxidation, and cytotoxicity. Conclusions Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy. [ABSTRACT FROM AUTHOR]

Background and Aim: 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. Methods: 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 CD11c+ CD103+ dendritic cells (DCs) and regulatory T cells (Tregs) in mesenteric lymph nodes of parent mice and their pups was analyzed. Results: Oral administration of heat‐killed probiotics to pregnant dams significantly decreased inflammation induced by dextran sodium sulfate in pups. Probiotic treatment increased the number of CD103+ DCs, and the expression of β8‐integrin in CD103+ DCs and Tregs in mesenteric lymph nodes, not only in dams themselves but also in their offspring. Conclusions: Oral 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. [ABSTRACT FROM AUTHOR]

Background: The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia. Aims: This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan. Methods: In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death. Results: The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae. Conclusion: Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Aim: We recently reported that lipoprotein lipase (LPL)‐mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non‐alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin‐like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. Methods: Angptl4‐deficient or wild‐type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine‐ and choline‐deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4‐deficient HSCs. Results: In the NASH model, Angptl4‐deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4‐deficient mice than in those from wild‐type mice. Treatment with Angptl4 reversed low‐density lipoprotein‐induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency‐induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor‐β (TGF‐ß) pseudoreceptor, bone morphogenetic protein, and activin membrane‐bound inhibitor, and sensitized HSCs to TGF‐β‐induced activation in vivo and in vitro. Conclusions: Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH. [ABSTRACT FROM AUTHOR]

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H 2 O 2 -dependent formation of a PPARγ2 and transportin (Tnpo)1 complex via redox-sensitive disulfide bonds between cysteine (Cys)176 and Cys180 of the former and Cys512 of the latter. Using hepatocyte cultures and mouse models, we show that cytosolic H 2 O 2 /Tnpo1-dependent nuclear translocation enhances the amount of DNA-bound PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases. Image 1 • PPARγ2 forms disulfide bonds with Tnpo1. • Both Cys176 and Cys180 of PPARγ2 form disulfide bonds with Cys512 of Tnpo1. • H 2 O 2 promotes PPARγ2/Tnpo1 nuclear entry. • Redox-dependent PPARγ2/Tnpo1 nuclear entry promotes hepatic triglyceride accumulation. [ABSTRACT FROM AUTHOR]

Aim: Liver fibrosis is a life‐threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation, partly by enhancing signaling through sterol regulatory element‐binding protein 2 (SREBP2) and microRNA‐33a (miR‐33a), which resulted in HSC sensitization to transforming growth factor‐β (TGFβ)‐induced activation in a “vicious cycle” of liver fibrosis. Methods: Human HSCs were isolated from surgical liver specimens from control patients and patients with liver fibrosis. C57BL/6 mice were treated with carbon tetrachloride for 4 weeks and concurrently given SREBP2‐siRNA‐ or anti‐miR‐33a‐bearing vitamin A‐coupled liposomes. Results: In human activated HSCs obtained from patients with liver fibrosis, FC accumulation was enhanced independently of serum cholesterol levels through increased signaling by both SREBP2 and miR‐33a. This increased FC accumulation enhanced Toll‐like receptor 4 (TLR4) protein levels and lowered the TGFβ‐pseudoreceptor Bambi (bone morphogenetic protein and activin membrane‐bound inhibitor) mRNA levels in HSCs. Notably, in a mouse liver fibrosis model, reduction of FC accumulation, specifically in activated HSCs by suppression of SREBP2 or miR‐33a expression using SREBP2‐siRNA‐ or anti‐miR‐33a‐bearing vitamin A‐coupled liposomes, downregulated TLR4 signaling, increased Bambi expression, and consequently ameliorated liver fibrosis. Conclusions: Our results suggest that FC accumulation in HSCs, as an intracellular mediator promoting HSC activation, contributes to a vicious cycle of HSC activation in human and mouse liver fibrosis independent of serum cholesterol levels. Targeting FC accumulation‐related molecules in HSCs through a vitamin A‐coupled liposomal system represents a favorable therapeutic strategy for liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: We isolated two novel probiotics strains (s193 and s292) from Funazushi, which is a traditional Japanese fermented food, and evaluated its effects on DSS-induced colitis to determine the possible underlying mechanisms.Methods: A single colony from homogenized Funazushi was isolated by its ability to suppress TNF-α in RAW 264.7. Effect of probiotics on colonic inflammation induced by DSS was evaluated. Effect of probiotics on Treg induction by CD11c+ dendritic cells (DCs) of MLNs were analyzed.Results: Two novel probiotics strains classified into the genus Lactobacillus were isolated (s193 and s292), and those strains showed stronger anti-inflammatory effects on DSS-induced colitis than those of L. gasseri isolated from the gut. mRNA expression β8 integrin in CD11c+DCs of MLNs and the number of Tregs in the large intestine were significantly increased by s193 and s292 administration compared with L. gasseri administration. Bone marrow DCs treated with s193 and s292 highly increased β8 integrin, and those cells strongly induced differentiation of CD4+ T cells into Tregs. Differentiation of Tregs was remarkably inhibited by anti-β8 integrin antibody treatment.Conclusions: Strains s193 and s292 demonstrate strong anti-inflammatory effects on DSS-induced colitis through induction of β8 integrin expression on DCs. Our results suggested that Japanese traditional fermented foods are valuable sources for probiotics that are effective for IBD therapy and treatment. [ABSTRACT FROM AUTHOR]

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular painkillers, but they have serious side effects, not only in the upper gastrointestinal tract but also in the small intestine. It is well known that psychological stress may exacerbate various gastrointestinal diseases. The aim of this study was to determine whether psychological stress exacerbates NSAID enteropathy and to determine the possible underlying mechanisms for this.Methods: Experiment 1: mice were exposed to water avoidance stress (WAS) or sham stress for 1 h per day for 8 consecutive days, and then enteropathy was induced by indomethacin. Experiment 2: cecal contents from stress (-) or (+) mice were transplanted into mice that had received antibiotics and in which NSAID enteropathy had been induced without WAS. Experiment 3: mifepristone, a glucocorticoid receptor antagonist, was injected before WAS for 8 days. Small intestinal injury, mRNA expression of TNFα, intestinal permeability, and the microbial community were assessed.Results: Psychological stress exacerbated NSAID enteropathy and increased intestinal permeability. Psychological stress induced changes in the ileal microbiota that were characterized by increases in the total number of bacteria and the proportion of Gram-negative bacteria. The increased susceptibility to NSAIDs and intestinal permeability due to WAS was transferable via cecal microbiota transplantation. The increased permeability and aggravation of NSAID enteropathy caused by WAS were blocked by the administration of mifepristone.Conclusions: This study demonstrated a relationship between NSAID enteropathy and psychological stress, and showed the utility of studying the intestinal microbiota in order to elucidate the pathophysiology of NSAID enteropathy. It also showed the impact of stress on the intestinal microbiota and the mucosal barrier in gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Key points Luminal lipid in the duodenum modulates gastroduodenal functions via the release of gut hormones and mediators such as cholecystokinin and 5-HT., The effects of luminal short-chain fatty acids (SCFAs) in the foregut are unknown., Free fatty acid receptors (FFARs) for long-chain fatty acids (LCFAs) and SCFAs are expressed in enteroendocrine cells. SCFA receptors, termed FFA2 and FFA3, are expressed in duodenal enterochromaffin cells and L cells, respectively., Activation of LCFA receptor (FFA1) and presumed FFA3 stimulates duodenal HCO3− secretion via a glucagon-like peptide (GLP)-2 pathway, whereas FFA2 activation induces HCO3− secretion via muscarinic and 5-HT4 receptor activation., The presence of SCFA sensing in the duodenum with GLP-2 and 5-HT signals further supports the hypothesis that luminal SCFA in the foregut may contribute towards the generation of functional symptoms., Abstract Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short-chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO3− secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long-chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon-like peptide (GLP)-1, whereas FFA2 colocalised with 5-HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase-IV (DPPIV) inhibition, at the same time as increasing GLP-2 portal blood concentrations. Acetate-induced DBS was partially inhibited by monocarboxylate/HCO3− exchanger inhibition without affecting GLP-2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose-dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5-HT3 receptor antagonists, but was inhibited by atropine and a 5-HT4 antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP-2 release, enhanced by DPPIV inhibition and inhibited by a GLP-2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP-2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5-HT4 receptor activation. SCFA/HCO3− exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone release and possibly signal neural activation may be implicated in the pathogenesis of functional dyspepsia. [ABSTRACT FROM AUTHOR]

Phlebosclerotic colitis is a rare and recently known disease entity and its etiology is still to be elucidated. Some phlebosclerotic colitis cases are difficult to distinguish from collagenous colitis because of the similarity of pathological findings. In all Japanese case reports of phlebosclerotic colitis in which an association with the use of Chinese herbal medicine is suspected, sansisi (gardenia fruit) was included, suggesting pathogenesis of this disease. We report a case of phlebosclerotic colitis that was difficult to be distinguished from collagenous colitis, and an association with the use of Chinese herbal medicine was suspected as the cause of the disease. [ABSTRACT FROM AUTHOR]

Background: Although the incidence of inflammatory bowel diseases (IBD) in Japan has increased, the prevalence of celiac disease is considered very low with the lowest genetic disposition. IBD is reported as the most common comorbidity because of the high positive rate of serological celiac markers. The aim of this study was to examine the current incidence of celiac disease, especially in IBD patients in Japan, where both wheat consumption and incidence of IBD have increased. Methods: A total of 172 patients with IBD and 190 controls in Japan were screened for serum antibody of tissue transglutaminase and deaminated gliadin peptide. In sero-positive patients, HLA testing and upper gastrointestinal endoscopy with duodenal biopsy was performed. Some of the sero-positive patients started a gluten-restricted or unrestricted diet, and serological change was determined. Results: The positivity of both serum antibodies was significantly higher in IBD and correlated with disease activity. However, no biopsy-defined or HLA-defined true celiac disease was found. A decrease in serum antibody titers was observed with a gluten-restricted diet. Conclusions: Despite the increased incidence of IBD and high positivity for serum celiac antibody in Japanese IBD patients, no true-positive celiac disease was noted, suggesting the presence of gluten intolerance in these populations. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is an intractable colonic disease, and it shows several endoscopic findings. Recently, it was reported that the expression level of mucosal tumor necrosis factor alpha (TNF-α) was useful for predicting patient response to infliximab. However, no data regarding the value of endoscopic findings to predict treatment efficacy or cytokine expression level exist. Objective: We investigated the expression of leukocyte adhesion-related molecules and cytokines in colonic mucosa and compared it to endoscopic findings. Methods: One hundred and fifty-nine patients were enrolled. Tissue samples were obtained by colonic biopsy from patients with UC. Colitis activity was determined by Matts' criteria. The degree of mRNA expression of TNF-α, interferon gamma (IFN-γ), interleukin (IL)-8, IL-17A, and mucosal vascular addressin adhesion molecule-1 (MAdCAM-1) in mucosal samples was determined by real-time quantitative polymerase chain reaction. These expression levels were compared with the degree of Matts' grade and individual endoscopic findings. Results: The expression of TNF-α, IFN-γ, IL-8, IL-17A, and MAdCAM-1 mRNA significantly increased as Matts' endoscopic grade elevated. Actively inflamed mucosa with spontaneous hemorrhage revealed a significantly increased expression level of TNF-α mRNA than that without spontaneous hemorrhage. No other individual endoscopic parameter was significantly correlated with the expression level of TNF-α mRNA. Conclusions: Inflamed mucosa with spontaneous hemorrhage may suggest increased expression of TNF-α mRNA levels in colonic mucosa of UC patients, which could predict a lower response to infliximab treatment and more aggressive induction regime or change to other therapy should be taken into account. [ABSTRACT FROM AUTHOR]

Psychological stress is an environmental factor considered to be a precipitating factor of inflammatory bowel disease. Interleukin (IL)-18 plays a role in stress-induced aggravation in some diseases. The aim of this study was to establish a model of murine colitis exacerbated by psychological stress and to clarify the role of IL-18 in this model. Male C57BI/6 mice and IL-l8-/- mice were used for this study. The mice received dextran sulfate sodium (DSS) for induction of colitis. Some mice were exposed to psychological stress using a communication box. Body weight, colonic length, and histological inflammation were measured for assessment of colitis. Tumor necrosis factor (TNF)-α and IL-I 8 expression in the colon and IL-18 expression in the adrenal gland were analyzed using real-time PCR. The effect of anti-IL- 18 antibody was also investigated. Effects of TNF-α and IL- 18 on cytokine expressions were studied using the colonic epithelial cell line LS 1 74T. Induction of psychological stress in DSS-treated wild-type mice significantly exacerbated colitis with enhanced expression of promflammatory cytokines and IL-18. However, induction of psychological stress in DSS-treated IL-18-/- mice did not aggravate colitis compared with that in the IL-18-/- group given only DSS treatment. Stress-induced aggravation of colitis was ameliorated significantly by anti-IL- 18 antibody treatment. IL- 18 did not enhance TNF-α-induced expression of intercellular adhesion molecule-l or IL-8 in L5174T. We established a model of colitis exacerbated by psychological stress. Psychological stress enhanced IL-18 expression and plays a promflammatory role in stress-induced aggravation of colitis. [ABSTRACT FROM AUTHOR]

Background and Aim: Semiconductive laser irradiation has been used to treat early gastric cancer. However, the long-term follow up results have not been reported. The objective of the present study was to assess retrospectively the clinical usefulness of diode laser irradiation for early gastric cancer. Methods: The subjects of this study were 13 patients (14 lesions) selected from 125 patients with early gastric cancer who were treated by endoscopy during the period from September 1995 to February 2003. The macroscopic tumor type was superficial type, including eight lesions of 0′–IIc and six lesions of 0′–IIa. Histological diagnoses were eight cases (nine lesions) of well-differentiated adenocarcinoma, three cases of moderately differentiated adenocarcinoma and two cases of poorly differentiated adenocarcinoma. After injection with indocyanine green solution (1 mg/mL) into the submucosal layer, a semiconductive diode laser (30–40 W/s) was irradiated by the non-contacting method. Results: The total amount of laser irradiation for 14 lesions was 9568.80 ± 7197.01 J on average. There was no major complication. In the period up to December 2007, six patients survived and seven patients died. However, no-one died of progression of gastric cancer. The mean survival times of all patients, survivors and patients who died were 5 years 2.8 months; 6 years 4.5 months; and 4 years 11.7 months, respectively. Conclusions: Early gastric cancer can be successfully treated by laser therapy with few complications and good prognosis. This method is expected to be most suitable and effective for elderly patients with serious underlying disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES: PD-L1 (also B7-H1) and PD-L2 (also B7-DC) are ligands for programmed death-1 (PD-1), which is a member of the CD28/B7 superfamily of costimulatory molecules and plays an inhibitory role on the periphery. Impaired regulation of this system may cause disruption to self-tolerance leading to autoimmunity; however, the role of these molecules in the liver is unknown. Therefore, we examined the expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases. METHODS: We examined the liver expression of these molecules in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with no previous medical treatment using immunohistochemical staining and real-time PCR, and compared with chronic hepatitis type C (CHC) as a control. RESULTS: Although PD-1, PD-L1, and PD-L2 were expressed in the liver in AIH, PBC, as well as CHC, the expressions were relatively lower in PBC. In AIH, despite more severe inflammation than in CHC, the expression of these molecules was not greater than in CHC, and when compared with the relative expression of PD-L1, PD-L2 was lower in AIH. PD-L1 and PD-L2 expressions were well correlated with the level of IFN-γ; however, relatively decreased induction for PD-L1 and PD-L2 by IFN-γ was observed in AIH or PBC than in CHC. CONCLUSION: Modulation of PD-1/PD-L1 and PD-L2 systems may play a role in the development of autoimmune liver diseases. [ABSTRACT FROM AUTHOR]