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Abstract Texture and color enhancement imaging (TXI) may improve the visibility of gastric tumors and allow their early detection. However, few reports have examined the utility of TXI. Between June 2021 and October 2022, 56 gastric tumors in 51 patients undergoing endoscopic submucosal dissection at Fukuchiyama City Hospital were evaluated preoperatively using conventional white light imaging (WLI), narrow-band imaging (NBI), and TXI modes 1 and 2. The color differences of the tumors and surrounding mucosae were evaluated using the CIE 1976 L*a*b color space, Additionally, the visibility scores were scaled. Of the 56 gastric tumors, 45 were early gastric cancers, and 11 were adenomas. Overall, the color difference in TXI mode 1 was considerably higher compared to WLI (16.36 ± 7.05 vs. 10.84 ± 4.05; p

Abstract Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.

Introduction: Whether white blood cell (WBC) counts are predictors for the effectiveness of thiopurine treatment in ulcerative colitis (UC) has been inconclusive in previous studies with small sample sizes. We investigated the association between WBC counts and future relapses in UC patients in a large-scale multi-center study. Methods: This retrospective cohort study enrolled a total of 723 UC patients in remission from 33 hospitals and followed up for 3 years. Relapse was defined as a need for treatment intensification. The risk of relapse was compared among patients with the baseline WBC counts

Background/Objectives: Circulating bile acid (BA) profiles change with lifestyle and are closely related to intestinal BA metabolisms such as deconjugation and conversion to secondary BAs. The composition of BA in the blood is involved in systemic nutrient metabolism and intestinal health. Herein, we explored the associations of lifestyle and physical fitness with the circulating BA profile of middle-aged men. Methods: Data of 147 male participants (aged 50–64 years; BMI < 26 kg/m2; no medication for diabetes or dyslipidemia) from the Japan Multi-Institutional Collaborative Cohort study were analyzed. Serum concentrations of 15 types of BAs were examined for associations with variables on dietary habits, physical-activity habits, and physical fitness. Results: Green tea intake was positively associated with the deconjugation ratio of total BAs (p = 0.028) and negatively associated with secondary BA levels (free deoxycholic acid [DCA] (p = 0.078), glyco-DCA (p = 0.048), and tauro-DCA (p = 0.037)). In contrast, physical activity was negatively associated with the deconjugation ratio (p = 0.029) and secondary BA levels (free DCA (p = 0.098), and free lithocholic acid (p = 0.009)). Grip strength was also negatively associated with secondary BA levels (tauro-DCA (p = 0.041)) but was not associated with the deconjugation ratio. Energy and fat intake and skeletal muscle mass were not associated with the deconjugation ratio or secondary BA levels. Conclusions: The study findings suggest that lifestyle-associated changes in serum deconjugated and secondary BAs indicate improvements in nutrient metabolism and the intestinal environment.

Abstract Colonic mucus layers protect intestinal tissues against intestinal bacteria. We investigated the effects of dietary fiber and its metabolites on mucus production in the colonic mucosa. Mice were fed a partially hydrolyzed guar gum (PHGG)-containing diet and a fiber-free diet (FFD). The colon mucus layer, fecal short-chain fatty acid (SCFA) levels, and gut microbiota were evaluated. Mucin 2 (MUC2) expression was assessed in SCFA-treated LS174T cells. The role of AKT in MUC2 production was investigated. The mucus layer in the colonic epithelium was significantly increased in the PHGG group compared with that in the FFD group. In the PHGG group, an increase in Bacteroidetes in the stool was observed, and fecal acetate, butyrate, propionate, and succinate levels were significantly increased. However, MUC2 production was significantly increased only in succinate-stimulated LS174T cells. The succinate-induced MUC2 production was associated with AKT phosphorylation. Succinate mediated the PHGG-induced increase in the colon mucus layer.

Summary: Habitual exercise alters the intestinal microbiota composition, which may mediate its systemic benefits. We examined whether transplanting fecal microbiota from trained mice improved skeletal muscle metabolism in high-fat diet (HFD)-fed mice. Fecal samples from sedentary and exercise-trained mice were gavage-fed to germ-free mice. After receiving fecal samples from trained donor mice for 1 week, recipient mice had elevated levels of AMP-activated protein kinase (AMPK) and insulin growth factor-1 in skeletal muscle. In plasma, bile acid (BA) deconjugation was found to be promoted in recipients transplanted with feces from trained donor mice; free-form BAs also induced more AMPK signaling and glucose uptake than tauro-conjugated BAs. The transplantation of exercise-acclimated fecal microbiota improved glucose tolerance after 8 weeks of HFD administration. Intestinal microbiota may mediate exercise-induced metabolic improvements in mice by modifying circulating BAs. Our findings provide insights into the prevention and treatment of metabolic diseases.

Introduction: Although the efficacy of 5-aminosalicylic acid (ASA) suppositories for ulcerative colitis (UC) has been reported in many studies, many studies have also described poor adherence to 5-ASA suppository regimens. We aimed to identify the clinical background factors that influence adherence to 5-ASA suppositories to improve adherence and efficacy of the treatment. Methods: We conducted a retrospective cohort study of 61 patients with active UC who were using 5-ASA suppositories. All patients underwent endoscopy and rectal biopsy for histological diagnosis prior to 5-ASA suppository treatment. The efficacy of 5-ASA suppository treatment was compared in relation to clinical background factors (sex, age, disease duration, disease type, clinical activity, Ulcerative Colitis Endoscopic Index of Severity, histological activity, serum C-reactive protein level, concomitant use of immunomodulators, history of steroid use, and dose of oral 5-ASA). Results: The efficacy of 5-ASA suppositories was significantly related to low Lichtiger Colitis Activity Index (LCAI) scores and proctitis type prior to its use. In terms of sex, females tended to show higher efficacy. Multivariate logistic regression analysis using these three factors showed high predictive value for the efficacy of 5-ASA suppositories (AUC, 0.788; sensitivity, 87.2%; and specificity, 63.7%). Conclusion: This study is the first to extract clinical background factors for predicting the efficacy of 5-ASA suppositories. The use of 5-ASA suppositories in patients who are expected to show efficacy will be effective in improving patient co-operation.

Abstract Background The role of IL-12/23 in the pathogenesis of ulcerative colitis (UC) is unclear. We analyzed mucosal IL-12/23 expression and its relationship with endoscopic severity, histological activity, and UC relapse. Methods Rectal biopsies were collected from 70 UC patients with clinical remission. IL-12, IL-23, IFN-γ, IL-17A, and IL-17F mRNA expression was measured by real-time PCR. Endoscopic severity and histological activity were evaluated using the Mayo endoscopic subscore (MES) and the Geboes score, respectively. Results The longest follow-up period was 51 months. Thirty-four patients relapsed during the study period. Samples from these subsequently relapsed patients formed the “relapse” group, while those from patients that did not relapse formed the “remission” group. IL-12 (P = 0.0003) and IL-23 (P = 0.014) mRNA expression was significantly higher in the relapse than the remission group. Expression of IL-23 (P = 0.015) but not IL-12 (P = 0.374) was correlated with MES. However, in patients with an MES of 0 and 1, IL-12 expression was statistically higher in the relapse than the remission group (P = 0.0015, P = 0.0342). IL-12 and IL-23 expression did not vary significantly between histologically active and inactive mucosa; both were higher in histologically inactive patients in the remission group (IL-12: P = 0.0002, IL-23: P = 0.046). Conclusions Rectal IL-12 and IL-23 expression was elevated in the relapse group, but IL-12 was more strongly associated with UC relapse, irrespective of endoscopic severity and histological activity. Mucosal IL-12 was elevated in patients with deep mucosal healing. Our results suggest an important role of IL-12 in UC pathogenesis and the molecular mechanism of UC relapse.

Abstract Background and Aim Several studies have identified postinduction therapy predictors of long‐term outcomes of ulcerative colitis (UC) in patients who experienced the first attack of the disease or relapsed after therapy. We aimed to identify the preinduction therapy predictors at admission that predicted early colectomy in patients with moderate to severe UC. Methods Ninety‐five patients with moderate to severe UC who underwent induction therapy at the Kyoto Prefectural University of Medicine hospital between August 2008 and March 2020 were retrospectively included and categorized into two groups: the colectomy group (n = 27) and the noncolectomy group (n = 68). The clinical parameters (age, gender, disease extent, and disease activity on admission), induction therapies administered [including 5‐aminosalicylic acid, steroids, immunomodulators, calcineurin inhibitor, and anti‐Tumor Necrosis Factor (TNF)‐α antibodies], and laboratory data (hemoglobin, albumin, C‐reactive protein, and cytomegalovirus reactivation on admission) were evaluated and compared between the two groups. Multivariate logistic regression analyses were performed to identify significant predictors of early colectomy, and P

Abstract Background Species-level genetic characterization of complex bacterial communities has important clinical applications in both diagnosis and treatment. Amplicon sequencing of the 16S ribosomal RNA (rRNA) gene has proven to be a powerful strategy for the taxonomic classification of bacteria. This study aims to improve the method for full-length 16S rRNA gene analysis using the nanopore long-read sequencer MinION™. We compared it to the conventional short-read sequencing method in both a mock bacterial community and human fecal samples. Results We modified our existing protocol for full-length 16S rRNA gene amplicon sequencing by MinION™. A new strategy for library construction with an optimized primer set overcame PCR-associated bias and enabled taxonomic classification across a broad range of bacterial species. We compared the performance of full-length and short-read 16S rRNA gene amplicon sequencing for the characterization of human gut microbiota with a complex bacterial composition. The relative abundance of dominant bacterial genera was highly similar between full-length and short-read sequencing. At the species level, MinION™ long-read sequencing had better resolution for discriminating between members of particular taxa such as Bifidobacterium, allowing an accurate representation of the sample bacterial composition. Conclusions Our present microbiome study, comparing the discriminatory power of full-length and short-read sequencing, clearly illustrated the analytical advantage of sequencing the full-length 16S rRNA gene.

Abstract Aims/Introduction Gut dysbiosis is generally associated with type 2 diabetes mellitus. However, the effect of habitual dietary intake on gut dysbiosis in Japanese patients with type 2 diabetes mellitus has not yet been explicated. This study investigated whether alteration of the gut microbiota was influenced by dietary intake of sucrose in Japanese patients with type 2 diabetes mellitus. Materials and Methods In this cross‐sectional study, 97 patients with type 2 diabetes mellitus and 97 healthy individuals were matched by age and sex, and then, fecal samples were obtained. Next‐generation sequencing of the 16S ribosomal ribonucleic acid gene was carried out, and functional profiles for the gut microbiota were analyzed. We selected the top 30 gut microbial genera and top 20 functional profiles for the gut microbiota specified by the weighted average difference method. The association between gut microbial genera or functional profiles and habitual dietary intake was investigated by Spearman’s rank correlation coefficient, and then, clustering analysis was carried out to clarify the impact of habitual dietary intake. Results The Actinobacteria phylum was highly abundant in patients with type 2 diabetes mellitus, whereas the Bacteroidetes phylum was less abundant. Diabetic‐type gut microbes, specifically Bacteroides and Bifidobacterium, were altered by sucrose intake at the genus level. Furthermore, sucrose intake was associated with glycolysis/gluconeogenesis in the diabetic‐type functional profiles of the gut microbiota. Conclusions The gut microbiota and functional profiles for the gut microbiota in patients with type 2 diabetes mellitus were significantly different from those in healthy individuals. Furthermore, we showed that sucrose intake was closely associated with these differences.

Smoking affects eating habits; however, few studies on smoking and the gut microbiota have reported the effects of diet in detail. This cross-sectional study aimed to determine the association between smoking and the gut microbiota, considering the impact of smoking on dietary intake. Dietary habits and the composition of the gut microbiota were assessed in 195 men with type 2 diabetes (164 non-current smokers and 31 current smokers) using a brief self-administered diet history questionnaire and 16S ribosomal RNA gene sequencing of fecal samples. The data were compared according to the current smoking status of the participants. Current smokers had high alcohol and sugar/sweetener intake and low fruit intake. The proportion of the Coprococcus genus was higher among current smokers. Multiple regression analysis adjusted for current smoking, age, exercise habits, alcohol intake, sugar and sweetener intake, and fruit intake showed that smoking was associated with the proportion of the Coprococcus genus. Current smoking was associated with both dietary intake and composition of the gut microbiota. Although dietary intake should be considered when investigating the association between smoking and the gut microbiota, the results suggest that the direct effect of smoking is more significant.

The microbiota associated with relapse in patients with quiescent ulcerative colitis (qUC) remains unclear. Our objective was to analyze the fecal microbiota of Japanese patients with qUC and identify the relapse-associated microbiota. In this study, 59 patients with qUC and 59 healthy controls (HCs) were enrolled (UMIN 000019486), and their fecal microbiota was compared using 16S rRNA gene amplicon sequencing. We followed their clinical course up to 3.5 years and analyzed the relapse-associated microbiota. Potential functional changes in the fecal microbiota were evaluated using PICRUSt software and the Kyoto Encyclopedia of Genes and Genomes database. There were significant differences in fecal microbiota diversity between HC and qUC subjects, with 13 taxa characterizing each subject. Despite no significant difference in variation of microbiota in a single sample (α diversity) between patients in sustained remission and relapsed patients, the variation in microbial communities between samples (β diversity) was significantly different. Prevotella was more abundant in the sustained remission patients, whereas Faecalibacterium and Bifidobacterium were more abundant in the relapsed patients. We clustered the entire cohort into four clusters, and Kaplan–Meier analysis revealed the subsequent clinical course of each cluster was different. We identified 48 metabolic pathways associated with each cluster using linear discriminant analysis effect size. We confirmed the difference in microbiota between patients with qUC and HCs and identified three genera associated with relapse. We found that the clusters based on these genera had different subsequent clinical courses and activated different metabolic pathways.

Intestinal ischemia-reperfusion (IR) injury is a complex, multifactorial, and pathophysiological condition with high morbidity and mortality, leading to serious difficulties in treatment, especially in humans. Heme oxygenase (HO) is the rate-limiting enzyme involved in heme catabolism. HO-1 (an inducible form) confers cytoprotection by inhibiting inflammation and oxidation. Furthermore, nuclear factor-erythroid 2-related factor 2 (Nrf2) positively regulates HO-1 transcription, whereas BTB and CNC homolog 1 (Bach1) competes with Nrf2 and represses its transcription. We investigated the role and potential mechanism of action of HO-1 in intestinal IR injury. Intestinal ischemia was induced for 45 min followed by 4 h of reperfusion in wild-type, Bach1-deficient, and Nrf2-deficient mice, and a carbon monoxide (CO)-releasing molecule (CORM)-3 was administered. An increase in inflammatory marker levels, nuclear factor-κB (NF-κB) activation, and morphological impairments were observed in the IR-induced intestines of wild-type mice. These inflammatory changes were significantly attenuated in Bach1-deficient mice or those treated with CORM-3, and significantly exacerbated in Nrf2-deficient mice. Treatment with an HO-1 inhibitor reversed this attenuation in IR-induced Bach1-deficient mice. Bach1 deficiency and treatment with CORM-3 resulted in the downregulation of NF-κB activation and suppression of adhesion molecules. Together, Bach1, Nrf2, and CO are valuable therapeutic targets for intestinal IR injury.

Gut microbiota are involved in both host health and disease and can be stratified based on bacteriological composition. However, gut microbiota clustering data are limited for Asians. In this study, fecal microbiota of 1803 Japanese subjects, including 283 healthy individuals, were analyzed by 16S rRNA sequencing and clustered using two models. The association of various diseases with each community type was also assessed. Five and fifteen communities were identified using partitioning around medoids (PAM) and the Dirichlet multinominal mixtures model, respectively. Bacteria exhibiting characteristically high abundance among the PAM-identified types were of the family Ruminococcaceae (Type A) and genera Bacteroides, Blautia, and Faecalibacterium (Type B); Bacteroides, Fusobacterium, and Proteus (Type C); and Bifidobacterium (Type D), and Prevotella (Type E). The most noteworthy community found in the Japanese subjects was the Bifidobacterium-rich community. The odds ratio based on type E, which had the largest population of healthy subjects, revealed that other types (especially types A, C, and D) were highly associated with various diseases, including inflammatory bowel disease, functional gastrointestinal disorder, and lifestyle-related diseases. Gut microbiota community typing reproducibly identified organisms that may represent enterotypes peculiar to Japanese individuals and that are partly different from those of indivuals from Western countries.

Viscous submucosal injection materials (SIMs) that are clinically used in endoscopic treatments for early gastrointestinal cancer and polyps contribute to the treatment effects. However, the relationship between SIM characteristics [such as injection pressure (IP) and submucosal elevation height (SEH)] and viscosity has not been evaluated. The aim of this study was to analyze this relationship and elucidate whether it is possible to predict the SIM characteristics by viscosity measurements. Viscosity, IP, and SEH of conventional and developing SIMs were measured, and the correlation between these values was evaluated. A newly developed measurement model accurately measured IP. The magnitude of IP increased as the endoscopic injection needle gauge, injection speed, and concentration of SIM were increased. The strongest correlations were observed between viscosity at a shear rate of 103 s−1 and IP (correlation coefficient > 0.9, p 0.9, p

This cross-sectional study aimed to clarify the characteristic gut microbiota of Japanese patients with type 2 diabetes (T2DM) using t-distributed stochastic neighbor embedding analysis and the k-means method and to clarify the relationship with background data, including dietary habits. The gut microbiota data of 383 patients with T2DM and 114 individuals without T2DM were classified into red, blue, green, and yellow groups. The proportions of patients with T2DM in the red, blue, green, and yellow groups was 86.8% (112/129), 69.8% (81/116), 76.3% (90/118), and 74.6% (100/134), respectively; the red group had the highest prevalence of T2DM. There were no intergroup differences in sex, age, or body mass index. The red group had higher percentages of the Bifidobacterium and Lactobacillus genera and lower percentages of the Blautia and Phascolarctobacterium genera. Higher proportions of patients with T2DM in the red group used α-glucosidase inhibitors and glinide medications and had a low intake of fermented soybean foods, including miso soup, than those in the other groups. The gut microbiota pattern of the red group may indicate characteristic changes in the gut microbiota associated with T2DM in Japan. These results also suggest that certain diabetes drugs and fermented foods may be involved in this change. Further studies are needed to confirm the relationships among traditional dietary habits, the gut microbiota, and T2DM in Japan.

Gut eubiosis is essential for the host’s health. In athletes, the gut microbiota can be altered by several factors, including diets. While eubiotic gut microbiota in elite rugby players has been reported, our survey found that university rugby players suffered from loose stools and frequent urgency to defecate. To establish the causes of the condition, the microbiota and the concentrations of organic acids in fecal samples of university male rugby players (URP) were analyzed and compared with those of age-matching, non-rugby playing males (control). Body mass indices were significantly (p < 0.05) different between groups. Chao1 index was significant (p < 0.05) lower in URP than in control. The relative abundances of phyla Firmicutes and Bacteroidetes were significantly (p < 0.05) higher and lower, respectively, in URP than in control. Potential pathobiont genera Collinsella, Enterobacter, and Haemophilus were significantly (p < 0.05) abundant, whereas beneficial Akkermansia was lower (p < 0.05) in URP than in control. Succinate, a potential causative of gut inflammation, was five-fold higher in URP than in controls. Our findings all but confirmed that the dysbiotic status of gut in URP.

Objective: To reveal the importance of histidine in intestinal epithelial cells, we investigated whether reduction in histidine concentration affects cell viability and apoptosis in rat intestinal epithelial cells (IEC-6). Methods: Culture cells were incubated in DMEM with or without histidine. Cell viability was measured by the MTT assay. The expression of caspase-3, -8, -9, and -12 was evaluated by western blot analysis. Activated caspase-3 was used as an apoptosis index. To determine the apoptosis pathway, activated caspase-8, -9, and -12 were also examined. Mitochondrial dysfunction was evaluated by the mitochondrial membrane potential assay. Some experiments were also performed on other cells (gastric mucosal cells or kidney cells), to compare with the results of IEC-6 cells. Results: Histidine deficiency significantly reduced cell viability after 6 h and induced caspase-3-dependent apoptosis after 9 h, in IEC-6 cells. Also, histidine deficiency decreased the mitochondrial membrane potential after 6 h. Therefore, we speculated that apoptosis was induced by mitochondrial dysfunction. Additionally, histidine at concentrations higher than 10 μM prevented the decrease in cell viability and the facilitation of apoptosis in IEC-6 cells. In rat gastric mucosal cells, similar results to the IEC-6 histidine deficiency results were obtained, but not in rat kidney cells. Conclusions: This is the first report showing that histidine deficiency reduced cell viability and induced apoptosis in IEC-6 cells, and that a small amount of histidine supplementation prevented and improved the IEC-6 cell injury. This is a potential new clinical treatment against intestinal and/or gastric cell injury that would improve the patient's quality of life.

Two pyroglutamyl peptides with anti-colitic activity were identified in Japanese rice wine, sake, by oral administration of a small dose (0.1–1.0 mg/kg body weight) and in vivo activity-guided fractionation. Compounds in sake were fractionated by preparative isoelectric focusing followed by preparative reversed phase-liquid chromatography. Anti-colitic activity was evaluated using a dextran sulphate sodium (DSS)-induced colitis mouse model. The final active fraction contained three pyroglutamyl peptides: pyroglutamyl-tyrosine (pyroGlu-Tyr), pyroglutamyl-asparaginyl-isoleucine (pyroGlu-Asn-Ile) and pyroglutamyl-asparaginyl-isoleucyl-asparagyl-asparaginyl-proline (pyroGlu-Asn-Ile-Asp-Asn-Pro). Orally administrating artificially synthesized pyroGlu-Tyr (1.0 mg/kg body weight) and pyroGlu-Asn-Ile (0.1 and 1.0 mg/kg body weight) exhibited a significant protective effect against colitis in mice, whereas pyroGlu-Asn-Ile-Asp-Pro showed no significant effect. Additionally, administrating pyroGlu-Asn-Ile normalized colitis-induced colonic dysbiosis, whereas pyroGlu-Tyr did not. These results suggest that identified pyroglutamyl peptides exhibited an anti-colitic activity via different mechanisms.

The human gut microbiota is involved in host health and disease development. Therefore, lifestyle-related diseases such as hypertension (HT), hyperlipidemia (HL), and type 2 diabetes mellitus (T2D) may alter the composition of gut microbiota. Here, we investigated gut microbiota changes related to these diseases and their coexistence. This study involved 239 Japanese subjects, including healthy controls (HC). The fecal microbiota was analyzed through the isolation of bacterial genomic DNA obtained from fecal samples. Although there were no significant differences in the microbial structure between groups, there was a significant difference in the α-diversity between HC and the patients in whom two diseases coexisted. Moreover, Actinobacteria levels were significantly increased, whereas Bacteroidetes levels were significantly decreased in all disease groups. At the genus level, Bifidobacterium levels were significantly increased in the HL and T2D groups, as were those of Collinsella in all disease groups. In contrast, Alistipes levels were significantly lower in the HL group. Furthermore, metabolic enzyme families were significantly increased in all disease groups. Interestingly, the structure and function of the gut microbiota showed similar profiles in all the studied diseases. In conclusion, several changes in the structure of the gut microbiota are associated with T2D, HT, and HL in Japanese subjects.

Metabolic syndrome, whose main diagnostic component is obesity, is a risk factor for lifestyle-related diseases, type 2 diabetes, and cardiovascular disease. Diet is known to affect the prevalence of metabolic syndrome. However, the effect of diet on metabolic syndrome in Japanese subjects has not been thoroughly explored. In the present study, we investigated the effect of carotenoid-rich vegetables, particularly lycopene- and lutein-rich vegetables, on the metabolic syndrome in obese Japanese men. We conducted an 8-week long randomized, double-blinded, controlled clinical trial in which, 28 middle-aged (40 ≤ age < 65) Japanese men with high body mass index (BMI ≥ 25) were randomized into four dietary groups: high lycopene + high lutein (HLyHLu), high lycopene + low lutein (HLyLLu), low lycopene + high lutein (LLyHLu), and low lycopene + low lutein (LLyLLu). Our results showed that daily beverage-intake increased the plasma levels of carotenoids without adverse effects, and the visceral fat level was significantly decreased in all the groups. The waist circumference was significantly decreased only in the HLyLLu group, whereas the CoQ10 oxidation rate was decreased in all the groups. The gene expression profiles of whole blood samples before and after ingestion differed only in the LLyLLu group, indicating the effect of carotenoids on gene expression profile. In conclusion, our results suggest that dietary uptake of carotenoid-rich vegetables increases their concentration in blood and reduces the intra-abdominal visceral fat.

Backgrounds. Magnifying endoscopy with blue laser imaging (ME-BLI) for diagnosis of early gastric cancer (EGC) is as effective as magnifying endoscopy with narrow-band imaging (ME-NBI). However, there are different EGCs in microstructure visualization between ME-BLI and ME-NBI. This study aimed to clarify the pathological features of the EGCs, in which microstructure visualization was different between ME-NBI and ME-BLI. Methods. EGCs were classified into groups A (irregular microsurface pattern (MSP) in ME-BLI and absent MSP in ME-NBI), B (irregular MSP in two modalities), or C (absent MSP in two modalities), according to the vessel plus surface classification. We compared the pathological features of EGCs between the three groups. Results. 17, four, and five lesions could be evaluated in detail in groups A, B and C, respectively. Well-differentiated adenocarcinomas with shallow crypts were more frequent in group A than in group B (58.8 and 0%, resp.). The mean crypt depth of group A was significantly shallower than that of group B (56 ± 20, 265 ± 64 μm, resp., P=0.0002). Conclusions. ME-BLI could better visualize the microstructures of the EGCs with shallow crypts compared with ME-NBI. Therefore, ME-BLI could enable a more accurate diagnosis of EGC with shallow crypts.

BACKGROUND: Transnasal esophagogastroduodenoscopy (EGD) without sedation has been reported to be safe and tolerable. It has recently been used widely in Japan for the detection of upper gastrointestinal disease. Alternatively, transoral examination using a thin endoscope has also been reported to be highly tolerable.

Partially hydrolyzed guar gum (PHGG) is a water-soluble dietary fiber and is used in solid and liquid food to regulate gut function. The aim of this study was to investigate effects of PHGG on bowel movements (stool form and frequency), plasma bile acids, quality of life, and gut microbiota of healthy volunteers with a tendency toward diarrhea, i.e., irritable bowel syndrome diarrhea (IBS-D)-like symptoms. A randomized, double-blind, placebo-controlled, and parallel trial was performed on 44 healthy volunteers (22 males, 22 females, 41.9 ± 6.3 years old (average ± SD)) with minimum 7 bowel movements every week, wherein above 50% of their stool was between the Bristol stool scale (BSS) value of 5 and 6. Intake of the PHGG for 3 months significantly improved stool form, evaluated using BSS, and had no effects on stool frequency. BSS was significantly normalized in the group consuming the PHGG compared with the placebo. Comprehensive fecal microbiome analysis by the 16S rRNA-sequence method detected significant changes in the ratio of some bacteria, such as an increase of Bifidobacterium (p < 0.05) in the PHGG group. Our results suggest that intake of PHGG improves human stool form via regulating intestinal microbiota.

Background/Aims: Although the cytotoxicity of aspirin against the intestinal epithelium is a major clinical problem, little is known about its pathogenesis. We assessed the involvement of Multi Drug Resistance (MDR) 1 in intestinal epithelial cell injury caused by aspirin using MDR1 gene-transfected Caco2 cells. Methods: Caco2 cells were treated with various concentrations of aspirin for 24 h. After treatment of Caco2 cells with verapamil, a specific inhibitor of MDR1, we assessed the extent of cell injury using a WST-8 assay at 24 h after aspirin-stimulation. We performed the same procedure in MDR1 gene-transfected Caco2 cells. To determine the function of MDR1 in the metabolism of aspirin, flux study was performed using 14C-labeled aspirin. Results: The level of aspirin-induced cell injury was higher in verapamil-treated Caco2 cells than in control cells and was less serious in MDR1-transfected Caco2 cells than in control vector-transfected cells. The efflux of 14C-labeled aspirin was higher in verapamil-treated Caco2 cells than in control cells. Conclusion: These data suggest that aspirin effux occurs through the MDR1 transporter and that the MDR1 transporter is involved in the pathogenesis of aspirin-induced cell injury.

Background and study aims: Linked color imaging (LCI) is a new image-enhanced endoscopy technique using a laser light source to enhance slight differences in mucosal color. The aim of this study was to compare the usefulness of LCI and conventional white light imaging (WLI) endoscopy for diagnosing Helicobacter pylori (H. pylori). Patients and methods: We retrospectively analyzed images from 60 patients examined with WLI and LCI endoscopy between October 2013 and May 2014. Thirty patients had H. pylori infections, and other thirty patients tested negative for H. pylori after eradication therapy. Four endoscopists evaluated the 2 types of images to determine which was better at facilitating a diagnosis of H. pylori infection. Results: H. pylori infection was identified with LCI by enhancing the red appearance of the fundic gland mucosa. The accuracy, sensitivity, and specificity for diagnosing H. pylori infection using WLI were 74.2 %, 81.7 %, and 66.7 %, respectively, while those for LCI were 85.8 %, 93.3 %, and 78.3 %, respectively. Thus, the accuracy and sensitivity for LCI were significantly higher than those for WLI (P = 0.002 and P = 0.011, respectively). The kappa values for the inter- and intraobserver variability among the 4 endoscopists were higher for LCI than for WLI. Conclusions: H. pylori infection can be identified by enhancing endoscopic images of the diffuse redness of the fundic gland using LCI. LCI is a novel image-enhanced endoscopy and is more useful for diagnosing H. pylori infection than is WLI.

Background/Aims. The aim of this study was to evaluate the endoscopic recognition of esophageal squamous cell carcinoma (ESCC) using four different methods (Olympus white light imaging (O-WLI), Fujifilm white light imaging (F-WLI), narrow band imaging (NBI), and blue laser imaging- (BLI-) bright). Methods. We retrospectively analyzed 25 superficial ESCCs that had been examined using the four different methods. Subjective evaluation was provided by three endoscopists as a ranking score (RS) of each image based on the ease of detection of the cancerous area. For the objective evaluation we calculated the color difference scores (CDS) between the cancerous and noncancerous areas with each of the four methods. Results. There was no difference between the mean RS of O-WLI and F-WLI. The mean RS of NBI was significantly higher than that of O-WLI and that of BLI-bright was significantly higher than that of F-WLI. Moreover, the mean RS of BLI-bright was significantly higher than that of NBI. Furthermore, in the objective evaluation, the mean CDS of BLI-bright was significantly higher than that of O-WLI, F-WLI, and NBI. Conclusion. The recognition of superficial ESCC using BLI-bright was more efficacious than the other methods tested both subjectively and objectively.

A 50-year-old female became aware of skin yellowing and consulted another hospital where she was diagnosed intraoperatively with duodenal cancer because of lymph node metastases around the aorta. Endoscopy revealed type IIa + IIc cancer distal to the duodenal papilla, and biopsy allowed a diagnosis of well-differentiated adenocarcinoma. Computed tomography revealed a large number of lymph node metastases around the aorta and in the left supraclavicular cavity. The patient was given many regimens of chemotherapy, mainly containing S-1, and multidisciplinary treatment, and achieved long-term survival for 6 years and 1 month. This is a valuable case suggesting the usefulness of this therapeutic approach. In view of the fact that duodenal cancer is a relatively rare disease and the possibility that the incidence of this disease may increase in the future, it seems essential to collect additional data from multicenter prospective studies towards the goal of establishing a standard method of treatment for this disease.

Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and antiinflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects. Keywords:: aspirin, gastric mucosal injury, tight junction, zonula occludens (ZO)-1, rebamipide

Red wine polyphenolic compounds have been demonstrated to possess antioxidant properties, and several studies have suggested that they might constitute a relevant dietary factor in the protection from coronary heart disease. The aim of the present study is to examine whether red wine extracts (RWE) can ameliorate oxysterol-induced endothelial response, and whether inhibition of adhesion molecule expression is involved in monocyte adhesion to endothelial cells. Surface expression and mRNA levels of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) were determined by ELISA and RT-PCR performed on human aortic endothelial cells (HAEC) monolayers stimulated with 7b-hydroxycholesterol or 25-hydroxycholesterol. Incubation of HAEC with oxysterols (10 muM) increased expression of adhesion molecules in a time-dependent manner. Pretreatment of HAEC with RWE at final concentrations of 1, 10, and 100 ng/ml significantly inhibited the increase of surface protein expression and mRNA levels. Adherence of monocytes to oxysterol-stimulated HAEC was increased compared to that of unstimulated cells. Treatment of HAEC with RWE significantly inhibited adherence of monocytes. These results suggest that RWE works as an anti-atherogenic agent through the inhibition of endothelial-dependent adhesive interactions with monocytes induced by oxysterols

Helicobacter pylori-infected gastrointestinal mucosa is frequently infiltrated by polymorphonuclear leukocytes (PMN) and monocytes, and these invading cells have been implicated in gastrointestinal mucosal inflammation. To clarify the efficacy of polaprezinc, a chelate compound consisting of zinc and L-carnosine, against H pylori-induced inflammation including PMN infiltration, the in vitro effects of this drug on interleukin (IL)-8 production by an established gastric cancer cell line (MKN 45 cells) and on PMN-endothelial cell adhesive interactions was investigated. Polaprezinc and zinc sulphate inhibited IL-8 production by MKN 45 cells in response to stimulation with H pylori water extract (HPE) in a dose-dependent manner from 10-7 M to 10-5 M. In addition, the expression of CD11b and CD18 on PMN and PMN-dependent adhesion to endothelial cells elicited by HPE was inhibited by polaprezinc and zinc sulphate in a concentration-dependent manner. L-carnosine did not have any effects on IL-8 production or PMN-endothelial cell interactions. These results suggest that polaprezinc, mainly the zinc component, may inhibit H pylori-induced PMN-mediated gastric inflammation by attenuating CD11b/CD18 expression on PMN and IL-8 production from gastric epithelial cells.

Background and aimsAzathioprine (AZA) is widely used for the treatment of inflammatory bowel disease (IBD) patients. AZA is catabolized by thiopurine S-methyltransferase (TPMT), which exhibits genetic polymorphisms. It has also been reported that 5-aminosalicylic acid (5-ASA) inhibits TPMT activity, and that increased 6-thioguanine nucleotide (6-TGN, a metabolite of AZA) blood concentrations result in an increased number of ADRs. In this study, single nucleotide polymorphisms (SNPs) related to differential gene expression affecting AZA drug metabolism in combination therapy with 5-ASA were examined.MethodsTo identify genetic biomarkers for the prediction of 6-TGN blood concentration, ExpressGenotyping analysis was used. ExpressGenotyping analysis is able to detect critical pharmacogenetic SNPs by analyzing drug-induced expression allelic imbalance (EAI) of premature RNA in HapMap lymphocytes. We collected blood samples on 38 patients with inflammatory bowel disease treated with AZA and corroboration of the obtained SNPs was attempted in clinical samples.ResultsA large number of SNPs with AZA/5-ASA-induced EAI within the investigated HapMap lymphocytes was identified by ExpressGenotyping analysis. The respective SNPs were analyzed in IBD patients' blood samples. Among these SNPs, several that have not yet been described to be induced by AZA/5-ASA were found. SNPs within SLC38A9 showed a particular correlation with patients' 6-TGN blood concentrations.ConclusionsBased on these results, ExpressGenotyping analysis and genotyping of patients appears to be a useful way to identify inter-individual differences in drug responses and ADRs to AZA/5-ASA. This study provides helpful information on genetic biomarkers for optimized AZA/5-ASA treatment of IBD patients.

BACKGROUND: Previous studies have demonstrated that less-differentiated T cells are ideal for adoptive T cell transfer therapy (ACT) and that fibronectin CH296 (FN-CH296) together with anti-CD3 resulted in cultured cells that contain higher amounts of less-differentiated T cells. In this phase I clinical trial, we build on these prior results by assessing the safety and efficacy of FN-CH296 stimulated T cell therapy in patients with advanced cancer. METHODS: Patients underwent fibronectin CH296-stimulated T cell therapy up to six times every two weeks and the safety and antitumor activity of the ACT were assessed. In order to determine immune function, whole blood cytokine levels and the number of peripheral regulatory T cells were analyzed prior to ACT and during the follow up. RESULTS: Transferred cells contained numerous less-differentiated T cells greatly represented by CD27+CD45RA+ or CD28+CD45RA+ cell, which accounted for approximately 65% and 70% of the total, respectively. No ACT related severe or unexpected toxicities were observed. The response rate among patients was 22.2% and the disease control rate was 66.7%. CONCLUSIONS: The results obtained in this phase I trial, indicate that FN-CH296 stimulated T cell therapy was very well tolerated with a level of efficacy that is quite promising. We also surmise that expanding T cell using CH296 is a method that can be applied to other T- cell-based therapies. TRIAL REGISTRATION: UMIN UMIN000001835.

Purpose. The aim of this study was to examine the characteristics of difficult cases and the learning curve in colorectal endoscopic submucosal dissection (ESD). Methods. We studied 518 colorectal tumors treated by ESD. Patients were divided into 2 groups such as the difficult ESD group and non-difficult ESD group in view of procedure time and procedure speed, respectively. The clinical features in each group were analyzed, and we also examined cases with severe fibrosis. Furthermore, we divided all cases into 5 periods according to experience of ESDs and investigated the rates of difficult and perforation cases. Results. In view of both procedure time and procedure speed, there were significant differences about mean tumor size, rates of severe fibrosis and perforation, and en bloc resection rate between the two groups. Severe fibrosis was detected in protruding tumors >40 mm in diameter. With respect to the learning curve, the rate of difficult and perforation cases decreased significantly in the late periods compared to the first period. Conclusions. Large tumor size, high rates of severe fibrosis and perforation, and low rate of en bloc resection are related with difficult ESD cases. The increasing of experiences can decrease the rate of difficult cases and perforation.

Aim. Chronic gastritis was assessed serologically, endoscopically and histologically to identify correlations between these methods. Methods. Subjects comprised 319 patients who had provided informed consent. Serological assessment of chronic gastritis was based on the pepsinogen test method. Endoscopic gastritis and histological gastritis were assessed and scored according to the Kimura-Takemoto classification system and the updated Sydney classification system respectively, and correlations between these three methods were studied. Results. Pepsinogen I/II ratio showed a significant correlation to the extent of mononuclear cell infiltration of the gastric corpus. When histological gastritis was divided, on the basis of the distribution of mononuclear cell infiltration, into gastritis limited to the antrum and corpus gastritis, these types were distinguished with high accuracy using a pepsinogen I/II ratio of 3 as the cutoff. A good correlation was also seen between pepsinogen I/II ratio and development of atrophy in endoscopic gastritis, where groups with and without advanced atrophy were also distinguished with high accuracy using a cutoff value of 3. Conclusion. Significant correlations exist between serum pepsinogen levels, endoscopic gastritis, and histological gastritis. Pepsinogen I/II ratio allows prediction of the existence of endoscopic gastritis and histological gastritis, or the extent of their development, with high accuracy.

A 68-year-old man with hemophilia A and liver cirrhosis caused by hepatitis C virus was referred to our hospital to receive prophylactic endoscopic treatment for gastroesophageal varices (GOV). He had large, tense, and winding esophageal varices (EV) with cherry red spots extending down to lesser curve, predicting the likelihood of bleeding. Esophageal endoscopic injection sclerotherapy (EIS) was performed with a total 15 mL of 5% ethanolamine oleate with iopamidol (EOI). Radiographic imaging during EIS demonstrated that 5% EOI reached the afferent vein of the varices. He was administered sufficient factor VIII concentrate before and after EIS to prevent massive bleeding from the varices. Seven days after EIS, upper gastrointestinal endoscopy (UGIE) showed that the varices were eradicated almost completely. Eighteen months after EIS, the varices continued to diminish. We report a successful case of safe and effective EIS for GOV in a high-risk cirrhotic patient with hemophilia A.

Peroxisome proliferator-activated receptor 𝛾 (PPAR𝛾) is a nuclear receptor that is known to play a central role in lipid metabolism and insulin sensitivity as well as inflammation and cell proliferation. According to the results obtained from studies on several animal models of gastrointestinal inflammation, PPAR𝛾 has been implicated in the regulation of the immune response, particularly inflammation control, and has gained importance as a potential therapeutic target in the management of gastrointestinal inflammation. In the present paper, we present the current knowledge on the role of PPAR𝛾 ligands in the gastrointestinal tract.