Search

Wilson disease is an inherited copper metabolism disorder. We herein report a novel endoscopic finding in three men with Wilson disease. These patients underwent upper endoscopy due to gastrointestinal symptoms or during follow-up. In each case, endoscopy revealed lustrous white erosions surrounded by an erythematous mucosa in the greater curvature of the gastric body. A biopsy of the lesions showed orcein-positive tissue, indicating copper deposition, in the interstitial stroma and fundic glands of the mucosa. All patients had been receiving treatment with zinc acetate. These endoscopic findings might have been related to the cytotoxicity of the accumulated copper and zinc acetate.

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1–S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients.Significance: FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. Cancer Res; 78(7); 1643–56. ©2018 AACR.

Supplementary Table S1. Clinical characteristics of healthy subjects and colorectal cancer patients; Supplementary Table S2. Bacterial marker candidates identified by metagenome sequencing; Supplementary Table S3. Primers and probes used in this study; Supplementary Table S4. Abundances of m1704941 (gene maker level, 99.13% identity) and F. nucleatum (species level) in fecal samples of CRC patients by metagenome sequencing; Supplementary Table S5. Abundances of bacterial candidates in fecal samples of CRC patients and healthy control subjects; Supplementary Table S6. Bivariate correlation analysis showing the correlation between bacterial candidates and CRC patients; Supplementary Table S7. The occurrence rates of bacterial candidates in fecal samples of CRC patients and healthy control subjects; Supplementary Table S8. Pairwise comparison of ROC curves; Supplementary Table S9. Correlations of bacterial abundance, FIT with CRC diagnosis and staging; Supplementary Table S11. Combining bacterial markers and FIT in diagnosing CRC.

Purpose: Gut microbiota have been implicated in the development of colorectal cancer. We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for colorectal cancer diagnosis.Experimental Design: Subjects (total 439; 203 colorectal cancer and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for the quantification of bacterial marker candidates.Results: Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal samples of 203 colorectal cancer patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r = 0.801–0.934, all P < 0.0001). Fn was significantly more abundant in colorectal cancer than controls (P < 0.0001), with AUROC of 0.868 (P < 0.0001). At the best cut-off value maximizing sum of sensitivity and specificity, Fn discriminated colorectal cancer from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn + Ch + m7-Bc) showed an improved diagnostic ability compared with Fn alone (AUROC = 0.886, P < 0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical testing for the detection of colorectal cancer.Conclusions: Stool-based colorectal cancer–associated bacteria can serve as novel noninvasive diagnostic biomarkers for colorectal cancer. Clin Cancer Res; 23(8); 2061–70. ©2016 AACR.

Supplementary Figure S1. Good consistency in quantification of nusG/F. nucleatum (Fn) was achieved by two experimenters using our convenient platform. Two samples with outlier highlevels of Fn were further excluded so as to show more clearly the good consistency even in samples with relatively low levels of Fn. Abundances of Fn were shown in arbitrary unit; Supplementary Figure S2. Contaminant human DNA had little effect on the new qPCR platform. (A) A representative example of qPCR evaluation of the internal control on a mixture of 10 randomly selected fecal samples added with different concentrations of human DNA. (B) A representative example of duplex qPCR evaluation of the internal control and F. nucleatum on a randomly selected fecal sample added with different concentrations of human DNA; Supplementary Figure S3. Metagenome sequencing data showed that combination with other markers improved the diagnostic ability of Fusobacterium nucleatum (Fn) for colorectal cancer. ROC curves for Fn alone and simple linear combination of all the five selected bacterial marker candidates including Fn, Bacteroides clarus (Bc), Clostridium hathewayi (Ch), one undefined species (labeled as m7), and Roseburia intestinalis (Ri). The best cutoff values that maximize sensitivity and specificity were determined for Fn and 5-markers individually in the metagenome sequencing cohort with 74 CRC patients and 54 controls. AUROC, area under the receiver operating characteristic curve; PPV, positive predictive value; NPV, negative predictive value.

Low-volume polyethylene glycol plus ascorbic acid (PEG-Asc) reduces the dosage of colonoscopic bowel preparation (BP) solution, but is still poorly tolerated. Adding laxatives to the BP solution reduces the volume of fluid required, without affecting quality. This study aimed to compare 1-L PEG-Asc plus 24 mg senna (1L-PEG/AS) and conventional 2-L PEG-Asc (2L-PEG/A) regimens on BP quality and patient tolerability.A single-center, randomized, investigator-blinded, non-inferiority trial was performed between June and August 2022. Outpatients scheduled for colonoscopy were randomized (1:1) to the 1L-PEG/AS or 2L-PEG/A group. The Boston Bowel Preparation Scale (BBPS) was used to evaluate BP quality. Adverse events and tolerability were surveyed using questionnaires.Overall, 344 patients received 1L-PEG/AS or 2L-PEG/A regimens. The baseline characteristics and adverse events of the two groups were comparable. The 1L-PEG/AS group showed non-inferior adequate BP rates compared with the 2L-PEG/A group (88% vs. 89%, P=1.00); overall BBPS was 7.1±1.5 and 7.2±1.5, respectively (P=0.39). Higher willingness to repeat the BP was observed in the 1L-PEG/AS group (85% vs. 62%, P0.01).The 1L-PEG/AS regimen was comparable to the 2L-PEG/A regimen in terms of BP adequacy, requiring lesser BP solution volumes, with better patient tolerance. Thus, it may be a suitable alternative to the conventional BP solution for colonoscopy.

Background and Aim Although chronic diarrhea is a major digestive disorder, it has not been well studied. The aims of this study were to investigate the prevalence and risk factors of chronic diarrhea in the Japanese population and to assess the relationship between stool type and frequency and symptoms related to chronic diarrhea. Method A total of 13 668 adults who underwent a medical checkup at MedCity21 were enrolled, and 9540 who met the inclusion criteria participated in the study. Participants with chronic diarrhea were defined as those who typically had a Bristol Stool Form Scale of type 6 or 7. Results The prevalence of chronic diarrhea was 3.0%. The risk factors for chronic diarrhea were younger age (odds ratio [OR] 0.984, 95% confidence interval [CI] 0.972–0.996), male sex (OR = 2.270, CI = 1.730–2.960), alcohol intake on ≥5 days per week (OR = 2.390, CI = 1.860–3.060), not getting adequate sleep (OR = 0.712, CI = 0.559–0.907), skipping breakfast ≥3 times a week (OR = 1.490, CI = 1.120–1.980), and absence of diabetes mellitus (OR = 0.384, CI = 0.179–0.824). Only 23.5% of the participants in the diarrhea group had ≥3 bowel movements per day. Chronic diarrhea was significantly associated with heartburn, nausea, stomach ache, abdominal bloating and distension, and feeling of stress. Conclusions Our study shows that chronic diarrhea is common in Japan with a prevalence of 3.0%; unique risk factors related to gender, age, and irregular lifestyle were identified. An understanding of bowel habit in the healthy population is helpful for the assessment of change in bowel habit associated with gastrointestinal disorders., The prevalence of chronic diarrhea among the participants of a Japanese medical checkup was 3.0%. Our study revealed that male sex, drinking alcohol for more than 5 days per week, not getting adequate sleep, skipping breakfast more than three times a week, and absence of diabetes mellitus were risk factors for chronic diarrhea.

Introduction: The COVID-19 outbreak abruptly restricted gastrointestinal (GI) endoscopy services during the first wave of the pandemic. We aimed to assess the impact of COVID-19 on the practice of GI endoscopy in Asian countries. Methods: This was an International Questionnaire-based Internet Survey conducted at multiple facilities by the International Gastrointestinal Consensus Symposium. A total of 166 respondents in Japan, China, Hong Kong, South Korea, Philippines, Thailand, Indonesia, and Singapore participated in this study. Results: The volume of endoscopic screening or follow-up endoscopies and therapeutic endoscopies were markedly reduced during the first wave of the pandemic, which was mainly attributed to the decreased number of outpatients, cancellations by patients, and adherence to the guidelines of academic societies. The most common indications for GI endoscopy during the first wave were GI bleeding, cholangitis or obstructive jaundice, and a highly suspicious case of neoplasia. The most common GI symptoms of COVID-19 patients during the infected period included diarrhea, nausea, and vomiting. The pandemic exacerbated some GI diseases, such as functional dyspepsia and irritable bowel syndrome. There were cases with delayed diagnosis of cancers due to postponed endoscopic procedures, and the prescription of proton pump inhibitors/potassium-competitive acid blockers, steroids, immunosuppressive agents, and biologics was delayed or canceled. The personal protective equipment used during endoscopic procedures for high-risk patients were disposable gloves, disposable gowns, N95 or equivalent masks, and face shields. However, the devices on the patient side during endoscopic procedures included modified surgical masks, mouthpieces with filters, and disposable vinyl boxes or aerosol boxes covering the head. Furthermore, the time for education, basic research, clinical research, and daily clinical practice decreased during the first wave. Conclusion: This study demonstrated that the COVID-19 pandemic profoundly affected the method of performing GI endoscopy and medical treatment for patients with GI diseases in Asian countries.

A total of 306 patients with eosinophilic esophagitis (EoE) were analyzed at our department. Proton pump inhibitors or potassium-competitive acid blockers were used as the first-line treatment in 286 (93.5%) patients. Fifty-five (18.0%) patients received topical steroid swallowing therapy. During 17.7-month mean follow-up, 46.4% of the patients were followed-up with no medications, 37.3% of the patients received maintenance or on-demand therapy using acid-suppressive drugs, and 9.8% of the patients received maintenance therapy with steroid swallowing. The majority of patients with EoE were treated using a therapeutic strategy similar to that used for gastroesophageal reflux disease. However, some patients were refractory to the treatment. Current real-world treatment strategies for Japanese patients with EoE are clarified.

Objectives: A 50–100 mg rectal dose of diclofenac or indomethacin is recommended for prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP); however, limited data are available regarding the appropriate dose to prevent PEP in elderly patients. We aimed to evaluate the efficacy and safety of 25 mg diclofenac in preventing PEP in elderly patients. ......

Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities. Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities. Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%–50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs. Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff.

Background Gastric microbiome, other than Helicobacter pylori, plays a role in the tumorigenesis of gastric cancer (GC). Patients who undergo endoscopic submucosal dissection for early GC have a high risk of developing metachronous GC even after successful eradication of H. pylori. Thus, we investigated the microbial profiles and associated changes in such patients after the eradication of H. pylori. Methods A total of 19 H. pylori-infected patients with early GC who were or to be treated by endoscopic resection, with paired biopsy samples at pre- and post-eradication therapy, were retrospectively enrolled. Ten H. pylori-negative patients were enrolled as controls. Biopsy samples were analyzed using 16S rRNA sequencing. Results H. pylori-positive patients exhibited low richness and evenness of bacteria with the deletion of several genera, including Blautia, Ralstonia, Faecalibacterium, Methylobacterium, and Megamonas. H. pylori eradication partially restored microbial diversity, as assessed during a median follow-up at 13 months after eradication therapy. However, post-eradication patients had less diversity than that in the controls and possessed a lower abundance of the five genera mentioned above. The eradication of H. pylori also altered the bacterial composition, but not to the same extent as that in controls. The microbial communities could be clustered into three separate groups: H. pylori-negative, pre-eradication, and post-eradication. Conclusion Changes in dysbiosis may persist long after the eradication of H. pylori in patients with a history of GC. Dysbiosis may be involved in the development of both primary and metachronous GC after the eradication of H. pylori in such patients.

Background: We previously reported that nonsteroidal anti-inflammatory drugs (NSAIDs) induced small intestinal damage through nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-dependent interleukin-1β secretion in mice. Our further study demonstrated that colchicine, a therapeutic agent for gout, significantly suppressed NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation in mice. However, clinical efficacy of colchicine for NSAID-induced small intestinal damage has not been established. Objectives: We examined the clinical efficacy of colchicine in patients with NSAID-induced severe small intestinal damage as an animal-to-human translational research. Methods: This is a single-center, single-arm, prospective pilot study. From February 2017 to March 2019, we performed video capsule endoscopy (VCE) to screen 10 patients who took NSAIDs continuously for more than 3 months, and 7 of those with severe small intestinal damage were enrolled. Participants were treated with oral colchicine 0.5 mg twice daily for 8 weeks and thereafter followed up with blood tests and VCE. Results: After 8 weeks of colchicine treatment, complete healing was achieved in 4 patients (57.1%), and the median number of small erosions decreased significantly from 7.0 (range, 5.0–10.5) to 0.0 (range, 0.0–2.3) (p = 0.031). One patient withdrew due to diarrhea, and 5 patients revealed slightly elevated liver enzymes during the study. No other adverse events including changes in blood tests and clinical symptoms were observed. Conclusions: Colchicine treatment achieved a high rate of complete healing in patients with NSAID-induced severe small intestinal damage.

Esophageal injury often results in a scar, leading to refractory strictures. The NLRP3 inflammasome activates caspase-1, causing the maturation of interleukin (IL)-1β. Here, we aimed to investigate the preventive effect of pirfenidone (PFD), an antifibrotic drug, on esophageal stricture after ulcer healing and studied its mechanism by focusing on the activation of the NLRP3 inflammasome.Esophageal ulcers were induced in rats via the local application of acetic acid in the serosa. PFD was intraperitoneally administered to the rats 3 days after ulcer induction. The effect of PFD on esophageal stricture after ulcer healing was assessed by esophagography on day 9. The protein levels of mature caspase-1 and IL-1β were assessed by western blotting.The ulcers fully developed 3 days after induction and were almost scarred by day 9 with severe strictures. PFD promoted ulcer healing and attenuated fibrotic collagen in the submucosa by suppressing the increase in NLRP3, cleaved caspase-1, and mature IL-1β expression, improving stricture rate (PFD vs vehicle = 55% vs 81%). Exogenous IL-1β abolished the therapeutic effects of PFD on ulcer healing and stricture formation. Furthermore, NLRP3 and caspase-1 inhibitors mimicked the effects of PFD on ulcer healing and stricture formation, with suppression of the increase in cleaved caspase-1 and mature IL-1β proteins and expression of fibrosis-related molecules including transforming growth factor (TGF)-β1.The NLRP3 inflammasome promotes esophageal stricture formation following ulcer healing, and PFD exerts potential prophylactic activity against strictures, possibly via the inhibition of the NLRP3/IL-1β/TGF-β1 axis.

研究グループは、経鼻内視鏡検査中の患者からの飛沫拡散が、患者にサージカルマスクを装着させるという簡単な方法で抑制されることを本研究で明らかにしました。内視鏡検査は、内視鏡術者への新型コロナウイルス感染のリスクが高い処置です。経鼻内視鏡検査でも経口内視鏡検査と同様にマスクを用いる簡便な方法で飛沫の拡散を抑制でき、術者の感染が予防できることが明らかになりました。本研究では、まず、マネキンと噴霧器を用いた模擬実験を行い、マスク未装着時には経鼻内視鏡中に口から約1.5m拡散する飛沫が、マスクを用いた防御法により完全に抑制されることが確認され、マスクが飛沫拡散防止に有用であることを実証しました。続いて実際に、大阪市立大学医学部附属病院先端予防医療部附属クリニックMedCity21で732名の患者に対して本方法を用いて経鼻内視鏡検査を施行したところ、全例で明らかな有害事象は認められず、安全面でも問題ないことを確認しました。本研究成果を用いることによって新型コロナウイルス感染症終息の見通しがつかない中でも必要な内視鏡検査をより安全に実施できるようになることが期待されます。, The Coronavirus-19 (COVID-19) pandemic continues to accelerate worldwide. Since endoscopy may pose a risk for transmission, there is a medical need to establish a "new normal" for endoscopic procedures that reduce the risk. Although we previously reported a technique to prevent infection during endoscopy, it did not completely block leakage of aerosol droplets through the hole in a modified mask....

The incidence of rebleeding in obscure GI bleeding (OGIB) remains unclear. This study used capsule endoscopy (CE) to determine the long-term rebleeding rate and predictive factors for rebleeding in patients with OGIB.This single-center, observational study enrolled consecutive patients with OGIB who underwent CE as the first small intestinal examination between March 2004 and December 2015 and were followed up through medical records or letters.Three hundred eighty-nine patients were included in the analysis. Survival curve analysis showed that the overall cumulative rebleeding rate in OGIB during the 5 years was 41.7%. Multivariate analysis using the Cox proportional hazards model revealed that overt OGIB (hazard ratio [HR], 2.017; 95% confidence interval [CI], 1.299-3.131; P = .002), anticoagulants (HR, 1.930; 95% CI, 1.093-3.410; P = .023), positive balloon-assisted enteroscopy findings after CE (HR, 2.927; 95% CI, 1.791-4.783; P .001), and iron supplements without therapeutic intervention (HR, 2.202; 95% CI, 1.386-3.498; P = .001) were associated with rebleeding, whereas a higher minimum hemoglobin level (HR, .902; 95% CI, .834-.975; P = .009) and therapeutic intervention (HR, .288; 95% CI, .145-.570; P .001) significantly reduced the risk of rebleeding. Among the Charlson Comorbidity Index components, liver cirrhosis was an independent predictor associated with rebleeding in patients with OGIB (HR, 4.362; 95% CI, 2.622-7.259; P .001) and in patients with negative CE findings (HR, 8.961; 95% CI, 4.424-18.150; P .001).Rebleeding is common during the long-term follow-up of patients with OGIB. Careful follow-up is required for patients with liver cirrhosis or previous massive bleeding.

Constipation has been considered the key risk factor for diverticulosis occurrence, but the underlying mechanism is unclear. We investigated the factors associated with diverticulosis, focusing on the association of constipation severity with the localization and number of diverticula.We analyzed consecutive patients who underwent colonoscopy between March and December 2019. Chronic constipation was diagnosed as constipation meeting Rome IV criteria or as that requiring laxative therapy for more than 6 months. The degree of constipation was scored using the Constipation Scoring System (CSS).We assessed 1014 patients. Multivariate analysis revealed that age, alcohol consumption, and hypertension were positively associated with diverticulosis, whereas chronic constipation was negatively associated with diverticulosis (odds ratio [OR] = 0.74; 95% confidence interval [CI], 0.55-0.99). When assessed according to the location of diverticula, right-sided diverticula were significantly associated with a lower incidence of constipation (OR = 0.94; 95% CI, 0.89-0.98), whereas neither left-sided nor bilateral diverticula was associated with constipation. This negative association of diverticula with constipation was stronger in patients with a high CSS score. In stratified analysis, the number of diverticula decreased with increasing degree of constipation (Chronic constipation was negatively associated with colonic diverticulosis. The association increased with the degree of constipation and was strong only in cases with right-sided diverticula and those with ≥3 diverticula.

Background and Aim: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1β (IL-1β) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. Methods: Small intestinal mucositis was induced in wild-type, NLRP3–/–, and caspase-1–/– mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1β or IL-18, or neutralizing antibody against IL-1β. Results: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1β and protein expression of cleaved caspase-1 and mature IL-1β. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3–/– mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1β and neutralized by IL-1β antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1β were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. Conclusions: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1β maturation.

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1β, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect.

Non-steroidal anti-inflammatory drugs (NSAIDs) induce small intestinal damage. It has been reported that rebamipide, a mucoprotective drug, exerts a protective effect against NSAID-induced small intestinal damage; however, the underlying mechanism remains unknown. In this study, we investigated the significance of the small intestinal microbiota in the protective effect of rebamipide against indomethacin-induced small intestinal damage in mice. A comprehensive analysis of the 16S rRNA gene sequencing revealed an alteration in the composition of the small intestinal microbiota at the species level, modulated by the administration of rebamipide and omeprazole. The transplantation of the small intestinal microbiota of the mice treated with rebamipide suppressed the indomethacin-induced small intestinal damage. Omeprazole, a proton pump inhibitor, exacerbated the indomethacin-induced small intestinal damage, which was accompanied by the alteration of the small intestinal microbiota. We found that the transplantation of the small intestinal microbiota of the rebamipide-treated mice ameliorated indomethacin-induced small intestinal damage and the omeprazole-induced exacerbation of the damage. These results suggest that rebamipide exerts a protective effect against NSAID-induced small intestinal damage via the modulation of the small intestinal microbiota, and that its ameliorating effect extends also to the exacerbation of NSAID-induced small intestinal damage by proton pump inhibitors.

Background and aim The inflammasomes promote pro-caspase-1 cleavage, leading to processing of pro-interleukin (IL)-1β into its mature form. We investigated the role of the IL-1β and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in gastric injury in mice receiving water-immersion restraint stress (WIRS), focusing on the cyclooxygenase (COX)-2/prostaglandin (PG) E2 axis. Methods To induce gastric injury, the mice were placed in a restraint cage and immersed in the water bath to the level of the xiphoid process. Protein levels of mature caspase-1 and IL-1β were assessed by western blotting. Results Water-immersion restraint stress induced gastric injury with increase in IL-1β expression by activation of NLRP3 inflammasome. Exogenous IL-1β attenuated the injury, whereas anti-IL-1β neutralizing antibody and IL-1β receptor antibody aggravated it. NLRP3-/- and caspase-1-/- mice enhanced the injury with reducing of mature IL-1β, and this aggravation was reduced by exogenous IL-1β supplementation. Toll-like receptor 4-/- mice were hyporesponsive to WIRS in terms of mature IL-1β production. Rabeprazole attenuated the injury with preventing inflammasome activation. WIRS injured the stomach with promotion of COX-2 mRNA and PGE2 production, and exogenous IL-1β enhanced these molecules, while IL-1β immunoneutralization exerted opposite effect. PGE2 supplementation abolished the hypersensitivity in NLRP3-/- and caspase-1-/- mice through negative regulation of inflammatory cytokines. Conclusion These results suggest that NLRP3 inflammasome-derived IL-1β plays a protective role in stress-induced gastric injury via activation of the COX-2/PGE2 axis. Toll-like receptor 4 signaling and gastric acid may be involved in NLRP3 inflammasome activation.

Background and study aims Eosinophilic gastrointestinal disorders are classified into eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis according to the site of eosinophilic infiltration. Although well established in eosinophilic esophagitis, endoscopic findings in eosinophilic gastritis and eosinophilic gastroenteritis with regard to gastric lesions have not been clearly described. The aim of this study was to identify endoscopic findings of gastric lesions associated with eosinophilic gastrointestinal disorders. Patients and methods Out of 278 patients with eosinophilic gastrointestinal disorders, 18 had eosinophilic gastritis or eosinophilic gastroenteritis confirmed by biopsy; their endoscopic images were analyzed retrospectively. The association between endoscopic findings and number of eosinophils in the gastric mucosa was investigated. Results Erythema was most frequently observed (72 %), followed by ulcers (39 %), discoloration (33 %), erosions (28 %), nodularity (28 %), and polyps (28 %). There were several unique endoscopic findings such as submucosal tumor-like deep large ulcers in three patients, antral Penthorum-like appearances (small nodules radially lined toward the pyloric ring) in three patients, “muskmelon-like appearances” (discolored mucosa-composed mesh pattern) in three patients, multiple white granular elevations in two patients, cracks (appearance of furrows similar to those in eosinophilic esophagitis) in five patients, and antral rings in one patient. No significant association was observed between endoscopic findings and number of gastric eosinophils. Conclusions Several unique endoscopic findings of gastric lesions were observed in patients with eosinophilic gastritis or eosinophilic gastroenteritis. Submucosal tumor-like ulcers, antral Penthorum-like appearances, muskmelon-like appearances, and cracks might be associated with eosinophilic gastrointestinal disorders.

Background and Aims Endoscopic and histological healing are associated with improved clinical outcomes in ulcerative colitis [UC]. We aimed to investigate the predictive value of faecal immunochemical test [FIT] for endoscopic and histological healing in UC. Methods We measured quantitative FIT and faecal calprotectin [FC] in 140 consecutive UC patients who underwent colonoscopy. We assessed the diagnostic accuracy of FIT for predicting endoscopic healing using the Mayo endoscopic subscore [MES 0/1] and for histological healing using the Geboes score [< 2.0] and Nancy index [grade ≤ 1]. The predictive abilities of FIT were compared with those of FC. Results FIT had an area under the curve [AUC] of 0.77 (95% confidence interval [CI] 0.67-0.86, p < 0.001) for endoscopic healing, an AUC of 0.77 [95% CI 0.67-0.86, p < 0.001] using the Geboes score, and 0.77 [95% CI 0.66-0.85, p < 0.001] using the Nancy Index for histological healing. The AUC of FIT was comparable to that of FC for endoscopic healing [p = 0.773] and histological healing [p = 0.767-0.960], and was comparable to colonoscopy for histological healing [p = 0.384-0.673]. FIT < 50 ng/ml predicted endoscopic healing with a sensitivity, specificity, and positive predictive value [PPV] of 72%, 68%, and 82%, respectively, and for histological healing with a sensitivity, specificity, and PPV of 73-75%, 67%, and 78-80%, respectively. Combining FIT with FC led to a higher specificity [90%] for histological healing. Over 85% of patients with FIT < 50 ng/ml and FC < 50 μg/g achieved histological healing. Conclusions FIT is highly sensitive and accurate to predict endoscopic and histological healing in UC. It represents a promising non-invasive tool for monitoring mucosal healing in UC.

Purpose: Gut microbiota have been implicated in the development of colorectal cancer. We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for colorectal cancer diagnosis. Experimental Design: Subjects (total 439; 203 colorectal cancer and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for the quantification of bacterial marker candidates. Results: Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal samples of 203 colorectal cancer patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r = 0.801–0.934, all P < 0.0001). Fn was significantly more abundant in colorectal cancer than controls (P < 0.0001), with AUROC of 0.868 (P < 0.0001). At the best cut-off value maximizing sum of sensitivity and specificity, Fn discriminated colorectal cancer from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn + Ch + m7-Bc) showed an improved diagnostic ability compared with Fn alone (AUROC = 0.886, P < 0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical testing for the detection of colorectal cancer. Conclusions: Stool-based colorectal cancer–associated bacteria can serve as novel noninvasive diagnostic biomarkers for colorectal cancer. Clin Cancer Res; 23(8); 2061–70. ©2016 AACR.