BACKGROUND:Uric acid (UA) is an endogenous antioxidant that protects against neuroinflammatory diseases. Although irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction, the role of UA in IBS remains unclear. METHODS:An experimental rat model of IBS was induced using laser-induced shock waves (LISW) applied to the head. Hyperuricemia (HUA) was induced by intraperitoneal administration of inosine monophosphate and potassium oxonate. Visceral hypersensitivity was assessed by colorectal distension. Ileal mucosal permeability was measured using the Evans blue method. CRFR1 mRNA expression in the rectum, IL-10 and TGF-β1 expression in the ileum, and IL-1α, IL-1β, and TNF expression in the medial prefrontal cortex (mPFC) and paraventricular nucleus (PVN) were quantified by qRT-PCR. Vagal involvement was assessed using subdiaphragmatic vagotomy or atropine treatment. KEY RESULTS:LISW increased visceral hypersensitivity, ileal mucosal permeability, and rectal CRFR1 expression and reduced IL-10 expression in the ileum. HUA significantly ameliorated these changes. HUA was also associated with reduced IL-1β expression in the mPFC and reduced IL-1α and IL-1β expression in the PVN in LISW-treated animals. Importantly, the ameliorative effects of HUA on visceral hypersensitivity were abolished by vagotomy or atropine treatment. CONCLUSIONS AND INFERENCES:Hyperuricemia ameliorated LISW-induced visceral hypersensitivity, improved ileal mucosal permeability, restored IL-10 expression in the ileal mucosa, and reduced proinflammatory cytokine expression in the brain. The loss of HUA-induced suppression of visceral hypersensitivity after vagotomy or atropine treatment suggests the possible involvement of vagal and cholinergic brain-gut communication.

OBJECTIVES:Paneth cell metaplasia (PCM), a metaplastic change associated with chronic inflammation in ulcerative colitis (UC), may be linked to UC-associated neoplasia (UCAN). However, no endoscopic method currently exists for detecting PCM. This study aimed to develop and validate a novel endoscopic staining technique-CV-SCAN-for identifying PCM and UCAN, and to explore the molecular characteristics of the stained areas. METHODS:This retrospective observational study included 131 patients with UC undergoing surveillance colonoscopy. CV-SCAN involved spraying an ultra-diluted solution (0.006%) of crystal violet from the descending colon to the rectum. Biopsies were obtained from stained and non-stained areas and evaluated histologically and molecularly. RNA expression profiles were analyzed via microarray and real-time RT-PCR. The diagnostic performance of CV-SCAN for detecting PCM was assessed, along with its correlation with UCAN history. RESULTS:CV-SCAN visualized sharply demarcated, purple-stained areas corresponding to PCM or UCAN. PCM was significantly associated with a history of UCAN. Uniform, dark staining was characteristic of PCM, while UCAN showed heterogeneous staining with small round pits. CV-SCAN achieved a sensitivity of 81.3% and a specificity of 84.9% for PCM detection. Molecular analysis revealed upregulation of Paneth cell-specific (DEFA5, DEFA6), small intestinal (CCL25, APOC3), and UCAN-associated (IL17RC) genes, along with downregulation of SATB2 in stained areas. CONCLUSIONS:CV-SCAN is a novel and effective endoscopic staining method for detecting PCM and UCAN in patients with UC. It enables risk stratification through direct visualization of precancerous changes and may facilitate early detection and targeted surveillance.

OBJECTIVES:A meta-analysis showed that serum folate concentrations, but not vitamin B12 concentrations, are lower in patients with ulcerative colitis compared to healthy controls. However, no epidemiological study has investigated the association between dietary intake of folate, vitamin B12, vitamin B6, vitamin B2, and vitamin B1 and the risk of ulcerative colitis. This study examines this association using data from a multicenter, hospital-based, case-control study. METHODS:The study included 384 cases of ulcerative colitis diagnosed within the past 3 years and 665 controls. Data were collected through a self-reported questionnaire. Dietary information was obtained using a 169-item semi-quantitative food frequency questionnaire. Adjustment was made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of ulcerative colitis, education level, and BMI. RESULTS:Higher dietary intakes of folate and vitamin B1 were independently associated with a decreased risk of ulcerative colitis after adjusting for confounding factors. The adjusted odds ratio for extreme quartiles was 0.60 [95% confidence interval (CI): 0.39 - 0.91, P for trend = 0.009) for folate and 0.54 (95% CI: 0.36 - 0.81, P for trend = 0.004) for vitamin B1. Dietary intake of vitamins B12, B6, or B2 was not independently associated with ulcerative colitis risk. CONCLUSION:This is the first study to demonstrate significant inverse relationships between dietary intake of folate and vitamin B1 and the risk of ulcerative colitis. Our results should be interpreted as exploratory and require validation through further, more focused studies.

Little is known about iatrogenic splenic injury (SI) as an adverse event after colonoscopy. SI is sometimes fatal because of hemorrhaging. We herein report a man who developed SI after colonoscopy. He recovered conservatively. His history of left hydronephrosis and insertion with a maximally stiffened scope were suspected as possible risk factors. Endoscopists should consider the possibility of SI when they encounter patients suffering from left-sided abdominal pain after colonoscopy. Careful interview concerning the medical history and gentle maneuvering around the splenic flexure can help avoid SI.

Background: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. Methods: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. Results: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. Conclusion: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

The gut-skin axis has recently been widely recognized, and both the gut and skin have been found to affect each other through a bidirectional connection; however, the precise mechanisms remain to be elucidated. Therefore, we aimed to investigate the effects of chronic skin damage (CSD) on mouse intestines. Following the CSD model, 4% sodium dodecyl sulfate was applied to the back-shaved murine skin six times for 2 weeks after tape stripping. The small and large intestines were analyzed histologically and immunologically, respectively. Intestinal permeability was measured using fluorescein isothiocyanate-conjugated-dextran. The role of interleukin-13 (IL-13) in the ileum was investigated using an anti-IL-13 antibody. Apoptotic intestinal cells were analyzed using TUNEL staining. Villus atrophy was observed in the small intestine in the CSD model, along with increased permeability. Mast cells, but not T cells, eosinophils, or innate lymph cell-2, were increased in the intestinal mucosa. However, no significant changes were observed in the large intestine. mRNA expression of IL-13 was increased only in the ileum of the CSD model. Apoptotic intestinal epithelial cells were significantly increased in the ileum of the CSD model. Administration of an anti-IL-13 antibody ameliorated the intestinal damage caused by CSD, along with decreased apoptotic cells and mast cell infiltration. Skin damage causes morphological changes in the small intestine, accompanied by increased intestinal permeability, possibly through the IL-13-induced apoptosis of mast cells in the epithelium. Surfactant-mediated mechanical skin damage can cause a leaky gut. Gut and skin have been found to affect each other through a bidirectional connection (gut-skin axis), though the precise mechanisms remain to be elucidated. In this study, surfactant-mediated mechanical chronic skin damage caused morphological changes in the small intestine of mice, accompanied by increased intestinal permeability, possibly through the interleukin-13-induced apoptosis of mast cells in the epithelium. Graphical Abstract

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.

BACKGROUND AND AIM:Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC.METHODS:The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy.RESULTS:Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001).CONCLUSIONS:We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

Background/Aims:Recent studies indicate that probiotics, which have attracted attention as a treatment for irritable bowel syndrome, affect intestinal homeostasis. In this study, we investigated whether Zygosaccharomyces sapae (strain I-6), a probiotic yeast isolated from miso (a traditional Japanese fermented food), could improve irritable bowel syndrome symptoms. Methods:Male Wistar rats were exposed to water avoidance stress (WAS). The number of defecations during WAS and the visceral hypersensitivity before and after WAS were evaluated using colorectal distension. Tight junction changes were assessed by Western blotting. Some rats were fed with strain I-6 or β-glucan from strain I-6. Changes in the intestinal microbiota were analyzed. The effect of fecal microbiota transplantation after WAS was evaluated similarly. Caco-2 cells were stimulated with interleukin-1β and tight junction changes were investigated after coculture with strain I-6. Results:The increased number of stool pellets and visceral hypersensitivity induced by WAS were suppressed by administering strain I-6. The decrease in tight junction protein occludin by WAS was reversed by the administration of strain I-6. β-Glucan from strain I-6 also suppressed those changes induced by WAS. In the rat intestinal microbiota, treatment with strain I-6 altered the β-diversity and induced changes in bacterial occupancy. Upon fecal microbiota transplantation, some symptoms caused by WAS were ameliorated. Conclusions:These results suggest that traditional fermented foods such as miso in Japan are valuable sources of probiotic yeast candidates, which may be useful for preventing and treating stress-induced visceral hypersensitivity.

Paneth cells play multiple roles in maintaining intestinal homeostasis. However, the clinical role of Paneth cell metaplasia (PCM) in ulcerative colitis (UC) remains unclear. We aimed to investigate the relationship between PCM and relapse in patients with UC and compare the usefulness of PCM with other histological indexes, including mucin depletion (MD) and basal plasmacytosis (BP). Patients with UC in clinical remission (CR) who underwent colonoscopy to confirm a Mayo endoscopic subscore (MES) ≦1 with biopsies from the distal colon were enrolled into this retrospective cohort study. Biopsy samples were evaluated for histological findings of PCM, MD, and BP. Clinical relapse was defined as partial Mayo score ≧3 or medication escalation. Multivariate analysis was performed to determine independent predictors of relapse among the three histological findings, MES, and patient background, and relapse prediction models were generated. Eighty-three patients were enrolled in this study (MES 0, n = 47; MES 1, n = 36). The number of PCM cases was significantly higher in patients with prolonged CR than that in those with relapse (p = 0.01). Multivariate analysis showed that the absence of PCM and MD were related to relapse in all the patients. In patients with MES 1, the absence of PCM was the only risk factor significantly and independently associated with relapse (hazard ratio, 4.51 [1.15–17.7]; p = 0.03). The absence of PCM was a histological risk factor for relapse in patients with MES 1, implying a protective role for PCM in remission and a new index for mucosal healing.

BACKGROUND:Although the involvement of intestinal microbiota in innate immunity has been reported recently, the pathogenicity of autoimmune pancreatitis (AIP) remains unclear. This study aimed to investigate whether probiotics ameliorate inflammation in AIP through interactions with innate immunity. MATERIALS AND METHODS:The AIP mouse model was generated by intraperitoneal administration of Escherichia coli to C56BL/6 female mice. Alterations in the intestinal microbiota in the AIP group were evaluated using high-throughput sequencing. Peritoneal macrophages (PMs) were collected and cocultured in vitro with Lactobacillus gasseri (LG) or ligands of Toll-like receptors (TLRs). LG was administered intraperitoneally to AIP model mice, and pancreatitis activity was evaluated to examine the ameliorative effects of LG. RESULTS:In the AIP model mice, inflammation was significantly induced in the pancreas, and the intestinal microbiota was altered with decreased LG. Antimicrobial treatment suppressed pancreatitis. In vitro, E. coli stimulation increased inflammatory cytokine expression, which was significantly decreased when the LG or TLR7 ligand was cocultured with PMs. Intraperitoneal administration of LG to AIP model mice significantly suppressed pancreatitis. CONCLUSION:The mouse model demonstrated the involvement of intestinal microbiota in pancreatitis, and LG administration suppressed pancreatitis, possibly through TLR7 signaling in PMs. LG may be a helpful probiotic for treating AIP.

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. 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. 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. 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.

Luminal antigens, nutrients, metabolites from commensal bacteria, bile acids, or neuropeptides influence the function and trafficking of immune cells in the intestine. Among the immune cells in the gut, innate lymphoid cells, including macrophages, neutrophils, dendritic cells, mast cells, and innate lymphoid cells, play an important role for the maintenance of intestinal homeostasis through a rapid immune response to luminal pathogens. These innate cells are influenced by several luminal factors, possibly leading to dysregulated gut immunity and intestinal disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and intestinal allergy. Luminal factors are sensed by distinct neuro-immune cell units, which also have a strong impact on immunoregulation of the gut. Immune cell trafficking from the blood stream through the lymphatic organ to lymphatics, an essential function for immune responses, is also modulated by luminal factors. This mini-review examines knowledge of luminal and neural factors that regulate and modulate response and migration of leukocytes including innate immune cells, some of which are clinically associated with pathological intestinal inflammation.

高齢者潰瘍性大腸炎は増加している．高齢発症者の方が若齢発症者より重症で，罹患範囲も広く，入院率や手術率も高頻度である．治療に伴う感染症や悪性腫瘍発症のリスクも非高齢者より高く，内科治療の選択に慎重さが必要である．原疾患と関係ない併存症の存在も治療方針の選択に重要な要素である．栄養状態指数の低下が高齢者の入院率や手術率と相関することが示され，暦の年齢よりフレイルが重要であると認識されつつある．しかし真の加齢程度をいかに評価するか，明確な指標は存在せず，栄養状態を改善させると転帰が改善するかも不明である．年齢が高くてもフレイルがなく，併存症もない場合は非高齢者と同様の治療ゴールを設定し，薬剤選択も通常通りで良いと考えられる．しかし内科治療による合併症のリスクが高い場合は，より安全性の高い薬剤選択が選択され，フレイルや併存症の多い場合は治療ゴールの設定をより低く置くような柔軟な対応が必要である．