Hiromitsu Ban

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis

BackgroundInterleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs).MethodsIL-33 mRNA expression was determined by real-time polymerase chain reaction (PCR). IL-33 expression in the IBD mucosa was evaluated by immunohistochemical methods.ResultsIL-33 mRNA expression was significantly elevated in active lesions from patients with ulcerative colitis (UC), but was not detected in inactive lesions from UC patients or in lesions from patients with either active or inactive Crohn’s disease. Colonic SEMFs were identified as a major source of IL-33 in the mucosa. IL-1β and tumor necrosis factor-α (TNF-α) significantly enhanced IL-33 mRNA and protein expression in isolated colonic SEMFs. IL-1β and TNF-α did not affect IL-33 expression in intestinal epithelial cell lines (HT-29 and Caco-2 cells). This IL-1β- and TNF-α-induced IL-33 mRNA expression was mediated by p42/44 mitogen activated protein kinase (MAPK) pathway-dependent activation of nuclear factor (NF)-κB and activator protein (AP)-1.ConclusionsIL-33, derived from colonic SEMFs, may play an important role in the pathophysiology of UC.

Epithelial expression of interleukin-37b in inflammatory bowel disease

Interleukin (IL)‐37 is a member of the IL‐1 cytokine family. We investigated IL‐37b expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, we analysed IL‐37b expression in human colonic epithelial cells. The human colonic epithelial cell line T84 and human colonic subepithelial myofibroblasts (SEMFs) were used. IL‐37b expression in the IBD mucosa was evaluated by immunohistochemistry. IL‐37b mRNA and protein expression were determined by real time‐polymerase chain reaction (PCR) and Western blotting, respectively. IL‐37b was not detected in the normal colonic mucosa. In the inflamed mucosa of IBD patients, epithelial IL‐37b expression was increased markedly. In ulcerative colitis (UC) and Crohns disease (CD) patients, IL‐37b expression was enhanced in the affected mucosa. In the intestinal epithelial cell line T84, the expression of IL‐37b mRNA and protein was enhanced by tumour necrosis factor (TNF)‐α. This IL‐37b induction by TNF‐α was mediated by nuclear factor (NF)‐κB and activator protein (AP)‐1 activation. Furthermore, IL‐37b inhibited TNF‐α‐induced interferon‐γ‐inducible protein (IP)‐10 expression significantly in human colonic SEMFs. Epithelial IL‐37b expression was increased in IBD patients, especially UC patients. IL‐37b may be involved in the pathophysiology of IBD as an anti‐inflammatory cytokine and an inhibitor of both innate and acquired immune responses.

Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease

Background and Aim:  There have been no reports on 6‐thioguanine nucleotide (6‐TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6‐mercaptopurine (6‐MP) therapy. The aim of this study was to assess 6‐TGN concentrations in Japanese IBD patients.

Increased number of FoxP3+CD4+ regulatory T cells in inflammatory bowel disease

FoxP3 is a member of the forkhead/winged helix family of transcription factors and plays a critical role in the development and function of CD4+CD25+ regulatory T cells (Tregs). In this study, we performed an immunohistochemical evaluation of FoxP3-expressing cells in inflammatory bowel disease (IBD) mucosa. Mucosal FoxP3 expression was evaluated by immunohistochemistry in samples from normal (n=30), ulcerative colitis (UC) (n=53) and Crohns disease (CD) (n=24) mucosa. There were no FoxP3-immunopositive cells in the normal colonic mucosa. In contrast, FoxP3-immunopositive cells were significantly increased in the inflamed regions of patients with active UC and CD. FoxP3-immunopositive cells completely coincided with some of the CD4-positive T cells. In conclusion, FoxP3-immunopositive Tregs were expanded in the inflamed mucosa of IBD patients. This suggests that these cells have impaired regulatory functions in the IBD mucosa.

Regulation of eotaxin-3/CC chemokine ligand 26 expression by T helper type 2 cytokines in human colonic myofibroblasts.

Eotaxins induce the trafficking of eosinophils to the sites of inflammation via CC chemokine receptor 3 (CCR3). In this study, we investigated eotaxin‐3/CC chemokine ligand 26 (CCL26) expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for eotaxin‐3 expression in human colonic myofibroblasts. Eotaxin‐3 mRNA and protein expression was evaluated by real time‐polymerase chain reaction (PCR) and enzyme‐linked immunosorbent assay (ELISA), respectively. Eotaxin‐3 mRNA expression was elevated significantly in the active lesions of ulcerative colitis (UC) patients. Significant elevations were also observed in the active lesions of Crohns disease (CD) patients, but this was significantly lower than that detected in the active UC lesions. There were no significant increases in the inactive lesions of UC or CD patients. Colonic myofibroblasts were identified as a major source of eotaxin‐3 in the colonic mucosa, and interleukin (IL)‐4 and IL‐13 enhanced eotaxin‐3 mRNA and protein expression significantly in these cells. There was a significant positive correlation between mucosal eotaxin‐3 and IL‐4 mRNA expression in the active lesions of IBD patients. The IL‐4‐ and IL‐13‐induced eotaxin‐3 mRNA expression was regulated by the signal transducer and activator of transcription‐6 (STAT‐6) and suppressor of cytokine signalling (SOCS)1‐mediated pathways. Interferon (IFN)‐γ acts as a negative regulator on the IL‐4‐ and IL‐13‐induced eotaxin‐3 expression via STAT‐1 activation. Eotaxin‐3 expression was elevated specifically in the active lesions of IBD, in particular UC. Eotaxin‐3 derived from colonic myofibroblasts may play an important role in the pathophysiology of UC.

Influence of potassium-competitive acid blocker on the gut microbiome of Helicobacter pylori-negative healthy individuals

We read with great interest two recent reports by Imhann et al 1 and Jackson et al .2 Through large population-cohort study, each group revealed that gastric acid inhibition by long-term use of proton pump inhibitors (PPIs) changes the gut microbiome to predispose to enteric infection including Clostridium difficile (CD) . Potassium-competitive acid blockers (P-CABs) have been reported to exert more potent gastric acid suppression than PPIs.3 ,4 The inhibitory effect of vonoprazan (TAK-438), a new P-CAB, on H+, K+-ATPase in vitro is approximately 400 times more potent than that of PPI (lansoprazole) (inhibitory concentration (IC)50 of vonoprazan 0.019 μM and lansoprazole 7.6 μM).5 We describe below that vonoprazan induces more complex alteration of the gut microbiome as compared with lansoprazole. We enrolled serum Helicobacter pylori IgG-negative healthy individuals to eliminate the influence of H. pylori infection on gastric acid secretion (see online supplementary table S1). The PPI group (n=11) took 30 mg of lansoprazole daily for 4 weeks, and the P-CAB group …

Comparison of energy metabolism and nutritional status of hospitalized patients with Crohn’s disease and those with ulcerative colitis

This study aimed to compare the nutritional status and energy expenditure of hospitalized patients with Crohn’s disease (CD) and those with ulcerative colitis (UC). Twenty-two hospitalized patients with CD and 18 patients with UC were enrolled in this study. We analyzed nutritional status upon admission by using nutritional screening tools including subjective global assessment, malnutrition universal screening tool, and laboratory tests. We measured resting energy expenditure (mREE) of the patients with indirect calorimetry and predicted resting energy expenditure (pREE) was calculated by using the Harris-Benedict equation. Results presented here indicate no significant difference in nutritional parameters and energy metabolism between CD and UC patients. In UC patients, a significant correlation was observed between mREE/body weight and disease activity detected by the Lichtiger and Seo indices. However, there was no correlation between mREE/body weight and Crohn’s disease activity index in CD patients. Inflammatory cytokine interleukin-6 levels correlated with mREE/pREE in CD and UC patients while tumor necrosis factor-α was not. In conclusion, energy expenditure significantly correlated with disease activity in UC patients but not in CD patients. These results indicate that establishing daily energy requirements based on disease activity of UC is imperative for improving the nutritional status of patients.

The DPP-IV inhibitor ER-319711 has a proliferative effect on the colonic epithelium and a minimal effect in the amelioration of colitis

Dipeptidyl-peptidase IV (DPP-IV) inhibitors are expected to prolong the half-life of Glucagon-like peptide (GLP-2) as well as GLP-1, and may result in the promotion of epithelial cell proliferation and regeneration. The aim of this study was to investigate whether a DPP-IV inhibitor can promote epithelial proliferation and attenuate dextran sodium sulfate (DSS)-induced colitis. Nine-week-old female C57/B6 mice were given a single dose of ER-319711 to assess the changes in plasma GLP-2 concentrations. Ten mice were divided into two groups: a vehicle group and an ER-319711 group. ER-319711 was administered orally for 7 days. The mice were then given bromodeoxyuridine (BrdU) intraperitoneally 2 h before sacrifice on day 7. Twenty-six mice were divided into three groups: a vehicle group, a DSS-induced colitis group and a DSS-induced colitis treated with ER-319711 group. The mice were given DSS for 5 days and sacrificed on day 14. Plasma GLP-2 levels were elevated in response to ER-319711. The ER-319711 group had a significantly decreased body weight from days 1 to 3. The number of BrdU positive cells per crypt and the crypt height were increased in the ER-319711 group. The DSS + ER-319711 group had a decreased body weight transition. The disease activity index and colon length showed an amelioration of colitis in the DSS + ER-319711 group. DPP-IV inhibitors are thought to promote the proliferation of the intestinal epithelium. However, the amelioration of DSS-induced colitis was only partial.

Efficacy of the Kyoto Classification of Gastritis in Identifying Patients at High Risk for Gastric Cancer

Objective The Kyoto gastritis classification categorizes the endoscopic characteristics of Helicobacter pylori (H. pylori) infection-associated gastritis and identifies patterns associated with a high risk of gastric cancer. We investigated its efficacy, comparing scores in patients with H. pylori-associated gastritis and with gastric cancer. Methods A total of 1,200 patients with H. pylori-positive gastritis alone (n=932), early-stage H. pylori-positive gastric cancer (n=189), and successfully treated H. pylori-negative cancer (n=79) were endoscopically graded according to the Kyoto gastritis classification for atrophy, intestinal metaplasia, fold hypertrophy, nodularity, and diffuse redness. Results The prevalence of O-II/O-III-type atrophy according to the Kimura-Takemoto classification in early-stage H. pylori-positive gastric cancer and successfully treated H. pylori-negative cancer groups was 45.1%, which was significantly higher than in subjects with gastritis alone (12.7%, p<0.001). Kyoto gastritis scores of atrophy and intestinal metaplasia in the H. pylori-positive cancer group were significantly higher than in subjects with gastritis alone (all p<0.001). No significant differences were noted in the rates of gastric fold hypertrophy or diffuse redness between the two groups. In a multivariate analysis, the risks for H. pylori-positive gastric cancer increased with intestinal metaplasia (odds ratio: 4.453, 95% confidence interval: 3.332-5.950, <0.001) and male sex (1.737, 1.102-2.739, p=0.017). Conclusion Making an appropriate diagnosis and detecting patients at high risk is crucial for achieving total eradication of gastric cancer. The scores of intestinal metaplasia and atrophy of the scoring system in the Kyoto gastritis classification may thus be useful for detecting these patients.

Familial and multiple gastrointestinal stromal tumors with fair response to a half-dose of imatinib.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Since our first report in 1998, approximately 30 families with multiple GISTs due to a germline gain-of-function mutation of c-kit have been reported. We herein present a case of a family with multiple GISTs that have a germline c-kit mutation in exon 11 (Del-Val560) in two siblings. One of the patients showed a fair response to treatment with a half-dose of imatinib (200 mg/day). There are few reports describing the response to imatinib in familial GISTs and this drug appears to be a promising therapeutic option.