Mitsushige Sugimoto

Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype.

Acid inhibitory effects of proton pump inhibitors (PPIs) are influenced by CYP2C19 genotype. In contrast, the potent acid inhibition of vonoprazan is not influenced by CYP2C19 genotype.

NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease

BackgroundNUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD).MethodsTwo hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays.ResultsThe NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1xa0%, respectively. The allelic frequency was 10.2xa0%. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9xa0%) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (Pxa0=xa01.7xa0×xa010−5). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8xa0weeks) (Pxa0=xa01.03xa0×xa010−4) and late (>8xa0weeks) leukocytopenia (Pxa0=xa04.3xa0×xa010−4). The decrease in WBC count at 2 and 4xa0weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (nxa0=xa02) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (Pxa0=xa00.001).ConclusionsThese results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.

Comparison of the gut microbial community between obese and lean peoples using 16S gene sequencing in a Japanese population

Altered gut microbial ecology contributes to the development of metabolic diseases including obesity. In this study, we performed 16S rRNA sequence analysis of the gut microbiota profiles of obese and lean Japanese populations. The V3–V4 hypervariable regions of 16S rRNA of fecal samples from 10 obese and 10 lean volunteers were sequenced using the Illumina MiSeqTMII system. The average body mass index of the obese and lean group were 38.1 and 16.6 kg/m2, respectively (p<0.01). The Shannon diversity index was significantly higher in the lean group than in the obese group (p<0.01). The phyla Firmicutes and Fusobacteria were significantly more abundant in obese people than in lean people. The abundance of the phylum Bacteroidetes and the Bacteroidetes/Firmicutes ratio were not different between the obese and lean groups. The genera Alistipes, Anaerococcus, Corpococcus, Fusobacterium and Parvimonas increased significantly in obese people, and the genera Bacteroides, Desulfovibrio, Faecalibacterium, Lachnoanaerobaculum and Olsenella increased significantly in lean people. Bacteria species possessing anti-inflammatory properties, such as Faecalibacterium prausnitzii, increased significantly in lean people, but bacteria species possessing pro-inflammatory properties increased in obese people. Obesity-associated gut microbiota in the Japanese population was different from that in Western people.

Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease.

Background:Interleukin (IL)-36 (IL-36&agr;, IL-36&bgr;, and IL-36&ggr;) is a recently reported member of the IL-1 cytokine family. In this study, we investigated IL-36 expression in the inflamed mucosa of patients with inflammatory bowel disease and characterized the proinflammatory actions of IL-36 cytokines in human colonic epithelial cells. Methods:IL-36 mRNA expression was evaluated using real-time PCR. IL-36 protein expression was analyzed using immunoblotting and immunohistochemical technique. Intracellular signaling pathways were evaluated by immunoblotting and by specific siRNA-transfected cells. Results:The mRNA expression of IL-36&agr; and IL-36&ggr;, but not of IL-36&bgr;, was enhanced in the inflamed mucosa of patients with inflammatory bowel disease, in particular, in ulcerative colitis. Immunohistochemical analysis showed that T cells, monocytes, and plasma cells are the source of IL-36&agr; and IL-36&ggr; in colonic mucosa. DNA microarray analysis indicated that IL-36&agr; induces the mRNA expression of CXC chemokines and acute phase proteins in intestinal epithelial cell line, HT-29 cells. IL-36&agr; and IL-36&ggr; dose-dependently and time-dependently induced the mRNA and protein expression of CXC chemokines (CXCL1, CXCL2, CXCL3 etc.) in HT-29 and Widr cells. Stimulation with IL-36&agr; and IL-36&ggr; assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex and induced the activation of NF-&kgr;B and AP-1 and also the phosphorylation of MAPKs. MAPK inhibitors and siRNAs specific for NF-&kgr;B and c-Jun AP-1 significantly reduced IL-36–induced CXC chemokine expression. Conclusions:IL-36&agr; and IL-36&ggr; may play a proinflammatory role in the pathophysiology of inflammatory bowel disease through induction of CXC chemokines and acute phase proteins.

High Helicobacter pylori cure rate with sitafloxacin-based triple therapy.

Bacterial resistance of Helicobacter pylori to antibiotics is increasing and it often leads to failure of antibiotic treatment. A new sitafloxacin‐based triple therapy was developed to counter this situation; the fluoroquinolone sitafloxacin has a low minimum inhibitory concentration for H. pylori.

Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis.

Proton pump inhibitors (PPIs) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) and used as the first‐line therapy for gastroesophageal reflux disease (GERD). However, while several studies have examined the influence of CYP2C19 polymorphism on GERD treatment with PPIs, most have had small sample sizes and were conducted in a single center. Here, we used meta‐analysis to investigate whether or not the CYP2C19 rapid metabolizer (RM) genotype is a risk factor for GERD patients being refractory to PPI therapy.

Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease

BackgroundThe mucosa-associated gut microbiota directly modulates epithelial and mucosal function. In this study, we investigated the mucosa-associated microbial community in patients with inflammatory bowel disease (IBD), using endoscopic brush samples.MethodsA total of 174 mucus samples from 43 patients with ulcerative colitis (UC), 26 with Crohn’s disease (CD) and 14 non-IBD controls were obtained by gentle brushing of mucosal surfaces using endoscopic cytology brushes. The gut microbiome was analyzed using 16S rRNA gene sequencing.ResultsThere were no significant differences in microbial structure among different anatomical sites (the ileum, cecum and sigmoid colon) within individuals. There was, however, a significant difference in microbial structure between CD, UC and non-IBD controls. The difference between CD and non-IBD controls was more marked than that between UC patients and non-IBD controls. α-Diversity was significantly lower in UC and CD patients than non-IBD controls. When comparing CD patients with non-IBD controls, the phylum Proteobacteria was significantly increased and the phyla Firmicutes and Bacteroidetes were significantly reduced. These included a significant increase in the genera Escherichia, Ruminococcus (R. gnavus), Cetobacterium, Actinobacillus and Enterococcus, and a significant decrease in the genera Faecalibacterium, Coprococcus, Prevotella and Roseburia. Comparisons between CD and UC patients revealed a greater abundance of the genera Escherichia, Ruminococcus (R. gnavus), Clostridium, Cetobacterium, Peptostreptococcus in CD patients, and the genera Faecalibacterium, Blautia, Bifidobacterium, Roseburia and Citrobacter in UC patients.ConclusionsMucosa-associated dysbiosis was identified in IBD patients. CD and UC may be distinguishable from the mucosa-associated microbial community structure.

Efficacy and safety of single fecal microbiota transplantation for Japanese patients with mild to moderately active ulcerative colitis.

BackgroundThe clinical utility of fecal microbiota transplantation (FMT) in patients with ulcerative colitis (UC) is still controversial. We investigated the efficacy and safety of single FMT for patients with mild to moderately active UC in a Japanese population.MethodsFifty-seven patients were evaluated for eligibility, and 16 patients were excluded. Forty-one patients with UC refractory to standard medical therapy were treated with single FMT by colonoscopic administration. Changes in the fecal microbiota were assessed by 16S ribosomal DNA based terminal restriction fragment length polymorphism analysis.ResultsAt 8xa0weeks after FMT, no patient achieved clinical remission, and 11 of 41 patients (26.8xa0%) showed clinical response. The full Mayo score and the Mayo clinical score significantly decreased at week 8 [full Mayo score 5.5xa0±xa02.4 (meanxa0±xa0standard deviation) at initiation and 4.6xa0±xa02.2 at week 8, Pxa0<xa00.004; Mayo clinical score 4.0xa0±xa02.0 at initiation and 3.0xa0±xa01.9 at week 8, Pxa0<xa00.001], but there were no statistically significant effects on the Mayo endoscopic score. No adverse events occurred after FMT or during the follow-up period of 8xa0weeks. The proportion of Bifidobacterium was significantly higher in the donor feces used for responders than in the donor feces used for nonresponders. The proportion of Lactobacillales and Clostridium cluster IV were significantly higher in the donor feces used for nonresponders.ConclusionsSingle FMT by colonoscopy was performed safely in all patients, but sufficient clinical efficacy and microbial restoration were not confirmed in patients with mild to moderately active 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 0.019u2005μM and lansoprazole 7.6u2005μM).5 We describe below that vonoprazan induces more complex alteration of the gut microbiome as compared with lansoprazole.nnWe 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 30u2005mg of lansoprazole daily for 4u2005weeks, and the P-CAB group …

Influence of prostate stem cell antigen gene polymorphisms on susceptibility to Helicobacter pylori-associated diseases: a case-control study.

Patients with duodenal ulcer have a reduced risk of developing gastric cancer compared to those without. Recently, the prostate stem cell antigen (PSCA) rs2294008 C>T polymorphism was found to be associated with different pathogenesis of duodenal ulcer and gastric cancer developments. However, whether PSCA rs2294008 C>T polymorphism is associated with severity of gastric mucosal atrophy is unclear. We examined the influence of the PSCA rs2294008 C>T polymorphism on susceptibility to H. pylori‐related diseases and the relationships between PSCA polymorphism and gastric mucosal atrophy.