研究者データベース

綾部 時芳(アヤベ トキヨシ)
先端生命科学研究院 生命機能科学研究部門 細胞生物科学分野
教授

基本情報

所属

  • 先端生命科学研究院 生命機能科学研究部門 細胞生物科学分野

職名

  • 教授

学位

  • 医学博士(旭川医科大学)

ホームページURL

J-Global ID

研究キーワード

  • 潰瘍性大腸炎   クローン病   腸内細菌   腸内環境   脳腸相関   生活習慣病   医食同源   炎症性腸疾患   線維症治療   腸からみた食と健康   感染症   幹細胞   パネト細胞   消化管   defensin   抗菌ペプチド   自然免疫   粘膜免疫   再生医療   消化器病学   Paneth Cell   

研究分野

  • ライフサイエンス / 免疫学
  • ライフサイエンス / 消化器内科学

職歴

  • 2006年04月 - 現在 北海道大学大学院先端生命科学研究院 教授
  • - 現在 北海道大学病院 客員臨床教授(兼任)
  • - 2019年03月 北海道大学大学院生命科学院 副学院長・生命融合科学コース長
  • 旭川医科大学客員教授(兼任)
  • 旭川医科大学第三内科 講師
  • 旭川医科大学消化管再生修復医学講座 客員助教授
  • 米国カリフォルニア大学アーバイン校医学部病理学講座 研究員
  • 旭川医科大学第三内科 助手

学歴

  • 1989年 -   旭川医科大学大学院医学研究科修了(医学博士)
  • 1984年 -   旭川医科大学医学部卒業

所属学協会

  • 米国実験病理学会   腸内細菌学会   日本分子生物学会   北海道医学会   日本消化器内視鏡学会   日本癌学会   日本再生医療学会   日本食品免疫学会   日本消化器免疫学会   日本免疫学会   日本消化器病学会   日本内科学会   米国消化器病学会   国際粘膜免疫学会   

研究活動情報

論文

  • Yuki Yokoi, Takahiro Adachi, Rina Sugimoto, Mani Kikuchi, Tokiyoshi Ayabe, Kiminori Nakamura
    Biochemical and biophysical research communications 545 14 - 19 2021年01月30日 [査読有り]
     
    Paneth cells and Lgr5+ intestinal stem cells (Lgr5+ ISCs) constitute the stem cell niche and maintain small intestinal epithelial integrity by recognizing various niche factors derived from subepithelial cells and external antigens. Although it has been known that interferon-γ (IFN-γ), a Th1 cytokine, is associated with intestinal epithelial disruption during inflammation as a niche factor, dynamics of Paneth cells and Lgr5+ ISCs in response to IFN-γ remain to be understood. Here we show that CAG-tdTomato;Lgr5-EGFP (CT-LE) mice generated in this study enable to identify Paneth cells and Lgr5+ ISCs separately by fluorescence signals. Lgr5+ ISCs underwent cell death a little earlier than Paneth cells in response to IFN-γ by simultaneous tracking using CT-LE mice. In addition, the timing of cell death in most Paneth cells overlapped with Lgr5+ ISCs, suggesting that Paneth cell depletion is induced directly by IFN-γ. Taken together, we established a novel simultaneous stem cell niche tracking method and clarified the involvement of both Paneth cells and Lgr5+ ISCs in stem cell niche damage induced by IFN-γ, further contribute to understanding the mechanism for maintaining intestinal homeostasis by stem cell niche.
  • Kiminori Nakamura, Yuki Yokoi, Rie Fukaya, Shuya Ohira, Ryuga Shinozaki, Takuto Nishida, Mani Kikuchi, Tokiyoshi Ayabe
    Frontiers in Immunology 11 570296 - 570296 2020年10月13日 [査読有り]
     
    © Copyright © 2020 Nakamura, Yokoi, Fukaya, Ohira, Shinozaki, Nishida, Kikuchi and Ayabe. Paneth cells contribute to intestinal innate immunity by sensing bacteria and secreting α-defensin. In Institute of Cancer Research (ICR) mice, α-defensin termed cryptdin (Crp) in Paneth cells consists of six major isoforms, Crp1 to 6. Despite accumulating evidences that α-defensin functions in controlling the intestinal microbiota, topographical localization of Paneth cells in the small intestine in relation to functions of α-defensin remains to be determined. In this study, we examined the expression level of messenger RNA (mRNA) encoding six Crp-isoforms and Crp immunoreactivities using singly isolated crypts together with bactericidal activities of Paneth cell secretions from isolated crypts of duodenum, jejunum, and ileum. Here we showed that levels of Crp mRNAs in the single crypt ranged from 5 x 103 to 1 x 106 copies per 5 ng RNA. For each Crp isoform, the expression level in ileum was 4 to 50 times higher than that in duodenum and jejunum. Furthermore, immunohistochemical analysis of isolated crypts revealed that the average number of Paneth cell per crypt in the small intestine increased from proximal to distal, three to seven-fold, respectively. Both Crp1 and 4 expressed greater in ileal Paneth cells than those in duodenum or jejunum. Bactericidal activities in secretions of ileal Paneth cell exposed to bacteria were significantly higher than those of duodenum or jejunum. In germ-free mice, Crp expression in each site of the small intestine was attenuated and bactericidal activities released by ileal Paneth cells were decreased compared to those in conventional mice. Taken together, Paneth cells and their α-defensin in adult mouse appeared to be regulated topographically in innate immunity to control intestinal integrity.
  • Hikaru Hanyu, Yuki Yokoi, Kiminori Nakamura, Tokiyoshi Ayabe, Keisuke Tanaka, Kinuko Uno, Katsuhiro Miyajima, Yuki Saito, Ken Iwatsuki, Makoto Shimizu, Miki Tadaishi, Kazuo Kobayashi-Hattori
    Toxins 12 10 2020年10月 [査読有り][通常論文]
     
    © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). The different effects of deoxynivalenol (DON) on intestinal barrier and stem cells by its route of exposure remain less known. We explored the toxic effects of DON on intestinal barrier functions and stem cells after DON microinjection (luminal exposure) or addition to a culture medium (basolateral exposure) using three-dimensional mouse intestinal organoids (enteroids). The influx test using fluorescein-labeled dextran showed that basolateral DON exposure (1 micromolar (µM) disrupted intestinal barrier functions in enteroids compared with luminal DON exposure at the same concentration. Moreover, an immunofluorescence experiment of intestinal epithelial proteins, such as E-cadherin, claudin, zonula occludens-1 (ZO-1), and occludin, exhibited that only basolateral DON exposure broke down intestinal epithelial integrity. A time-lapse analysis using enteroids from leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)-enhanced green fluorescence protein (EGFP) transgenic mice and 5-ethynyl-2-deoxyuridine (EdU) assay indicated that only the basolateral DON exposure, but not luminal DON exposure, suppressed Lgr5+ stem cell count and proliferative cell ratio, respectively. These results revealed that basolateral DON exposure has larger impacts on intestinal barrier function and stem cells than luminal DON exposure. This is the first report that DON had different impacts on intestinal stem cells depending on the administration route. In addition, RNA sequencing analysis showed different expression of genes among enteroids after basolateral and luminal DON exposure.
  • Yu Shimizu, Kiminori Nakamura, Aki Yoshii, Yuki Yokoi, Mani Kikuchi, Ryuga Shinozaki, Shunta Nakamura, Shuya Ohira, Rina Sugimoto, Tokiyoshi Ayabe
    Life Science Alliance 2020年06月 [査読有り][通常論文]
  • Yosuke Komatsu, Yu Shimizu, Megumi Yamano, Mani Kikuchi, Kiminori Nakamura, Tokiyoshi Ayabe, Tomoyasu Aizawa
    Metabolomics 16 4 2020年04月 [査読有り][通常論文]
  • Yukiko Hirabayashi, Kiminori Nakamura, Tsuyoshi Sonehara, Daisuke Suzuki, Satoru Hanzawa, Yu Shimizu, Tomoyasu Aizawa, Koshi Nakamura, Akiko Tamakoshi, Tokiyoshi Ayabe
    Mass spectrometry (Tokyo, Japan) 9 1 A0081  2020年 [査読有り][通常論文]
     
    Serotonin, an important neurotransmitter, is produced mainly in intestines, and serotonin levels in feces can be an indicator of the intestinal environment. Human feces, however, contain a large amount of contaminants, which vary widely owing to food contents and the intestinal environment, and these contaminants would be expected to interfere with the determination of serotonin levels in human feces. To remove these contaminants and determine serotonin levels, we developed a new method using solid phase extraction (SPE) and column-switching LC-MS/MS. Serotonin, labeled with a stable isotope, was added to human feces samples prior to SPE as an internal standard to correct for individual differences in matrix effects. The recovery rate for SPE was 55.9-81.0% (intraday) and 56.5-78.1% (interday) for feces from two subjects. We analyzed 220 fecal samples from 96 subjects including 76 pregnant and post-delivery women. The endogenous serotonin content per unit weight of dried feces was 0.09-14.13 ng/mg for pregnant and post-delivery women and 0.30-9.93 ng/mg for the remaining subjects.
  • Ryodai Yamamura, Koshi Nakamura, Naoya Kitada, Tomoyasu Aizawa, Yu Shimizu, Kiminori Nakamura, Tokiyoshi Ayabe, Takashi Kimura, Akiko Tamakoshi
    Bioscience of microbiota, food and health 39 1 11 - 17 2020年 [査読有り][通常論文]
     
    In recent years, short-chain fatty acids (SCFAs) have been reported to play an important role in maintaining human health. Fecal SCFA concentrations correlate well with colonic SCFA status and gut microbiota composition. However, the associations with the gut microbiota functional pathway, dietary intake, blood SCFAs, and fecal SCFAs remain uncertain. To clarify these relationships, we collected fecal samples, blood samples, and dietary habit data from 12 healthy adults aged 22-51 years. The relative abundance of several SCFA-producing bacteria, gut microbiota diversity, and functional pathways related to SCFA biosynthesis were positively associated with fecal SCFAs even after adjusting for age and sex. Furthermore, fecal acetate was likely to be positively associated with serum acetate. By contrast, dietary intake was not associated with fecal SCFAs. Overall, the present study highlights the potential usefulness of fecal SCFAs as an indicator of the gut microbiota ecosystem and dynamics of SCFAs in the human body.
  • Butyric acid and leucine induce alpha-defensin secretion from small intestinal Paneth cells
    Takakuwa A, Nakamura K, Kikuchi M, Sugimoto R, Ohira S, Yokoi Y, Ayabe T
    Nutrients 11(11), 2817 doi.org/10.3390/nu11112817 2019年11月 [査読有り][通常論文]
  • Shimizu Y, Sakuragi N, Nakamura K, Taira T, Ayabe T, Fukui A
    In vitro cellular & developmental biology. Animal 55 6 436 - 444 2019年06月 [査読有り][通常論文]
  • Yokoi Y, Nakamura K, Yoneda T, Kikuchi M, Sugimoto R, Shimizu Y, Ayabe T
    Scientific reports 9 1 2710  2019年02月 [査読有り][通常論文]
  • Pillai MR, Mihi B, Ishiwata K, Nakamura K, Sakuragi N, Finkelstein DB, McGargill MA, Nakayama T, Ayabe T, Coleman ML, Bix M
    PloS one 14 2 e0211244  2019年 [査読有り][通常論文]
  • Cobo ER, Holani R, Moreau F, Nakamura K, Ayabe T, Mastroianni JR, Eriguchi Y, Ouellette A, Chadee K
    Infection and immunity 86 10 2018年10月 [査読有り][通常論文]
  • Kan Yaguchi, Takahiro Yamamoto, Masaya Shimada, Rina Sugimoto, Kiminori Nakamura, Tokiyoshi Ayabe, Ryota Uehara
    Biochemical and biophysical research communications 504 1 231 - 237 2018年09月26日 [査読有り][通常論文]
     
    Near-haploidy is observed in certain cancer types, but ploidy-dependent alterations in gene regulation in the haploid state remain elusive. Here, by comparative transcriptome analysis between human isogenic haploid and diploid cell lines, we found lowering of cyclin D2 level in haploids. Acute genome duplication in haploids restored cyclin D2 expression to diploid level, indicating that the regulation of cyclin D2 expression is directly linked to ploidy. Downstream pathways of cyclin D2, such as Rb phosphorylation and p27 sequestration remained intact in haploids, suggesting that they adapt to lowered cyclin D level. Interestingly, however, haploid cells were more susceptible to cdk4/6 inhibition compared to diploids. Our finding indicates feasibility of selective growth suppression of haploid cells based on ploidy-linked gene regulation.
  • Eriguchi Y, Nakamura K, Yokoi Y, Sugimoto R, Takahashi S, Hashimoto D, Teshima T, Ayabe T, Selsted ME, Ouellette AJ
    JCI insight 3(18):e121886. 18 2018年09月 [査読有り][通常論文]
  • Cobo ER, Holani R, Moreau F, Nakamura K, Ayabe T, Mastroianni JR, Ouellette A, Chadee K
    Infection and immunity 2018年04月 [査読有り][通常論文]
  • Eiko Hayase, Daigo Hashimoto, Kiminori Nakamura, Clara Noizat, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Yuki Yokoi, Rina Sugimoto, Satomi Matsuoka, Takahide Ara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Takeshi Kondo, Rina Hiramine, Tomoyasu Aizawa, Yoshitoshi Ogura, Tetsuya Hayashi, Hiroshi Mori, Ken Kurokawa, Kazuma Tomizuka, Tokiyoshi Ayabe, Takanori Teshima
    JOURNAL OF EXPERIMENTAL MEDICINE 214 12 3507 - 3518 2017年12月 [査読有り][通常論文]
     
    The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as alpha-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant a-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of a-defensins. Administration of R-Spo1 or recombinant a-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.
  • Nakamura K, Sakuragi N, Takakuwa A, Ayabe T
    Bioscience of microbiota, food and health 35 2 57 - 67 2016年 [査読有り][通常論文]
  • Eriguchi Y, Nakamura K, Hashimoto D, Shimoda S, Shimono N, Akashi K, Ayabe T, Teshima T
    Transpl Infect Dis 17 5 702 - 706 2015年10月 [査読有り][通常論文]
     
    BackgroundIntestinal microbial ecology is actively regulated by Paneth cell-derived antimicrobial peptides, -defensins. Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (SCT). We previously demonstrated that Paneth cells are targeted by GVHD, and their expression of antimicrobial peptide -defensins is impaired, leading to a loss of physiological diversity among the microflora and development of bloodstream infection. Herein, we evaluated whether fecal levels of -defensins could be surrogate marker of intestinal dysbiosis. MethodsWe directly measured -defensin cryptdin-1 (Crp1) in fecal pellets of mice with GVHD by using a novel enzyme-linked immunosorbent assay. ResultsFecal levels of Crp1 were significantly decreased in mice with GVHD but unchanged in mice without GVHD after SCT. These were correlated with intestinal flora diversity. ConclusionWe demonstrate a link between reduced secretion of Paneth cell -defensins and dysbiosis of intestinal flora in GVHD. Fecal levels of -defensins could be surrogate markers for intestinal microbial homeostasis.
  • A. Nukuda, C. Sasaki, S. Ishihara, T. Mizutani, K. Nakamura, T. Ayabe, K. Kawabata, H. Haga
    ONCOGENESIS 4 e165  2015年09月 [査読有り][通常論文]
     
    Abnormally stiff substrates have been shown to trigger cancer progression. However, the detailed molecular mechanisms underlying this trigger are not clear. In this study, we cultured T84 human colorectal cancer cells on plastic dishes to create a stiff substrate or on collagen-I gel to create a soft substrate. The stiff substrate enhanced the expression of matrix metalloproteinase-7 (MMP-7), an indicator of poor prognosis. In addition, we used polyacrylamide gels (2, 67 and 126 kPa) so that the MMP-7 expression on the 126-kPa gel was higher compared with that on the 2-kPa gel. Next, we investigated whether yes-associated protein (YAP) affected the MMP-7 expression. YAP knockdown decreased MMP-7 expression. Treatment with inhibitors of epidermal growth factor receptor (EGFR) and myosin regulatory light chain (MRLC) and integrin-alpha 2 or integrin-beta 1 knockdown downregulated MMP-7 expression. Finally, we demonstrated that YAP, EGFR, integrin-alpha 2 beta 1 and MRLC produced a positive feedback loop that enhanced MMP-7 expression. These findings suggest that stiff substrates enhanced colorectal cancer cell viability by upregulating MMP-7 expression through a positive feedback loop.
  • Tomisawa S, Sato Y, Kamiya M, Kumaki Y, Kikukawa T, Kawano K, Demura M, Nakamura K, Ayabe T, Aizawa T
    Protein Expr purif 112 21 - 28 2015年08月 [査読有り][通常論文]
     
    Mammalian alpha-defensins contribute to innate immunity by exerting antimicrobial activity against various pathogens. To perform structural and functional analysis of alpha-defensins, large amounts of alpha-defensins are essential. Although many expression systems for the production of recombinant alpha-defensins have been developed, attempts to obtain large amounts of alpha-defensins have been only moderately successful. Therefore, in this study, we applied a previously developed aggregation-prone protein coexpression method for the production of mouse alpha-defensin cryptdin-4 (Crp4) in order to enhance the formation of inclusion bodies in Escherichia coil expression system. By using this method, we succeeded in obtaining a large amount of Crp4 in the form of inclusion bodies. Moreover, we attempted to refold Crp4 directly during the inclusion-body solubilization step under oxidative conditions. Surprisingly, even without any purification, Crp4 was efficiently refolded during the solubilization step of inclusion bodies, and the yield was better than that of the conventional refolding method. NMR spectra of purified Crp4 suggested that it was folded into its correct tertiary structure. Therefore, the method described in this study not only enhances the expression of alpha-defensin as inclusion bodies, but also eliminates the cumbersome and time-consuming refolding step. (C) 2015 Elsevier Inc. All rights reserved.
  • Risa Taira, Sayori Yamaguchi, Kyoko Shimizu, Kiminori Nakamura, Tokiyoshi Ayabe, Toshio Taira
    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION 56 2 149 - 154 2015年03月 [査読有り][通常論文]
     
    Recent studies suggest a relationship between intestinal microbiota and metabolic syndromes; however, the underlying mechanism remains unclear. To clarify this issue, we assessed the effects of bacterial cell wall components on adiponectin, leptin and resistin secretion from rat visceral adipocytes in vitro. We also measured the relative population of Firmicutes and Bacteroidetes in fecal microbiota and the amount of fecal mucin as an intestinal barrier function, when mice were fed a high-fat diet. In the present study, we demonstrated that bacterial cell wall components affect the secretion of adipokines, depending on the presence of antigens from gram-positive or gram-negative bacteria. Lipopolysaccharide markedly inhibited adiponectin, leptin, and resistin secretion, whereas peptidoglycan increased adiponectin secretion and decreased resistin secretion in vitro. In vivo experiments showed that the high-fat diet increased the population of Firmicutes and decreased that of Bacteroidetes. In contrast, the high-fat diet downregulated the stool output and fecal mucin content. These results demonstrate that bacterial cell wall components affect the onset of metabolic syndromes by mediating the secretion of adipokines from visceral adipose tissue. Furthermore, we believe that metabolic endotoxemia is not due to the increasing dominance of gram-negative bacteria, Bacteroidetes, but due to the depression of intestinal barrier function.
  • Yoshihiro Eriguchi, Hidetaka Uryu, Kiminori Nakamura, Sonoko Shimoji, Shuichiro Takashima, Hiromi Iwasaki, Toshihiro Miyamoto, Nobuyuki Shimono, Daigo Hashimoto, Koichi Akashi, Tokiyoshi Ayabe, Takanori Teshima
    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 19 10 1525 - 1529 2013年10月 [査読有り][通常論文]
     
    We recently demonstrated that expression of alpha-defensins, the major antimicrobial peptides produced by Paneth cells, was severely suppressed in mice with graft-versus-host disease (GVHD). In this study, we found that antibacterial lectin, regenerating islet-derived III gamma (RegIII gamma) was upregulated in villous enterocytes, thus demonstrating the reciprocal control of enteric antimicrobial proteins in GVHD. Upregulation of RegIII gamma was mediated by a mechanism independent upon radiation-induced intestinal tract damage. MyD88-mediated signaling in intestinal epithelium was required for RegIII gamma upregulation in GVHD and antibiotic therapy downregulated RegIII gamma expression. These results suggest that MyD88-mediated sensing of the intestinal microbes disregulated in GVHD induces RegIII gamma upregulation in GVHD and argue a role for RegIII gamma in the pathogenesis of GVHD. (C) 2013 American Society for Blood and Marrow Transplantation.
  • Kiwamu Takemoto, Tomoki Matsuda, Naoki Sakai, Donald Fu, Masanori Noda, Susumu Uchiyama, Ippei Kotera, Yoshiyuki Arai, Masataka Horiuchi, Kiichi Fukui, Tokiyoshi Ayabe, Fuyuhiko Inagaki, Hiroshi Suzuki, Takeharu Nagai
    SCIENTIFIC REPORTS 3 2629  2013年09月 [査読有り][通常論文]
     
    Chromophore-assisted light inactivation (CALI) is a powerful technique for acute perturbation of biomolecules in a spatio-temporally defined manner in living specimen with reactive oxygen species (ROS). Whereas a chemical photosensitizer including fluorescein must be added to specimens exogenously and cannot be restricted to particular cells or sub-cellular compartments, a genetically-encoded photosensitizer, KillerRed, can be controlled in its expression by tissue specific promoters or subcellular localization tags. Despite of this superiority, KillerRed hasn't yet become a versatile tool because its dimerization tendency prevents fusion with proteins of interest. Here, we report the development of monomeric variant of KillerRed (SuperNova) by direct evolution using random mutagenesis. In contrast to KillerRed, SuperNova in fusion with target proteins shows proper localization. Furthermore, unlike KillerRed, SuperNova expression alone doesn't perturb mitotic cell division. Supernova retains the ability to generate ROS, and hence promote CALI-based functional analysis of target proteins overcoming the major drawbacks of KillerRed.
  • Nakamura K, Sakuragi N, Ayabe T
    Anal Biochem 443 2 124 - 131 2013年 [査読有り][通常論文]
     
    Paneth cells at the base of small intestinal crypts secrete α-defensins, which contribute to innate immunity and shape composition of enteric microbiota. Efforts to establish a relationship between secreted α-defensins and disease have been hampered by a lack of sensitive assays to quantify luminal α-defensins. Here we report on a highly sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the mouse Paneth cell α-defensin cryptdin-4 (Crp4) in varied sources, including luminal contents rinsed from stomach to distal colon and fecal pellets. One pair of monoclonal antibodies (mAbs), selected from 10 rat hybridomas secreting Crp4-specific mAbs, was optimized for Crp4 detection and specificity in the sandwich ELISA. In CD1 mice, luminal Crp4 levels increased gradually from 6.8 ± 5.2 ng/ml in proximal small intestine to 54.3 ± 10.3 ng/ml in distal small intestine, and the peptide was detected in colonic lumen and feces. Secreted Crp4 was reduced significantly in feces of IL10 null mice, a model of inflammatory bowel disease (IBD) when compared with wild-type controls. This Crp4 sandwich ELISA enables accurate determinations of luminal α-defensins as biomarkers of Paneth cell function and enteric integrity in diverse disease states such as IBD, infectious disease, graft versus host disease, and obesity in association with dysbiosis of the intestinal microbiota. © 2013 Elsevier Inc. All rights reserved.
  • Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, Shimoda S, Iwasaki H, Shimono N, Ayabe T, Akashi K, Teshima T
    Blood 120 1 223 - 231 1 2012年07月 [査読有り][通常論文]
     
    Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, alpha-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of alpha-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT. (Blood. 2012;120(1):223-231)
  • Takahiro Ito, Hiroki Tanabe, Tokiyoshi Ayabe, Chisato Ishikawa, Yuhei Inaba, Atsuo Maemoto, Toru Kono, Toshifumi Ashida, Mikihiro Fujiya, Yutaka Kohgo
    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 227 1 39 - 48 2012年05月 [査読有り][通常論文]
     
    Paneth cells in the small intestine are able to sense luminal bacteria and secrete granules that contain antibacterial peptides. Human defensin (HD)-5 and -6 are antimicrobial peptides found in human Paneth cell granules, and are major bactericidal components. We investigated whether any constituents in the Paneth cell secretions showed chemotactic activity or stimulated cytokine secretion from intestinal epithelial cells, and assessed to what extent HD-5 and -6 were responsible for these activities. The secretions from human Paneth cells and recombinant HD-5 and -6 were evaluated to elucidate their effects on the chemotaxis of dendritic cells (DCs) in a migration assay. The Paneth cell secretions were chemotactic for immature DCs at concentrations ranging from 10 to 1,000 mu g/ml. HD-6 was active at 100 ng/ml, but HD-5 was not. Next, the stimulation of cytokine production by the T84 intestinal cell line was assessed using ELISA and/or an antibody array. The secretions more strongly stimulated interleukin (IL)-8 production than did the defensin peptides, and induced production of various cytokines by the antibody array. The secretions were also analyzed by high performance liquid chromatography (HPLC) and mass spectrometry (MS) in order to determine the components. A large number of molecules was found in the secretions, and HD-5 was identified as an immature propeptide. In conclusion, some constituents other than defensin in human Paneth cell secretions activated the migration of DCs and induced the production of inflammatory cytokines. Therefore, Paneth cells may play a role in the innate immunity associated with adaptive immune responses.
  • Nakamura K, Ayabe T
    Inflammation Regeneration 32 2 53 - 60 2012年 [査読有り][通常論文]
  • Conststruction of a novel expression system for cryptdin-4 by using inclusion body formation.
    Sato Y, Tomisawa S, Aizawa T, Sakai N, Kamiya M, Kikukawa T, Kumaki Y, Demura M, Ayabe T, Kawano K
    Peptide Science 2011 393 - 394 2012年 [査読有り][通常論文]
  • Isoleucine, an Essential Amino Acid, Induces the Expression of Human β Defensin 2 through the Activation of the G-Protein Coupled Receptor-ERK Pathway in the Intestinal Epithelia.
    Konno Y, Ashida T, Inaba Y, ItoT, Tanabe H, Maemoto A, Ayabe T, Mizukami Y, Fujiya M, Kohgo Y
    Food Nutrition Sciences 3 4 548 - 555 2012年 [査読有り][通常論文]
  • Sang-Hyun Son, Yuko Abe, Maiko Yuasa, Yutaka Yamagishi, Naoki Sakai, Tokiyoshi Ayabe, Koji Yamada
    CHEMISTRY LETTERS 40 4 378 - 380 2011年04月 [査読有り][通常論文]
     
    The Suzuki-Miyaura cross-coupling was found to be effective for the modification of aromatic heterocyclic rings in solvatochromic fluorophores, thereby providing quantitative evaluation of the ring effects on photophysical properties. The effect of heteroatom, a beta-substituent,and the number of rings in the aromatic moiety were investigated systematically.
  • Masuda K, Sakai N, Nakamura K, Yoshioka S, Ayabe T
    J Innate Immun 3 3 315 - 326 3 2011年 [査読有り][通常論文]
     
    Mouse Paneth cell alpha-defensins, termed cryptdins, are secreted into the intestinal lumen, have microbicidal activity, and contribute to intestinal innate immunity. Among them, cryptdin-4 (Crp4) has the most potent microbicidal activity. In the intestinal lumen, commensal bacteria colonize and elicit beneficial effects in the host. However, the effects of Crp4 against commensal bacteria are poorly understood. Thus, we investigated the bactericidal activities of Crp4 against commensal bacteria compared to noncommensal bacteria. Oxidized Crp4 showed only minimal or no bactericidal activity against 8 out of 12 commensal bacterial species, including Bifidobacterium bifidum and Lactobacillus Casei. We further addressed a role of the conserved disulfide bonds of Crp4 by analyzing reduced Crp4 (r-Crp4). r-Crp4 demonstrated significantly greater bactericidal activities against 7 of 12 commensal bacteria than did oxidized Crp4. Oxidized Crp4 and r-Crp4 elicited equivalently potent bactericidal activities against 11 of the 11 noncommensal bacteria tested, such as Salmonella enterica serovar Typhimurium, and against 5 of 12 commensal bacteria. Furthermore, when r-Crp4 was exposed to a processing enzyme of cryptdins, i.e. MMP-7, r-Crp4 was degraded and the bactericidal activities disappeared. These findings suggest that Crp4 has selective bactericidal activities against intestinal microbiota and that the activities are dependent on the disulfide bonds. Copyright (C) 2010 S. Karger AG, Basel
  • Koji Masuda, Kiminori Nakamura, Sawako Yoshioka, Rie Fukaya, Naoki Sakai, Tokiyoshi Ayabe
    RECENT ADVANCES IN TONSILS AND MUCOSAL BARRIERS OF THE UPPER AIRWAYS 72 97 - 99 2011年 [査読有り][通常論文]
     
    The antimicrobial peptide is one of major effectors of the innate immunity, and is common in the entire multicellular organisms. In mammals, one family of antibacterial peptide named defensins plays a central role in host defense, especially in the epithelial surface such as oral cavity, skin and the intestine. Recently, the importance of the antimicrobial peptides has been widely recognized. The epithelium of the gut is a largest surface that is exposed to various pathogens in the environment. It is the Paneth cells that produce antimicrobial peptides, alpha-defensins in the small intestine. Paneth cells contribute to mucosal innate immunity by sensing bacteria and releasing microbicidal activities mostly from activated alpha-defensins. In mice, alpha-defensins, named cryptdins, consisted of six major isoforms (cryptdin-1 to cryptdin-6), and among those cryptdin-4 is the most microbicidal, suggesting that cryptdin-4 has a pivotal role in innate immunity. Paneth cell alpha-defensins have selective activities against commensal bacteria which may be associated with compositions of intestinal microbiota in vivo and homeostasis of the entire intestine. In addition, Paneth cell alpha-defensins appeared to be regulated topographically to control intestinal integrity. Copyright (C) 2011 S. Karger AG, Basel
  • Yuhei Inaba, Toshifumi Ashida, Takahiro Ito, Chisato Ishikawa, Hiroki Tanabe, Atsuo Maemoto, Jiro Watari, Tokiyoshi Ayabe, Yusuke Mizukami, Mikihiro Fujiya, Yutaka Kohgo
    INFLAMMATORY BOWEL DISEASES 16 9 1488 - 1495 2010年09月 [査読有り][通常論文]
     
    Background: The etiology of inflammatory bowel disease (IBD) is associated with an altered microflora due to a failure of the immune system. This study investigated the expression of the intestinal antimicrobial peptide a-defensin, which plays a pivotal role in the regulation of the intestinal microflora in a representative model of IBD, interleukin (IL)-10-deficient mice. Methods: The expression of alpha-defensin/cryptdins in IL-10-deficient mice was assessed by real-time polymerase chain reaction (PCR) and acid/urea polyacrylamide gel (AU-PAGE). The alteration of alpha-defensin/cryptdins expression was compared with the inflammatory grade of mice intestine at various weeks from birth. Results: The weight, length, and inflammation grade of the mouse intestines were assessed at 5, 7, 9, 11, 13, and IS weeks from birth. While the weight of the large intestine was heavier at 15 weeks after birth in the IL-10-deficient mice than in the control mice, histological inflammation began from 7 weeks after birth. Real-time PCR and AU-PAGE identified a significant decrease in the expression of alpha-defensin/cryptdins at 7 weeks after birth in the IL-10 knockout mice, thus illustrating the involvement of alpha-defensin/cryptdins in the etiology of the intestinal inflammation in IBD. This study also identified the expression of alpha-defensin/cryptdins to be inversely proportional to age until 11 weeks, suggesting a relationship between the formation of the intestinal microflora and a reduction in the expression of alpha-defensin/cryptdins. Conclusions: The altered expression of antimicrobial peptide alpha-defensin may cause the onset of intestinal inflammation due to a failure to regulate intestinal microflora.
  • Akira Kawaguchi, Tadaki Suzuki, Takashi Kimura, Naoki Sakai, Tokiyoshi Ayabe, Hirofumi Sawa, Hideki Hasegawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 398 4 778 - 784 2010年08月 [査読有り][通常論文]
     
    Gene-encoded antimicrobial peptides (AMPS) are an essential component of the innate immune system in many species. Analysis of beta-defensin gene expression in mouse tissue using primers that were specific for conserved sequences located outside of the beta-defensin translated region identified a novel small gene. The novel gene had an open reading frame of 114 bp and encoded a predicted protein of 37 amino acid residues. A search of the genome database revealed that the gene locus and the sequence of exon 1 of this novel gene were similar to subgroup 1 mouse beta-defensins. A small peptide, K17 (FSPQMLQDIIEKKTKIL), derived from the amino acid sequence of this novel gene was synthesized. Circular dichroism (CD) spectroscopic analysis of chemically synthesized peptide demonstrated that the peptide exhibited random coil conformation in aqueous solution, but the peptide adopted helical conformation in the presence of trifluoroethanol or sodium dodecyl sulfate, a membrane-mimicking environment. The peptide exhibited bactericidal activity against Salmonella enterica serovar Typhimurium (Gram negative) and Staphylococcus aureus (Gram positive); it was not cytotoxic in cultures of mammalian cells or hemolytic in cultures of erythrocytes. These results suggested that K17 may be a candidate therapeutic for the treatment of bacterial infection. (C) 2010 Elsevier Inc. All rights reserved.
  • Chisato Ishikawa, Hiroki Tanabe, Atsuo Maemoto, Takahiro Ito, Jiro Watari, Toru Kono, Mikihiro Fujiya, Toshifumi Ashida, Tokiyoshi Ayabe, Yutaka Kohgo
    JOURNAL OF INNATE IMMUNITY 2 1 66 - 76 2010年 [査読有り][通常論文]
     
    Human defensin-5 (HD-5) is one of the major antimicrobial peptides secreted by Paneth cells in the human small intestine. HD-5 is produced and stored as a propeptide in Paneth cell granules, secreted in response to stimulation by cholinergic reagents or bacterial antigens. The activation process by trypsin occurs in the intestinal lumen to produce mature HD-5. This study evaluated the difference between proHD-5 and mature HD-5 in bactericidal activity and induction of chemokine secretion in vitro. Mature HD-5 showed bactericidal activities against all bacterial strains. Though, proHD-5 without enzymatic cleavage possessed less antimicrobial ability against Salmonella typhimurium and Escherichia Coli but not against Staphylococcus aureus. Mature HD-5 also induced intestinal epithelial cells to increase the protein and mRNA levels of interleukin-8. Furthermore, the peptides were applied to dextran sulfate sodium-induced mouse colitis. The expression of endogenous mouse defensins was not changed in the small intestine, and the additional injection of exogenous HD-5 improved mortality (p < 0.05). This study demonstrated the multifunctional roles of the activation process in human defensin and the possibility of using antimicrobial peptides for the treatment of inflammatory bowel diseases in future applications. Copyright (C) 2009 S. Karger AG, Basel
  • Shougo Tamura, Shizuka Amano, Toru Kono, Jun Kondoh, Kikuji Yamaguchi, Seiichi Kobayashi, Tokiyoshi Ayabe, Takanori Moriyama
    PROTEOMICS 9 24 5534 - 5543 2009年12月 [査読有り][通常論文]
     
    Royal jelly contains numerous components, including proteins. Major royal jelly protein (MRJP) 1 is the most abundant protein among the soluble royal jelly proteins. In its physiological state, MRJP 1 exists as a monomer and/or oligomer. This study focuses the molecular characteristics and functions of MRJP 1 oligomer. MRJP 1 oligomer purified using HPLC techniques was subjected to the following analyses. The molecular weight of MRJP 1 oligomer was found to be 290 kDa using blue native-PAGE. MRJP 1 oligomer was separated into 55 and 5 kDa spots on 2-D blue native/SDS-PAGE. The 55 kDa protein was identified as MRJP 1 monomer by proteome analysis, whereas the 5 kDa protein was identified as Apisimin by N-terminal amino acid sequencing, and this protein may function as a subunit-joining protein within MRJP 1 oligomer. We also found that the oligomeric form included noncovalent bonds and was stable under heat treatment at 56 C. Furthermore, MRJP 1 oligomer dose dependently enhanced and sustained cell proliferation in the human lymphoid cell line Jurkat. In conclusion, MRJP 1 oligomer is a heat-resistant protein comprising MRJP 1 monomer and Apisimin, and has cell proliferation activity. These findings will contribute to further studies analyzing the effects of MRJP 1 in humans.
  • Hiroki Tanabe, Tomonobu Sato, Jiro Watari, Atsuo Maemoto, Mikihiko Fijiya, Toru Kono, Toshifumi Ashida, Tokiyoshi Ayabe, Yutaka Kohgo
    HELICOBACTER 13 5 370 - 379 2008年10月 [査読有り][通常論文]
     
    Background and Aims: Chronic gastritis is caused by Helicobacter pylori infection, and gastritis is classified as inflammation, atrophy, and intestinal metaplasia. Detailed pathologic studies have shown that H. pylori settles on the surface of gastric mucosa, and that it is eliminated from metaplastic mucosa. However, its mechanism of natural protection is not well known. Methods: Antimicrobial human enteric defensin expression was determined in the RNA and protein levels. Recombinant enteric defensins were produced with a bacterial expression system and their anti-H. pylori activities were assessed by bactericidal assay. Results: Human enteric defensin (HD)-5 and HD-6 were detected in Paneth cells, which are observed in the gastric metaplastic mucosa as well as small intestinal epithelia. HD-5 protein was coexpressed with trypsin, which is considered to be an activating enzyme of HD-5. Less H. pylori was observed in the intestinal metaplasia with HD-5 expressing Paneth cells. The recombinant defensins showed killing activity against H. pylori at a low concentration in vitro. Conclusions: The human defensins that are expressed in the metaplastic Paneth cells eliminate H. pylori. Metaplastic change may be a purposive development of the human stomach.
  • Antimicrobial peptides in the gut innate immunity.
    Sakai N, Ayabe T
    Int J Probiotics Prebiotics 3 3 123 - 126 2008年 [査読有り][通常論文]
  • Hiroki Tanabe, Tokiyoshi Ayabe, Atsuo Maemoto, Chisato Ishikawa, Yuhei Inaba, Ryu Sato, Kentaro Moriichi, Kotaro Okamoto, Jiro Watari, Toru Kono, Toshifumi Ashida, Yutaka Kohgo
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 358 1 349 - 355 2007年06月 [査読有り][通常論文]
     
    alpha-Defensin is an antimicrobial peptide which plays an important role in innate immunity. Human defensin (HD)-5 is stored in the Paneth cells of the small intestine as a pro-form and is cleaved by trypsin, which is co-secreted from the Paneth cell granules. The mature HD-5 is protected from further digestion by the proteolysis enzyme, We generated both recombinant HD-5 and proHD-5, and the reduced form of each peptide in order to determine their physiological roles of the disulfide bonds. The reduced proHD-5 attenuated the bactericidal activity and the stability against the trypsin digestion. Human defensin was protected from the enzymatic degradation by disulfide bridges. We further purified the HD-5 with a disulfide variation in the small intestine of Crohn's disease patients. The HD-5 was sensitive to the trypsin treatment. These observations evidently predict that a defensin deficiency may be caused by a disulfide disorder in the disease. (c) 2007 Elsevier Inc. All rights reserved.
  • Atsuo Maemoto, Tokiyoshi Ayabe, Hiroki Tanabe, Yuhei Inaba, Toshifumi Ashida, Rie Fukaya, Naoki Sakai, Toru Kono, Yutaka Kohgo
    GASTROENTEROLOGY 132 4 A562 - A562 2007年04月 [査読有り][通常論文]
  • T Kono, Y Ebisawa, Tomita, I, N Chisato, K Kamiya, T Asama, T Ayabe, T Ashida, Y Kohgo, S Kasai
    JOURNAL OF CHEMOTHERAPY 17 2 224 - 227 2005年04月 [査読有り][通常論文]
     
    Irinotecan combined with continuous-infusion 5-fluorouracil (5FU) has been shown to be an effective and tolerable regimen in the treatment of Metastatic colorectal cancer (MCRC). Tegafur/uracil (UFT) during 5FU infusion enhances plasma 5FU concentration, mimics continuous 5FU infusion and delivers the drug to target tumor cells. We conducted a phase H trial of four-agent combined therapy for MCRC, giving patients (pts) intravenous irinotecan (30 mg/m(2) on day 1), leucovorin (LV, 200 mg/m(2) on day 1 and 2), 5FU (300 mg/m(2) on day 1 and 2), and UFT (400 mg/day for 14 days). The main endpoint was the objective tumor response rate. Sixteen pts with a good performance status were enrolled from February 2001 to May 2002. The response rate was 19% (3 partial responses), and 13 pts had stable disease. The median time to progression was 5.2 months, and the median survival time was 20.2 months. Considering the low toxicity and reasonable cost, this regimen deserves further investigation.
  • H Tanabe, T Ayabe, B Bainbridge, T Guina, RK Ernst, RP Darveau, SI Miller, AJ Ouellette
    INFECTION AND IMMUNITY 73 4 2312 - 2320 2005年04月 [査読有り][通常論文]
     
    Mouse Paneth cells respond to bacteria and bacterial cell surface antigens by discharging secretory granules into the lumen of small intestinal crypts (T. Ayabe et al., Nat. Immunol. 1:113-118, 2000). To investigate mechanisms regulating these responses, purified surface glycolipid molecules with known acyl chain modifications and attenuated properties were tested for the ability to stimulate Paneth cell secretion. The antigens included lipopolysaccharide (LPS) from wild-type and msbB-null Escherichia coli and phoP-null and phoP-constitutive Salmonella enterica serovar Typhimurium strains, as well as LPS, lipid A, and lipoteichoic acid from Pseudomonas aeruginosa and Listeria monocytogenes grown in Mg2+-limited media. Measurements of total secreted protein, secreted lysozyme, and the bactericidal peptide activities of collected secretions showed that the purified antigens elicited similar secretory responses from Paneth cells in mouse crypts ex vivo, regardless of glycolipid acyl chain modification. Despite their impaired Tlr4 pathway, Paneth cells in ex vivo C3H/HeJ mouse crypts released equivalent amounts of bactericidal peptide activity in response to purified bacterial antigens, including lipid A. Thus, mouse Paneth cells respond equivalently to purified bacterial cell envelope glycolipids, regardless of functional Tlr4, the structural properties of glycolipid acyl chains, or their association with virulence in humans.
  • T Ayabe, T Ashida, Y Kohgo, T Kono
    TRENDS IN MICROBIOLOGY 12 8 394 - 398 2004年08月 [査読有り][通常論文]
     
    The intestinal epithelium is the largest surface area that is exposed to various pathogens in the environment, however, in contrast to the colon the number of bacteria that colonize the small intestine is extremely low. Paneth cells, one of four major epithelial cell lineages in the small intestine, reside at the base of the crypts and have apically oriented secretory granules. These granules contain high levels of antimicrobial peptides that belong to the alpha-defensin family. Paneth cells secrete these microbicidal granules that contain alpha-defensins when exposed ex vivo to bacteria or their antigens, and recent evidence reveals that antimicrobial peptides, particularly a-defensins, that are present in Paneth cells contribute to intestinal innate host defense.
  • Y Ebisawa, T Kono, M Yoneda, T Asama, N Chisato, M Sugawara, K Ishikawa, J Iwamoto, T Ayabe, Y Kohgo, S Kasai
    JOURNAL OF SURGICAL RESEARCH 118 2 183 - 189 2004年05月 [査読有り][通常論文]
     
    Background. The role of nitric oxide (NO) in lipopolysaccharide (LPS) tolerance in the liver has been investigated in a number of previous studies, but it is still not clear whether NO is cytotoxic or cytoprotective. The aims of this study were to investigate whether low-dose LPS (LLPS)-induced hepatic production of NO is beneficial and to clarify the origins of cytoprotective NO-producing cells in the liver during LPS tolerance. Materials and methods. Male Wistar rats received saline or LLPS intraperitoneally (i.p.; 0.01-1000 mug/kg) followed by a high dose of LPS (HLPS, 5 mg/kg) at various time intervals (4-16 h). N-G-nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of inhibition of NOS. 4,5-Diaminofluorescein (DAF-2) was used to identify NO-producing cells in isolated liver cells in vitro. At various time points (4-16 h) after saline or LLPS (1 mug/kg, i.p.) injection, hepatocytes and Kupffer cells were isolated, incubated in 7 muM DAF-2 diacetate, and perfused with Krebs solution. Illumination at 495 nm revealed DAF-fluorescence (515 nm) in isolated cells under confocal laser fluorescence microscopy. The NO production in hepatocytes and Kupffer cells was assessed by the number of labeled cells per 1000 cells or per 100 cells, respectively. Results. Pretreatment with LLPS (0.1-100 mug/kg) resulted in a significant reduction (maximal at 8 h) of the HLPS-induced liver damage. L-NAME abolished the LLPS-induced protection. The NO production in hepatocytes was significantly increased and reached a maximum of 84% of all cells 8 h after LLPS administration. By contrast, the NO production in Kupffer cells remained constant at 95%, even following preinjection of LLPS. Conclusion. LLPS-induced NO in hepatocytes, but not in Kupffer cells, exhibits cytoprotective effects on HLPS-induced liver damage, suggesting that NO has a beneficial role in the induction of the early phase of LPS tolerance. (C) 2004 Elsevier Inc. All rights reserved.
  • T Kono, N Chisato, Y Ebisawa, T Asama, M Sugawara, T Ayabe, Y Kohgo, S Kasai, M Yoneda, T Takahashi
    JOURNAL OF SURGICAL RESEARCH 117 2 329 - 338 2004年04月 [査読有り][通常論文]
     
    Direct measurement of the release of nitric oxide (NO) from the myenteric plexus has been extremely difficult to date, due to the lack of suitable methodologies. We have developed a new bioimaging system to visualize the nitrergic neurons of the myenteric plexus and investigated whether NO production is impaired in dextran sulfate sodium (DSS)-induced colitis. Longitudinal muscle layers with the myenteric plexus intact were obtained from the rat colon and were incubated with 4,5-diaminofluorescein-2-diacetate (DAF-2DA) (7 mum) for 30 min. Illumination at 450-490 nm revealed the fluorescence in the myenteric plexus. Confocal laser microscopy and three-dimensional reconstruction techniques were used to quantify the changes in the amount of NO production by the myenteric plexus. Fluorescent double-labeled immunostaining for nNOS was performed to confirm the colocalization of nNOS in 4,5-diaminofluorescein (DAF-2)-positive cells. DAF-2 fluorescence was abolished by pretreatment with N-G-nitro-L-arginine methyl ester (L-NAME; a nonselective NOS inhibitor), 1-(2-trifluoromethylphenyl) imidazole (TRIM; a selective neuronal NOS inhibitor), and omega-conotoxin GVIA (an N-type Ca2+ channel blocker), but not by nifedipine (an L-type Ca2+ channel blocker). Fluorescent double-labeled immunostaining showed that DAF-2-positive cells colocalized with nNOS-positive cells. Oral administration of 5% DSS for 7 days induced distal colitis and the number of DAF-2-positive neurons were significantly reduced to 55 +/- 17% of control. DAF-2 offers a sensitive indicator for visualizing production of NO with high spatial resolution. This new system may contribute to the study of the pathophysiological role of the nitrergic pathway in the gastrointestinal tract. (C) 2004 Elsevier Inc. All rights reserved.
  • J Watari, Y Saitoh, M Fujiya, N Shibata, H Tanabe, Y Inaba, K Okamoto, A Maemoto, T Ohta, A Yasuda, T Ayabe, T Ashida, K Yokota, T Obara, Y Kohgo
    JOURNAL OF GASTROENTEROLOGY 39 2 104 - 112 2004年02月 [査読有り][通常論文]
     
    Background Syndecan-1 is known to play a role as a cell adhesion molecule, similar to E-cadherin, and is associated with the maintenance of epithelial morphology. The purpose of this study was to elucidate the role and alterations of syndecan-1 expression in comparison with those of E-cadherin in different cellular phenotypes of differentiated-type gastric cancers (DGCs). Methods. A total of 80 DGCs at an early stage, and their adjacent mucosa, were evaluated by both immunohistochemistry and in situ hybridization. Syndecan-1 and E-cadherin were assessed by immunohistochemical staining with an anti-syndecan-1 and an anti-E-cadherin antibody, respectively. Based on immunohistochemistry, DGCs and their surrounding mucosa were divided into four types: gastric type (G-type), ordinary type (O-type), complete-intestinal type (CI-type), and null type. Results. The expression sites of syndecan-1 mRNA mostly coincided with those of syndecan-1 protein. Syndecan-1 expression was significantly lower in G-type cancers (30%) than in O- (81%) and Cl-type cancers (92%) (P = 0.0001 and P = 0.004, respectively), but E-cadherin did not show this result. In addition, syndecan-1 expression was significantly reduced in DGCs comprised partly of poorly differentiated adenocarcinoma or signet-ring cell carcinoma, compared to DGCs demonstrating papillary and/or tubular adenocarcinoma (P = 0.02). G-type intestinal metaplasia (IM) surrounding the tumors was observed in 21% of G-type cancers, in 0% of O-, and in 10% of CI-type cancers (P = 0.01; G-type vs O-type). Reduction of syndecan-1 expression was significant in G-type IM (25%) compared to non-G-type IM (75%; P = 0.02). Conclusions. Syndecan-1 plays a role in the growth of G-type cancers at an early stage compared with E-cadherin changes, and the reduction of syndecan-1 expression in IM surrounding the tumors may influence the growth of G-type cancer.
  • Y Kohgo, T Ashida, A Maemoto, T Ayabe
    JOURNAL OF GASTROENTEROLOGY 38 51 - 54 2003年03月 [査読有り][通常論文]
     
    The recent development of effective and safe devices to remove leukocytes selectively from circulating blood has facilitated the application of leukocytapheresis for the treatment of inflammatory bowel disease (IBD). Successful results of preliminary trials of leukocytapheresis for IBD led to several nationwide multicenter clinical trials in Japan. As a result, five or six consecutive leukocytaphereses, which were undergone weekly, improved both symptoms and endoscopic findings in approximately 60%-80% of patients with ulcerative colitis (UC). In Japan, leukocytapheresis is now considered to be one of the standard treatments for UC patients with refractory disease to avoid surgery. Here, the current status of indications and mechanisms of action on UC are analyzed by reviewing the results of Japanese multicicenter trials, and the possible application for Crohn's disease is also discussed.
  • Yutaka Kohgo, Toshifumi Ashida, Atsuo Maemoto, Tokiyoshi Ayabe
    Journal of Gastroenterology 38 15 51 - 54 2003年 [査読有り][通常論文]
     
    The recent development of effective and safe devices to remove leukocytes selectively from circulating blood has facilitated the application of leukocytapheresis for the treatment of inflammatory bowel disease (IBD). Successful results of preliminary trials of leukocytapheresis for IBD led to several nationwide multicenter clinical trials in Japan. As a result, five or six consecutive leukocytaphereses, which were undergone weekly, improved both symptoms and endoscopic findings in approximately 60%-80% of patients with ulcerative colitis (UC). In Japan, leukocytapheresis is now considered to be one of the standard treatments for UC patients with refractory disease to avoid surgery. Here, the current status of indications and mechanisms of action on UC are analyzed by reviewing the results of Japanese multicicenter trials, and the possible application for Crohn's disease is also discussed.
  • M Fujiya, Y Saitoh, M Nomura, A Maemoto, K Fujiya, J Watari, T Ashida, T Ayabe, T Obara, Y Kohgo
    GASTROINTESTINAL ENDOSCOPY 56 4 535 - 542 2002年10月 [査読有り][通常論文]
     
    Background. Colonoscopy has an important role in the diagnosis of ulcerative colitis. However, colonoscopic findings are inadequate for the prediction of relapse without histologic examination. In this study, the role of magnifying colonoscopy in ulcerative colitis was evaluated. Methods: One hundred sixteen magnifying colonoscopy observations were made in 61 patients with ulcerative colitis between January 1994 and October 1998. A simple classification of magnifying colonoscopic findings into 5 categories was devised as follows: regularly arranged crypt openings, villous-like, minute defects of epithelium, small yellowish spots, and coral reef-like appearance. The colonoscopic findings by classification were compared with histopathologic findings, and the usefulness of the classification for predicting relapse was prospectively analyzed in 18 patients. Results: Compared with grade as determined by conventional colonoscopy, there was a better correlation between the classification of findings by magnifying colonoscopy and histopathologic findings (r(2) = 0.665, 0.807, respectively). Of 18 patients studied prospectively, 7 of 9 with minute defects of epithelium relapsed within 6 months, and the cumulative nonrelapsing rate was significantly lower in,patients with minute defects of epithelium compared with those without minute defects of epithelium (p = 0.0059). Moreover, minute defects of epithelium was found to be a significant independent predictive factor for relapse (multivariate analysis, Cox proportional hazards model; p = 0.0203). Conclusions: Our proposed classification of magnifying colonoscopic findings in patients with ulcerative colitis is useful for the evaluation of disease activity and for the prediction of periods of remission.
  • M Taniguchi, T Ayabe, T Ashida, Y Fujimoto, Y Kohgo
    BIOCHEMICAL GENETICS 40 9-10 339 - 349 2002年10月 [査読有り][通常論文]
     
    To clarify whether genetic polymorphisms in exon 14 of Coagulation factor XIII A-subunit gene (FXIIIA) affect phenotype expressions, we studied genetic polymorphisms in exon 14 of FXIIIA in a Japanese population and the relationship between the genetic polymorphisms and phenotype expression. Genetic polymorphisms in exon 14 of FXIIIA of 144 unrelated Japanese were analyzed by single-strand conformation polymorphism. Plasma FXIIIA antigen concentrations, FXIII activities, and phenotype were also determined by two-dimensional electrophoresis. The frequencies of the three genotypes, the homozygote (AD), the homozygote (BC) and the heterozygote (AD/BC), were 77.1, 0.7, and 22.2%, respectively. The gene frequencies of AD and BC were 0.88 and 0.12. We detected AD (GTT.GAG) and BC (ATT.CAG) at codon 650 and 651 of exon 14. There were no significant differences of FXIIIA antigen concentrations and FXIII activities between these genotypes. We detected three pl differences among them as being pls of 5.3, 5.6, 5.8 in the homozygote (AD) and the heterozygote (AD/BC), and a pl of 5.8 in the homozygote (BC). These polymorphisms affected isoelectric mobility, but did not affect protein levels, enzyme activities, or the molecular weight of FXIII.
  • F Orii, T Ashida, M Nomura, A Maemoto, T Fujiki, T Ayabe, S Imai, Y Saitoh, Y Kohgo
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 296 5 1286 - 1294 2002年09月 [査読有り][通常論文]
     
    We have previously reported that in peripheral blood mononuclear cells (PBMC), the augmented expression of the P isoform of the human glucocorticoid receptor (hGRbeta), as a putative dominant negative regulator of glucocorticoid action, is associated with glucocorticoid (GC) unresponsiveness of UC patients. In this study, we quantified the levels and serial changes of hGR transcripts in PBMC of IBD patients by a real-time fluorescence monitoring of PCR. As results, relative hGRbeta mRNA expression was significantly higher in the active stage of UC than in inactive periods of UC or CD patients. Longitudinal analysis revealed that bGRbeta mRNA expression in UC was increased after the relapse of inflammation, suggesting that the overproduction of cytokines during inflammation may be responsible. In in vitro culture experiments of human lymphoid cell (CEM) and human PBMC, IL-7, and IL-18 increased hGRbeta mRNA expression in these cells but GC itself did not. Through these analyses, it is indicated that the inflammatory cytokines altered the splicing condition of the primary transcript of hGR gene in IBD patients. (C) 2002 Elsevier Science (USA). All rights reserved.
  • J Watari, Y Saitoh, T Obara, M Fujiya, A Maemoto, T Ayabe, T Ashida, K Yokota, Y Orii, Y Kohgo
    AMERICAN JOURNAL OF GASTROENTEROLOGY 97 8 2109 - 2115 2002年08月 [査読有り][通常論文]
     
    OBJECTIVE: Serial colonoscopic observations were prospectively conducted to elucidate the natural history of nonpolypoid tumors. Furthermore, to clarify whether cell kinetic status affects the tumor development, proliferative indices, apoptotic indices, and K-ras codon 12 point mutations on biopsy specimens were investigated. METHODS: Seventy-five colorectal tumors, 13 polypoid and 62 nonpolypoid type (56 flat elevated and six depressed type) were studied. Proliferating and apoptotic cells were detected with anti-Ki-67 antibody and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, respectively. Point mutations at K-ras codon 12 were examined by enriched polymerase chain reaction-based restriction fragment length polymorphism assay. RESULTS: The average follow-up period was 22 months (range 1-50). The lesions of subsequent exophytic growth, unchanged shape, depressed growth, and disappearance were observed in 0%, 92%, 0%, and 8% of polypoid type, in 39%, 39%, 13%, and 9% of flat elevated type, and in 33%, 67%, 0%, and 0% of depressed type, respectively. There was no significant difference in tumor size between initial and follow-up colonoscopy. Nonpolypoid tumors apparently changed to the exophytic growth during 2 yr or more. The tumors with exophytic growth had significantly higher proliferative indices/apoptotic indices ratios than those with unchanged morphology and disappearance/depressed growth (p < 0.05, respectively). K-ras codon 12 point mutations did not correlate with tumor development. CONCLUSIONS: Cell kinetic status plays an important role in determining minute colorectal tumor development, but not K-ras codon 12 mutations. Minute nonpolypoid adenomas frequently tend to grow slowly, and nearly 40% of those become the exophytic growth with time. Most of minute nonpolypoid tumors seem to follow the adenoma-carcinoma sequence.
  • T Ayabe, H Wulff, D Darmoul, MD Cahalan, KG Chandy, AJ Ouellette
    JOURNAL OF BIOLOGICAL CHEMISTRY 277 5 3793 - 3800 2002年02月 [査読有り][通常論文]
     
    Paneth cells in small intestinal crypts secrete microbicidal alpha-defensins in response to bacteria and bacterial antigens (Ayabe, T., Satchell, D. P., Wilson, C. L., Parks, W. C., Selsted, M. E., and Ouellette, A. J. (2000) Nat. Immunol. 1, 113-138). We now report that the Ca2+-activated K+ channel mIKCa1 modulates mouse Paneth cell secretion. mIKCa1 cDNA clones identified in a mouse small intestinal crypt library by hybridization to human IKCa1 cDNA probes were isolated, and DNA sequence analysis showed that they were identical to mIKCa1 cDNAs isolated from erythroid cells and liver. The genomic organization was found to be conserved between mouse and human IKCa1 as shown by comparisons of the respective cDNA and genomic sequences. Reverse transcriptase-PCR experiments using nested primers amplified mIKCa1 from the lower half of bisected crypts and from single Paneth cells, but not from the upper half of bisected crypts, villus epithelium, or undifferentiated crypt epithelial cells, suggesting a lineage-specific role for mIKCa1 in mouse small bowel epithelium. The cloned mIKCa1 channel was calcium-activated and was blocked by ten structurally diverse peptide and nonpeptide inhibitors with potencies spanning 9 orders of magnitude and indistinguishable from that of the human homologue. Consistent with channel blockade, charybdotoxin, clotrimazole, and the highly selective IKCa1 inhibitors, TRAM-34 and TRAM-39, inhibited (similar to50%) Paneth cell secretion stimulated by bacteria or bacterial lipopolysaccharide, measured both as bactericidal activity and secreted cryptdin protein, but the inactive analog, TRAM-7, did not block secretion. These results demonstrate that mIKCa1 is modulator of Paneth cell a-defensin secretion and disclose an involvement in mucosal defense of the intestinal epithelium against ingested bacterial pathogens.
  • T Ayabe, DP Satchell, P Pesendorfer, H Tanabe, CL Wilson, SJ Hagen, AJ Ouellette
    JOURNAL OF BIOLOGICAL CHEMISTRY 277 7 5219 - 5228 2002年02月 [査読有り][通常論文]
     
    Paneth cells in small intestine crypts secrete microbicidal alpha-defensins, termed cryptdins, as components of enteric innate immunity. The bactericidal activity of cryptdins requires proteolytic activation of precursors by matrix metalloproteinase-7 (MMP-7; matrilysin) (Wilson, C. L., Ouellette, A. J., Satchell, D. P., Ayabe, T., Lopez-Boado, Y. S., Stratman, J. L., Hultgren, S. J., Matrisian, L. M., and Parks, W. C. (1999) Science 286, 113-117). Here, we report on the intracellular processing of cryptdin proforms in mouse Paneth cells. Peptide sequencing of MMP-7 digests of purified natural procryptdins identified conserved cleavage sites in the proregion between Ser(43) and Val(44) as well as at the cryptdin peptide N terminus between Ser(58) and Leu(59). Immunostaining co-localized precursor prosegments and mature cryptdin peptides to Paneth cell granules, providing evidence of their secretion. Extensive MMP-7-dependent procryptdin processing occurs in Paneth cells, as shown by Western blot analyses of intestinal crypt proteins and proteins from granule-enriched subcellular fractions. The addition of soluble prosegments to in vitro antimicrobial peptide assays inhibited the bactericidal activities of cryptdin-3 and -4 in trans, suggesting possible cytoprotective effects by prosegments prior to secretion. Levels of activated cryptdins were normal in small bowel of germ-free mice and in sterile implants of fetal mouse small intestine grown subcutaneously. Thus, the initiation of procryptdin processing by MMP-7 does not require direct bacterial exposure, and the basal MMP-7 content of germ-free Paneth cells is sufficient to process and activate a-defensin precursors. MMP-7-dependent procryptdin activation in vivo provides mouse Paneth cells with functional peptides for apical secretion into the small intestine lumen.
  • T Kono, M Yoneda, K Ohara, T Ayabe, N Chisato, Y Kohgo, S Kasai, A Terano, Y Tache
    INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 16 6 384 - 390 2001年11月 [査読有り][通常論文]
     
    Background and aims: The phenomenon of prostaglandin dependent adaptive cytoprotection has been well established in the stomach and duodenum but not in the colon. This study investigated whether it also occurs in the colon. Methods: Fisher rats received intracolonic administration (0.5 ml) of saline or acetic acid at low concentrations (0.01-5%) followed by high concentration (25%) at various intervals (10-720 min). The distal colon was removed 2 h after acetic acid (25%), and colonic injury was assessed macroscopically and histologically and scored. Indomethacin (5 mg/kg) or N-G-nitro-L-arginine methyl ester (10 mg/kg) was injected intraperitoneally 1 h or 30 min before pretreatment with 1% acetic acid. Results: Acetic acid (25%) administered into the colon induced 11.6+/-0.2 macroscopic scores and 10.0+/-0.4 histological scores in saline-pretreated rats, which were reduced to 0.3+/-0.2 and 1.8+/-0.5 by acetic acid (1%) pretreatment, respectively. The protective effect assessed macroscopically and histologically was dose related (0.01-1% acetic acid) and long lasting (maximal at 30 min and lasting up to 6 h). Indomethacin abolished the colonic adaptive cytoprotection while nitric oxide synthase inhibitor had no effect. Conclusions: These data show that prostaglandin dependent adaptive protection is induced by exposure of the colon to low concentrations of acetic acid, suggesting that endogenous defense mechanisms are increased in the colon by mild irritants.
  • High-frequency Ultrasound probes in the evaluation of colorectal neoplasia.
    Saitoh Y, Watari J, Fujiya M, Miyoshi Y, Maemoto A, Ayabe T, Ashida T, Ohta T, Kohgo Y
    Digestive Endosc 13 S14 - 18 2001年 [査読有り][通常論文]
  • S Sakamaki, N Takayanagi, N Yoshizaki, S Hayashi, T Takayama, J Kato, K Kogawa, N Yamauchi, N Takemoto, A Nobuoka, T Ayabe, Y Kohgo, Y Niitsu
    GUT 47 2 236 - 241 2000年08月 [査読有り][通常論文]
     
    Background and aims-Recent studies suggest that tropomyosin (TM) may act as a putative autoantigen in ulcerative colitis (UC). Recently, we identified, by computer homology analysis, a specific peptide (HIAEDADRK) in human TM that can bind to HLA-DPw9. The aim of this study was to investigate the presence of autoantibodies against this peptide in UC. Methods-Antibodies were measured by ELISA with a synthetic peptide in 20 healthy volunteers, 48 patients with UC, 26 with Crohn's disease (CD), eight with primary sclerosing cholangitis (PSC), and six with primary biliary cirrhosis (PBC). The functional significance of antibodies was investigated by antibody dependent cell mediated cytotoxicity (ADCC) against DPw9 transfected L cells using a standard Cr-51 release assay. Results-Optical density values (mean (SD)) of sera from patients with UC (1.40 (0.52)) and PSC (1.65 (0.12)) were significantly higher than those from healthy volunteers (0.32 (0.28)) (p<0.05), CD (0.50 (0.34)) (p<0.05) and PBC (0.14 (0.09)) (p<0.05). Values in UC decreased with clinical improvement. The ADCC activity of UC sera correlated well with antibody titre against this synthetic peptide. Conclusions-Anti-TM antibody was detected in UC sera by a specific peptide based ELISA with high reproducibility. This peptide may be an antigenic epitope of TM involved in the immunopathogenesis of UC and, perhaps, PSC.
  • Ayabe T, Satchell DP, Wilson CW, Parks WC, Selsted ME, Ouellette AJ
    Nature Immunol 1 2 113 - 118 2000年08月 [査読有り][通常論文]
     
    Paneth cells in mouse small intestinal crypts secrete granules rich in microbicidal peptides when exposed to bacteria or bacterial antigens. The dose-dependent secretion occurs within minutes and alpha-defensins, or cryptdins, account for 70% of the released bactericidal peptide activity. Gram-negative bacteria, Gram-positive bacteria, lipopolysaccharide, lipoteichoic acid, lipid A and muramyl dipeptide elicit cryptdin secretion. Live fungi and protozoa, however, do not stimulate degranulation. Thus intestinal Paneth cells contribute to innate immunity by sensing bacteria and bacterial antigens, and discharge microbicidal peptides at effective concentrations accordingly.
  • Honda M, Orii F, Ayabe T, Imai S, Ashida T, Obara T, Kohgo Y
    Gastroenterology 118 5 859 - 866 2000年05月 [査読有り][通常論文]
     
    Background & Aims. Recently, the glucocorticoid receptor beta (hGR beta) was suggested to play a role as a dominant negative regulator for determining glucocorticoid response. The aim of this study was to clarify whether reverse-transcription polymerase chain reaction (RT-PCR) analysis of hGR beta messenger RNA (mRNA) can predict the response to glucocorticoids in patients with ulcerative colitis. Methods: Total RNA obtained from peripheral blood mononuclear cells (PBMCs) of 23 patients with ulcerative colitis and 20 healthy volunteers was reverse transcribed; the resulting complementary DNA was amplified using specific primers for hGR alpha and hGR beta. Protein expression of hGR in PBMCs was confirmed by immunoprecipitation-Western blot analysis. Results: The expression of hGR alpha mRNA (477 base pairs) was detected in all patients and all healthy volunteers, In contrast, a hGR beta mRNA (366 base pairs) was detected in 1 (9.1%) of 11 glucocorticoid-sensitive patients, 10 (83.3%) of 12 glucocorticoid-resistant patients, and 2 (10%) of 20 healthy volunteers. The positive rate of hGR beta mRNA in the resistant group was significantly higher than that in the sensitive group (P = 0.0019). The hGR beta band could be detected by immunoprecipitation-Western blotting in hGR beta mRNA-positive patients. Conclusions: The results show that the expression of hGR beta mRNA in PBMCs examined by RT-PCR may serve as a novel predictor of glucocorticoid response in ulcerative colitis.
  • M Taruishi, Y Saitoh, J Watari, T Ashida, T Ayabe, K Takemura, K Yokota, T Obara, Y Kohgo
    RADIOLOGY 214 3 908 - 911 2000年03月 [査読有り][通常論文]
     
    For diagnostic ileography, the authors developed balloon-occluded endoscopic retrograde ileography and performed 77 studies in 36 consecutive patients with Crohn disease. Balloon-occluded endoscopic retrograde ileography proved to be useful in visualization of minute mucosal lesions such as aphthous ulcers and lymphoid hyperplasia in the dis-tal ileum, and satisfactory ileographic images of Crohn disease were obtained in 54 (70%) studies.
  • Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL, Hultgren SJ, Matrisian LM, Parks WC
    Science 286 5437 113 - 117 1999年10月 [査読有り][通常論文]
     
    Precursors of alpha-defensin peptides require activation for bactericidal activity. In mouse small intestine, matrilysin colocalized with alpha-defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors. Matrilysin-deficient (MAT(-/-)) mice Lacked mature cryptdins and accumulated precursor molecules. Intestinal peptide preparations from MAT(-/-) mice had decreased antimicrobial activity. Orally administered bacteria survived in greater numbers and were more virulent in MAT(-/-) mice than in MAT(+/+) mice Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.
  • Y Saitoh, T Obara, J Watari, M Nomura, M Taruishi, Y Orii, M Taniguchi, T Ayabe, T Ashida, Y Kohgo
    GASTROINTESTINAL ENDOSCOPY 48 4 362 - 370 1998年10月 [査読有り][通常論文]
     
    Background: Depressed type early colorectal cancers are found less frequently than other polypoid cancers although they have a higher submucosal invasion rate. Recently videocolonoscopy and chromoendoscopy have become available and precise descriptions of these lesions are now routine. Because endoscopic mucosal resection is designated for intramucosal and focally extended submucosal (m-sm1) cancers, an evaluation of the characteristic findings indicating invasion depth with these modalities is important. Methods: Between January 1991 and March 1996, 64 depressed type early colorectal cancers were detected and treated. When a faint abnormality of the mucosa was suspected by routine videocolonoscopy, 0.1% of indigo carmine solution was sprayed on the mucosal surface (chromoendoscopy). Colonoscopic findings of m-sm1 cancers and moderately and massively extended submucosal (sm2-3) cancers were retrospectively reviewed and compared with confirmed histologic findings. Results: Characteristic colonoscopic findings needed for surgical operation were as follows: (1) expansion appearance, (2) deep depression surface, (3) irregular bottom of depression surface, and (4) folds converging toward the tumor. By using these findings, the invasion depth of depressed type early colorectal cancers could be correctly determined in 58 of 64 lesions (91%). Conclusions: Characteristic colonoscopic findings obtained by a combination of videocolonoscopy and chromoendoscopy are useful for determination of the invasion depth of depressed type colorectal cancers, an essential factor in choosing a treatment modality.
  • T Aburano, Y Saito, N Shuke, T Ayabe, Y Kohgo, J Sato, Y Ishikawa
    CLINICAL NUCLEAR MEDICINE 23 8 509 - 513 1998年08月 [査読有り][通常論文]
     
    The diagnostic value of Tc-99m leukocyte imaging for evaluating disease activity and monitoring treatment response in ulcerative colitis was compared with that of colonoscopy. A total of 48 studies were performed in 28 patients with ulcerative colitis. Forty-six studies had both Tc-99m leukocyte imaging and colonoscopy within 2 weeks of each other, and the remaining two studies had only Tc-99m leukocyte imaging. In 46 studies, semiquantitative grading of colonic radioactivity by comparison with iliac crest marrow activity on radionuclide imaging correlated well with macroscopic grading based on Matts' criteria on colonoscopy, Fourteen (82%) of 17 studies with slight colonoscopic change showed a negative result on the radionuclide image. In 15 patients treated with glucocorticoids or leukapheresis, radionuclide imaging showed nearly the same statistical results as colonoscopy in monitoring treatment response. Tc-99m leukocyte imaging could be used as an alternative to colonoscopy to evaluate the disease activity of ulcerative colitis or to monitor the treatment response, although it is insensitive for detecting disease with only slight macroscopic changes.
  • Tokiyoshi Ayabe, Toshifumi Ashida, Yutaka Kohgo
    Therapeutic Apheresis 2 2 125 - 128 1998年 [査読有り][通常論文]
     
    Corticosteroids are effective in bringing about clinical remission for ulcerative colitis. However, relapsed cases are frequently refractory to corticosteroids. In addition, the long-term use of corticosteroids often causes serious side effects. We have already reported that leukocyte apheresis using a centrifugal procedure was effective for patients with corticosteroid-resistant ulcerative colitis after conducting a pilot study in 14 patients (1). In the present paper, the clinical efficacy of leukocyte apheresis using a centrifugal procedure was evaluated again for corticosteroid-resistant ulcerative colitis. Twenty-three patients with corticosteroid-resistant severely active ulcerative colitis were treated by centrifugal leukocyte apheresis. Eighteen patients (78.3%) achieved clinical remission which was evaluated by the clinical activity index within 4 weeks after apheresis. Both colonoscopic and histological examinations confirmed the beneficial effect of this procedure. No significant side effects were noticed throughout the therapy.
  • J Watari, Y Saitoh, T Obara, T Fujiki, M Taniguchi, M Nomura, T Ayabe, T Ohta, Y Orii, Y Kohgo
    RADIOLOGY 205 1 67 - 74 1997年10月 [査読有り][通常論文]
     
    PURPOSE: To diagnose depth of invasion of early flat and depressed nonpolypoid colorectal cancers with double-contrast barium enema examination. MATERIALS AND METHODS: Ninety-seven early nonpolypoid colorectal cancers, initially identified with colonoscopy, were investigated with double-contrast barium enema examination. Depth of invasion in resected specimens obtained with endoscopic mucosal or surgical resection was determined. Cancer confined to the mucosal layer or with focal extension to the submucosal layer was defined as Ca-m; moderate to massive extension of cancer into the submucosal layer was classified Ca-sm. RESULTS: In flat elevated and depressed cancels, converging folds and semilunar deformity were observed significantly more frequently in Ca-sm than in Ca-m tumors (P < .05 and P < .01, respectively). Sensitivities and specificities of these findings for Ca-sm tumor were 42%, 93% and 86%, 85%, respectively. Deep depression, irregular surface of the depression, and tumor size larger than 20 mm were also predictive findings for depressed Ca-sm tumors (P < .05); the specificity of each was 100%. With use of these radiographic predictors, overall accuracy for diagnosing depth of invasion was 85%. CONCLUSION: Findings on double-contrast barium enema study are highly predictive of depth of invasion of early nonpolypoid colorectal cancer. Radiographic findings of converging folds, semilunar deformity, deep depression, irregular surface of the depression, and tumor size are predictors of Ca-sm tumor.
  • K Yokota, Y Saito, K Einami, T Ayabe, Y Shibata, H Tanabe, J Watari, C Ohtsubo, N Miyokawa, Y Kohgo
    GASTROINTESTINAL ENDOSCOPY 46 3 268 - 272 1997年09月 [査読有り][通常論文]
  • T Ayabe, T Ashida, M Taniguchi, M Nomura, K Einami, M Taruishi, Y Saitoh, SB Santos, M Ono, Y Shibata, Y Kohgo
    INTERNAL MEDICINE 36 5 322 - 326 1997年05月 [査読有り][通常論文]
     
    Corticosteroids are effective in bringing about a clinical remission in patients with ulcerative colitis, However, in severely relapsed cases, corticosteroids are not always effective even when a high dosage is administered, In addition, the long-term use of corticosteroids often causes serious side effects, Therefore, an alternative treatment for active ulcerative colitis is necessary in order to avoid these clinical problems, In the present pilot study, the efficacy of leukocytapheresis using a centrifugal procedure was evaluated for corticosteroid-resistant, active ulcerative colitis, Fourteen patients with corticosteroid-resistant severely active ulcerative colitis were treated by leukocytapheresis. Thirteen patients (92.9 %) achieved clinical remission within 4 weeks after the apheresis, and remained in remission for 8 months on average without any additional corticosteroid therapy, In the remaining patient, in whom remission was not induced, a total colectomy was performed immediately after the fourth course of leukocytapheresis, No significant side effects were noticed throughout the therapy, Both colonoscopic and histological examinations confirmed the beneficial effect of this procedure in terms of the reduction of severe inflammation of the affected colon, We found that the expression of two adhesion molecules, L-selectin and VLA4a, on the surface of peripheral leukocytes was decreased after this new therapy.
  • K. Yokota, Y. Saito, K. Einami, T. Ayabe, Y. Shibata, H. Tanabe, J. Watari, C. Ohtsubo, N. Miyokawa, Y. Kohgo
    Gastrointestinal Endoscopy 46 3 268 - 272 1997年 [査読有り][通常論文]
  • Y Saitoh, T Obara, K Einami, M Nomura, M Taruishi, T Ayabe, T Ashida, Y Shibata, Y Kohgo
    GASTROINTESTINAL ENDOSCOPY 44 1 34 - 39 1996年07月 [査読有り][通常論文]
     
    Background: Flat and depressed nonpolypoid types of colorectal tumors have drawn much attention. Since endoscopic mucosal resection technique is available, it is of great importance to distinguish intramucosal carcinoma from invasive carcinoma because determination of the invasion depth is essential for choosing this therapy. The usefulness of high-frequency (20 MHz) ultrasound probes for preoperative staging of invasion depth in this type of colorectal tumor was evaluated. Methods: Forty-nine cases of flat and depressed tumors were examined with the ultrasound probe and diagnostic accuracy was confirmed by comparing ultrasonic images with the pathologic findings of the specimens resected either by endoscopic mucosal resection or surgical operation. Results: The normal colonic wall was visualized as a nine-layered structure and the muscularis mucosae was depicted in 37 (76%) of 49 cases. Flat and depressed tumors were visualized as hypoechoic lesions and the invasion depth was accurately diagnosed in 43 (88%) of 49 lesions. Conclusions: High-frequency ultrasound probes proved to be useful in determining the invasion depth and therapeutic strategy in flat and depressed colorectal tumors.
  • Y. Saitoh, T. Aburano, T. Takashio, N. Shuke, T. Ayabe, M. Nomura, Y. Kohgo, Y. Ishikawa, J. Satoh
    Kakuigaku 33 7 711 - 719 1996年 [査読有り][通常論文]
     
    Inflammatory imaging using 99mTc-HMPAO-labeled mixed leukocytes was assessed for use in treating 11 cases diagnosed as ulcerative colitis: 10 cases with total colitis and 1 with left-sided colitis. They consisted of 8 patients with relapse-remitting type and 3 with chronic continuous type. Radionuclide abdominal images were obtained at 1 hr, 4 hr and 24 hr after intravenous injection of 200 MBq prepared 99mTc leukocytes. Obvious colonic activity noted at 4 hr served as the basis for positive comparative criterion in the present study. The diagnostic efficacy of radionuclide imaging was compared with endoscopic findings (based on Matts' classification) and the clinical manifestations as reference. The sensitivity and specificity of this imaging were 83.3% and 85.7%, respectively, these values being consistent with endoscopic findings and clinical manifestations at sites of disease activity. All of positive images changed to negative after treatment by leukocyte apheresis or glucocorticoid. Based on these results, 99mTc leukocyte imaging can be used to accurately evaluate severity and treatment response in ulcerative colitis. Leukocytes may be closely related to the pathogenesis of ulcerative colitis.
  • K. Satoh, M. Nomura, T. Ayabe, M. Taruishi, K. Einami, Y. Saitoh, T. Ashida, Y. Shihata, Y. Kohgo, T. Saitoh, Y. Nakajima
    Journal of the Japan Society of Colo-Proctology 48 7 597 - 605 1995年 [査読有り][通常論文]
     
    Familial occurrence of ulcerative colitis (UC) is rare in Japan. Only 66 families were reported up to 1994. A family in which UC occurred in three members is presented, and HLA analysis was investigated. A 58-year-old female with a history of UC for 22 years has had alternating remission and relapse since the onset of UC. A 29-year-old male, her nephew, developed UC extending to the left colon 13 years ago. He suffered some relapses and the lesion involved the entire colon. A 24-year-old male, her nephew and his cousin, developed UC 2 years ago. Colonoscopic examination and barium enema study were performed, and he was diagnosed as having UC affecting the entire colon. Concerning HLA typing, all cases have A24-B52-DR2 which has been shown to be associated with Japanese UC patients. Though the cause of UC remains unknown, these findings imply that a hereditary predisposition may be involved in the etiology of UC.
  • Masaki Taruishi, Tokiyoshi Ayabe, Toshifumi Ashida, Yusuke Saitoh, Masafumi Nomura, Jiro Watari, Takeshi Obara, Yoshimi Shibata, Masayoshi Namiki
    GASTROENTEROLOGICAL ENDOSCOPY 35 2 281  1993年 [査読有り][通常論文]
     
    Aphthoid ulcer, known as an early lesion of Crohn's disease, and lymphoid hyperplasia (LH) of the colon were studied with a magnifying colonoscopy in Crohn's disease patients in terms of their incidence, distribution and changes with enteral nutrition (EN) therapy. With magnifying colonoscopy : FUJINON EVC-HM (Maximum magnification×14, focus 8mm), total colonoscopy was performed in 28 Crohn's patients. The incidence and distribution of aphtha and LH were studied as well as changes of those before and after EN therapy. In addition, 40 serial sections of biopsy specimens were used to detect granuloma/granulomatous lesions. The results were as follows 1. Aphtha and LH were observed in 14 (50.0%) and 12 (44.1%) of 28 Crohn's patients, respectively. 2. On serial sections of specimens biopsied from aphtha and LH, granuloma/granulomatous lesions were histologically revealed in 10 (71.4%) of 14 aphthas and 5 (41.7%) of 12 LH. 3. After EN therapy, aphtha disappeared or decreased in number in 6 (75%) of 8 patients, but LH increased in number or progressed to aphtha in 2 (40%) of 5 patients. These results suggested that aphtha and LH observed by magnifying colonoscopy appear to be early lesions of Crohn's disease, and EN therapy was effective to these lesions and may inhibit progression of Crohn's disease. © 1993, Japan Gastroenterological Endoscopy Society. All rights reserved.
  • T. Ayabe, I. Maekawa, T. Ashida, M. Taruishi, Y. Shibata, M. Namiki
    Japanese Journal of Cancer and Chemotherapy 20 15 2399 - 2403 1993年 [査読有り][通常論文]
     
    A 65-year-old man was admitted because of bleeding from gastric ulcer. A massive deposition of AL lambda type amyloid proteins in the gastric lesion was found. There were a few Bence-Jones (BJ) proteins in the urine, but serum M proteins and bone lesions were not found. Bone marrow puncture showed no dysplastic change of plasma cells. Moreover, there were no amyloid proteins deposited anywhere in the digestive tract examined, except for the stomach, nor were they found in the bone marrow, prostata, liver or kidneys. Gastric amyloidosis was diagnosed. Gastrectomy was performed because of uncontrollable bleeding. Sixteen months later, bone swelling occurred in the sternoclavicular joint and the 3rd rib. At that time, plasma cells with dysplasia and increasing levels of urine BJ protein were revealed. BJ type multiple myeloma was finally diagnosed. For remission induction, cyclo-VAMP chemotherapy was given in 3 courses. Decreased levels of urine BJ protein, diminished bone lesion, normalization of bone marrow and fewer amyloid deposits were seen, and partial response was obtained. The patient is well with no signs of recurrence evident 42 months after treatment. This is an interesting case of initial gastric amyloidosis that developed into BJ type multiple myeloma and was effectively treated with cyclo-VAMP chemotherapy.
  • T. Ayabe, I. Maekawa, T. Ashida, M. Taruishi, Y. Shibata, M. Namiki
    Japanese Journal of Cancer and Chemotherapy 20 10 1391 - 1395 1993年 [査読有り][通常論文]
  • Shinichiroh Kita, Syuh Onodera, Tokiyoshi Ayabe, Toshifumi Ashida, Shigeru Kitamori, Kinichi Yokota, Mikihiro Fujiya, Hiroyuki Saitoh, Kazuo Togashi, Yusuke Saitoh, Masayoshi Namiki
    GASTROENTEROLOGICAL ENDOSCOPY 34 4 846  1992年 [査読有り][通常論文]
     
    A 70-year-old man took an endoscopic examination in our hospital because of epigastric discomfort. A small elevated lesion divided by grooving erosions was found in the lesser curvature of the gastric antrum. In the biopsy specimen taken from this erosion, diffuse infiltration of B-lymphocytes with slight atypia (L26 + and MT1-) was observed. Under the diagnosis of malignant lymphoma, distal partial gastrectomy was performed on May 21, 1990. Lymphoma cells invaded to mucosal and upper submucosal layers within the extent of 0.7×0.5 cm in size without regional lymphonode metastasis. Pathological diagnosis of the lesion was as follows. It showed diffuse lymphoma, medium sized cell, type, B-cells (L26 +, TM1-and UCHL1-). Based on reported cases, characteristic findings of early gastric lymphoma revealed by endoscopy were discussed. The findings of gastric mucosa caused by lymphoma cell infiltration seemed to be “coarse granules surrounded by grooving erosions” (cobble stone appearance), which was also the case with our minute superficial lymphoma. Dye spreading method will usefull to get these findings and contribute to the endoscopic diagnosis of malignant lymphoma of the stomach in the early stage. © 1992, Japan Gastroenterological Endoscopy Society. All rights reserved.
  • Yoshimi Shibata, Tomofumi Ashida, Tokiyoshi Ayabe, Masaki Taruishi, Syuji Okuyama, Masanori Murakami, Yusuke Saitoh, Shigeru Kitamori, Takeshi Obara, Kazumichi Harada, Kiyoshi Okamura, Masayoshi Namiki
    GASTROENTEROLOGICAL ENDOSCOPY 33 6 1122 - 1 1991年 [査読有り][通常論文]
     
    The experimental colitis in rat induced by 2, 4, 6-trinitrobenzenesulfonic acid (TNB) was observed endoscopically. The lesions were induced by a method that was reported by Morris, et al with modifications. Briefly, the rats in experimental group were received intraluminal administration of 25mg TNB in 0.5 ml of 50% ethanol in distal colons. Other rats were administrated same amount of TNB in saline or 50% ethanol as controls. The endoscopic observations were performed with a Olympus BF-3 C 20 once a week for over 6 weeks. As a result, TNB+ethanol induced the ulcerations, erosions, and mucosal edema in the site of administration, those have persisted for over 4 weeks. The rats administrated only 50% ethanol had shallow ulcerative lesions. Those lesions were disappeared within two weeks, and the other rats administrated TNB in saline had no ulcerative lesions. Histological observations revealed that the lesions induced by TNB+ethanol were characterized by infiltration of lymphocytes and the granulomatous lesions in the mucosal and/or the submucosal layers. These findings were thought to have some similarity with lesions of Crohn's disease in human intestine. The mechanisms that TNB+ethanol has made the chronic inflammation in colon are not apparent, but some immunological response are thought to play an important role in this model. Because TNB is a hapten that binds easily to the proteins of cell-surface or intercellular matrix, the defense mechanisms against the altered-self would be employed in the sites of ulcerative lesions. Because of the simple technics to make and to evaluate the chronic inflammations in rats, this experimental system may serve a useful tool to elucidate the pathophysiological nature of inflammatory bowel diseases in human. © 1991, Japan Gastroenterological Endoscopy Society. All rights reserved.

書籍

  • 自然免疫と共生を紐解く小腸オルガノイド enteroid
    医歯薬出版社 2019年
  • 抗菌ペプチドによる自然免疫
    羊土社 2017年
  • 腸上皮のPaneth細胞が担う自然免疫・粘膜免疫
    (担当:単著)
    医歯薬出版社 2015年
  • 消化器病学 基礎と臨床
    西村書店 2013年
  • 微生物学実践問題
    南江堂 2011年
  • 腸内共生系のバイオサイエンス
    丸善出版 2011年
  • 臨床粘膜免疫学
    シナジー 2010年
  • IBD Research Vol.3 No.3
    先端医学社 2009年
  • 炎症・再生医学事典
    朝倉書店 2009年
  • 消化管症候群(第2版)下巻
    日本臨床社 2009年
  • 腸内フローラとクロストーク
    学会出版センター 2008年
  • 消化器と免疫45
    日本消化器免疫学会 2008年

講演・口頭発表等

  • Alpha-defensin異常による腸内細菌叢の破綻とIBD  [招待講演]
    綾部時芳
    第127回日本消化器病学会北海道支部例会 2020年09月 口頭発表(基調)
  • Paneth細胞が担う腸内細菌との共生と生体恒常性  [招待講演]
    綾部時芳
    第57回日本消化器免疫学会 2020年07月 口頭発表(招待・特別)
  • 腸内細菌はなぜ大切か? 自然免疫と腸内細菌から病気を紐解く  [招待講演]
    綾部時芳
    第45回札幌市医師会医学会 2020年02月 口頭発表(招待・特別)
  • Paneth cell in health and disease – an overview from intestinal homeostasis and inter organ network  [招待講演]
    綾部 時芳
    USC-HU Research Workshop “Gut-Organ Crosstalk” 2019年05月 口頭発表(招待・特別)
  • α-defensinによる腸内細菌叢の制御―共生と排除が疾病の鍵を握る  [招待講演]
    綾部 時芳
    第4回京滋腸内細菌研究会 2019年03月 口頭発表(招待・特別)
  • 腸からみた人の健康  [通常講演]
    綾部 時芳
    セルフヘルスケア×ビッグデータで創造する地方創生 2019年02月 口頭発表(基調)
  • 腸内細菌はなぜ注目されるのか? ―腸における排除と共生が疾患の鍵を握る  [招待講演]
    綾部 時芳
    川沿消化器病フォーラム 2018年11月 口頭発表(招待・特別)
  • α-defensinが担う腸内細菌の制御と疾病  [招待講演]
    綾部 時芳
    北海道消化管疾患研究会 2018年07月 口頭発表(招待・特別)
  • 腸はからだの司令塔:なぜ病気になるのか?  [招待講演]
    綾部 時芳
    岩見沢市健康と福祉を高めるセミナー 2017年10月 公開講演,セミナー,チュートリアル,講習,講義等
  • αディフェンシン:自然免疫,腸内細菌との共生,疾病への関与  [招待講演]
    綾部 時芳
    第69回日本生物工学会大会 2017年09月 シンポジウム・ワークショップパネル(指名)
  • 炎症性腸疾患とPaneth細胞:腸内細菌を制御する生体メカニズムの研究から  [招待講演]
    綾部 時芳
    第121回日本消化器病学会北海道支部例会 2017年09月 その他
  • 腸から健康と疾病に迫る―腸内細菌を制御するαディフェンシン―  [通常講演]
    綾部 時芳
    北大-NIMSジョイントシンポジウム 2017年04月 シンポジウム・ワークショップパネル(指名)
  • 腸内細菌を制御する抗菌ペプチドα-defensinと疾病  [招待講演]
    綾部 時芳
    第35回日本耳鼻咽喉科免疫アレルギー学会 2017年04月 公開講演,セミナー,チュートリアル,講習,講義等
  • Enteroidを用いたPaneth細胞の機能解明  [通常講演]
    綾部 時芳
    東京農業大学 先端研究プロジェクト最終年度報告会 2017年01月 その他
  • 腸内細菌を制御する自然免疫αディフェンシンからみた健康と疾病  [招待講演]
    綾部 時芳
    COI「食と健康の達人」拠点 筑波大学サテライト講演会 2016年09月 その他
  • Paneth細胞が担う腸内細菌との共生と疾患  [招待講演]
    綾部 時芳
    第44回日本潰瘍学会 2016年09月 その他
  • Enteroidを用いたPaneth細胞の機能可視化~顆粒分泌・再形成および免疫系クロストーク  [招待講演]
    綾部 時芳, 横井 友樹, 櫻木 直也, 中村 公則
    日本農芸化学会2016年度大会 2016年03月
  • 腸からみれば! 食品と免疫と腸内細菌がつくる“腸内環境”の解明と実用化  [招待講演]
    綾部 時芳, 櫻木 直也, 中村 公則
    日本農芸化学会2016年度大会 2016年03月
  • 腸における排除と共生-抗菌ペプチドと腸内細菌-  [招待講演]
    綾部 時芳
    第5回家畜感染症学会 2015年12月
  • 新しい腸内環境と脳腸相関  [招待講演]
    綾部 時芳
    第2回県西地域未来産業創造シンポジウム~認知症の予防を目指して 2015年08月
  • Paneth細胞と腸内細菌のクロストークからみた疾病  [招待講演]
    綾部 時芳
    第19回腸内細菌学会 2015年06月
  • あなたの知らない腸の世界~食と腸が健康を決める~  [招待講演]
    綾部 時芳
    北海道大学フード&メディカルイノベーション国際拠点開設記念「親子で楽しむ科学体験」 2015年06月
  • “うんち”が語る過去・現在・未来  [通常講演]
    綾部 時芳
    北海道大学フード&メディカルイノベーション国際拠点開設記念 食と腸内環境に関する「市民ワークショップ」 腸から健康になろう! 2015年06月
  • 免疫力を高める食生活とは?  [招待講演]
    綾部 時芳
    第8回これからの健康と栄養を考えるシンポジウム 2015年02月
  • 古くて新しい「腸内細菌と疾病」を腸内環境から考える  [招待講演]
    綾部 時芳
    第25回札幌IBDミニカンファレンス 2015年01月
  • 小腸陰窩における生命機能と疾病  [招待講演]
    綾部 時芳
    日本顕微鏡学会北海道支部講演会 2014年12月
  • 抗菌ペプチドαディフェンシンによる腸内環境の恒常性制御と疾病  [招待講演]
    綾部 時芳, 櫻木 直也, 中村 公則
    第20回日本エンドトキシン・自然免疫研究会 2014年12月
  • αディフェンシンによる腸内環境の制御と疾病 ―炎症性腸疾患、肥満、生活習慣病―  [招待講演]
    綾部 時芳
    北海道大学病院消化器内科学講演会 2014年10月
  • 腸内細菌を制御するαディフェンシンから疾病を眺める  [通常講演]
    綾部 時芳, 櫻木 直也, 中村 公則
    第51回日本消化器免疫学会総会 2014年07月
  • αディフェンシンによる腸内細菌の制御からみた排除と共生  [招待講演]
    綾部 時芳
    日本乳酸菌学会2013年度大会 2013年07月
  • 知らなかった腸の新常識と炎症性腸疾患  [招待講演]
    綾部 時芳
    北海道IBD医療講演会 2013年04月
  • αディフェンシンによる腸内細菌の制御~腸内環境を考える~  [招待講演]
    綾部 時芳
    北海道バイオ産業クラスターフォーラム 研究・技術シーズ公開会 ~“食と体”のサイエンス~ 2012年09月
  • 腸の謎を解くとIBDがきっとわかる  [招待講演]
    綾部 時芳
    第21回腸寿会講演会 2012年09月
  • αディフェンシンによる腸内細菌制御からみた健康と疾病  [招待講演]
    綾部 時芳
    日本食品免疫学会第5回シンポジウム 2012年06月
  • αディフェンシンが解き明かす腸内環境と病気 ― 自然免疫のパラダイムシフト ―  [招待講演]
    綾部 時芳
    高エネルギー加速器研究機構・北海道大学連携シンポジウム 2012年03月
  • Paneth細胞αディフェンシンによる腸内環境制御と炎症性腸疾患  [通常講演]
    綾部 時芳
    第27回IBD Club in Hamamatsu 2012年01月
  • Foods-induced innate immune responses of Paneth cell α-defensin uncover novel functions of foods.  [招待講演]
    Ayabe T, Kuroishi A, Kobayashi M, Nakamura K
    International Society for Nutraceuticals and Functional Foods Annual Conference (ISNFF2011) 2011年11月
  • Selection and regulation of intestinal microbiota by Paneth cell α-defensins.  [招待講演]
    Ayabe T, Nakamura K
    XIII International Union of Microbiological Societies 2011 Congress (IUMS2011) 2011年09月
  • 腸内環境がつくる病気 ― 感染症、炎症性腸疾患から生活習慣病まで ― とその対策  [招待講演]
    綾部 時芳
    札幌市医師会学術講演会 2011年09月
  • Regulation of microbiota by antimicrobial peptides in the gut.  [招待講演]
    Ayabe T, Masuda K, Nakamura K, Sakai N
    7th. International Symposium on Tonsil and Mucosal Barriers of the Upper Airways (ISTMB), Symposium-1 2011年07月
  • Paneth細胞による腸管自然免疫と腸内細菌の抑制  [招待講演]
    綾部 時芳
    京都消化管病態研究会 2011年02月
  • 腸管粘膜免疫とPaneth細胞の抗菌ペプチド、αディフェンシン  [通常講演]
    綾部 時芳
    第44回日本無菌生物ノートバイオロジー学会総会 2011年01月
  • 感染と闘う、頑張っている腸の話  [招待講演]
    綾部 時芳
    地域バイオ育成講座in恵庭「健康を通しての地域活性化」 2010年12月
  • αディフェンシンが解き明かす腸内細菌との共生  [招待講演]
    綾部 時芳
    北海道バイオ工業会 「食品・環境産業セミナー」~腸内細菌の解析と産業利用の展望~ 2010年11月
  • Paneth cells and antimicrobial peptides, α-defensins, in enteric innate immunity.  [招待講演]
    Ayabe T, Masuda K, Nakamura K, Sakai N
    6th. Annual Meeting of Japanese Association for Food Immunology, Symposium-2 2010年06月
  • Regulation of intestinal microbiota by Paneth cell α-defensins.  [招待講演]
    Ayabe T, Masuda K, Nakamura K, Sakai N
    The83rd Annual Meeting of Japanese Society for Bacteriology, International Symposium 2010年03月
  • 抗菌ペプチドによる腸管粘膜免疫の制御  [招待講演]
    綾部 時芳
    第13回バイオ治療法研究会 2009年12月
  • 自然免疫における抗菌ペプチドの役割  [招待講演]
    綾部 時芳
    第9回鎌倉カンファレンス 2009年04月
  • Antimicrobial peptides in the gut innate immunity.  [招待講演]
    Ayabe T, Fukaya R, Sakai N
    The 4th International Yakult Symposium 2007年11月
  • Paneth細胞の抗菌ペプチドによる腸内自然免疫  [招待講演]
    綾部 時芳
    第11回腸内細菌学会 2007年06月
  • Paneth cells and their α-defensin in innate immunity and in the pathology of Crohn’s disease.  [招待講演]
    Ayabe T, Fukaya R, Sakai N, Maemoto A, Tanabe H, Ashida T, Kohgo Y
    4th JSGE-AGA joint meeting on inflammatory bowel disease. 2007年04月
  • 抗菌ペプチドによる腸内自然免疫とその制御機構  [招待講演]
    綾部 時芳
    第15回腸内フローラシンポジウム「腸内フローラとクロストーク」 2006年10月

その他活動・業績

特許

  • パネト細胞群の製造方法、パネト細胞の抗微生物物質の分泌を促進する対象のスクリーニング方法およびパネト細胞からの分泌物の製造方法
    国立大学法人北海道大学  201103050366618393
  • 抗微生物物質産生・分泌促進剤
    国立大学法人北海道大学, 株式会社スリービー  201303081047870680
  • 抗菌性ペプチドの分泌促進剤
    株式会社ファンケル  201503017898988255
  • 腸管線維症処置剤
  • 抗菌性ペプチドの分泌誘導剤

受賞

  • 2012年 日本食品免疫学会学会賞
     
    受賞者: 綾部 時芳
  • 2012年 American Gastroenterological Association Fellow
  • 2006年 第6回旭川医科大学医学部医学科同窓会 医学奨励賞学術奨励賞
  • 2002年 Highest Award of Distinction, American Gastroenterological Association

共同研究・競争的資金等の研究課題

  • Paneth細胞が担う腸内細菌叢制御とその破綻による炎症性腸疾患の新規治療戦略
    日本学術振興会:科学研究費補助金 (基盤研究(B))
    研究期間 : 2018年04月 -2021年03月 
    代表者 : 綾部 時芳
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2011年 -2012年 
    代表者 : 綾部 時芳, 中村 公則
     
    本研究は、腸における排除と共生メカニズムを炎症性腸疾患の理解に重要な鍵を握るPaneth細胞が分泌するαディフェンシンの作用から解析し、炎症性腸疾患の病因・病態解明および新たな治療法を提案することを目的としている。本年度は、抗αディフェンシン抗体を用いてcryptdinのサンドイッチELISA法を構築して、マウス糞便中に分泌されたcryptdinを定量できることを確認した。正常ICRマウス、クローン病モデルSAMP1/YitマウスおよびIL10欠損マウスのPaneth細胞が分泌したcryptdin量を比較して、腸炎発症時のαディフェンシン異常について検討した。また、defensin-sensitive Salmonellaを用いて殺菌活性解析を行って、αディフェンシンの構造活性相関を検討した。さらに、小腸粘膜材料からわれわれの既報の方法(Ayabe T et al., Nature Immunol 2000)でPaneth細胞分泌物を得て、それらの殺菌活性を評価し、ELISAでの定量と比較して解析した。腸内細菌のメタゲノム解析を次世代シーケンサーを用いて腸炎モデルマウスと正常マウスの糞便から、腸内細菌の16s rRNA相同性によるプロファイル解析を行った。これらの検討により、in vivoでのαディフェンシンと腸内細菌叢が深く関連していることが示された。本研究で炎症性腸疾患に...

教育活動情報

主要な担当授業

  • 生命科学特別研究
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 生命科学院
  • 細胞機能科学特論
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : 生命現象、細胞情報伝達、シグナル分子、免疫、炎症、感染、癌、医学、創薬、医療
  • 生命科学文献講読
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 生命科学院
  • 大学院共通授業科目(一般科目):複合領域
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 大学院共通科目
    キーワード : 生命融合科学、生命情報分子科学、生命物質科学、細胞機能科学、生命機能制御科学、ソフトマター科学、ソフトマター材料科学、ソフトマター生命分子科学、ソフトマター生体物理学、ソフトマター医科学、SDGs
  • 海外研究インターンシップ
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 生命科学院
  • 生命融合科学概論
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : 生命融合科学、生命情報分子科学、生命物質科学、細胞機能科学、生命機能制御科学、ソフトマター科学、ソフトマター材料科学、ソフトマター生命分子科学、ソフトマター生体物理学、ソフトマター医科学、SDGs、
  • 生命科学研究
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
  • 食と健康特論演習
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 国際食資源学院
    キーワード : 健康,食,栄養学,環境,人類生態学,人間栄養学,脂質,酸化,糖鎖生物学,蛋白質,腸内環境,機能性食品
  • 生命科学実習
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
  • ソフトマター科学概論
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : ソフトマター科学、ソフトマター材料科学、ソフトマター生命分子科学、ソフトマター生体物理学、ソフトマター医科学、生命融合科学、生命情報分子科学、生命物質科学、細胞機能科学、生命機能制御科学、SDGs
  • 生命科学論文講読Ⅰ
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
  • 博士海外研究
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 生命科学院
    キーワード : 英語力、海外渡航、コミュニケーション、プレゼンテーション能力、異分野交流
  • 生命科学論文講読Ⅱ
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 生命科学院
  • 研究提案演習
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 生命科学院
    キーワード : 生命科学研究、ソフトマター科学研究、研究企画、提案書、大学教員、企業研究者
  • 細胞情報科学Ⅱ
    開講年度 : 2019年
    課程区分 : 学士課程
    開講学部 : 理学部
    キーワード : 微生物、感染、免疫、自然免疫、獲得免疫、粘膜免疫、貪食細胞、上皮細胞、補体、微生物認識受容体、抗菌ペプチド、抗原提示、リンパ球、T細胞、胸腺、B細胞、抗体、サイトカイン、がん、がん遺伝子、がん抑制遺伝子、分子標的治療

大学運営

委員歴

  • 2016年 - 現在   北海道IBD検討会   幹事
  • 2013年 - 現在   フード特区機構   アドバイザリーボード
  • 2013年 - 現在   北海道食品機能性表示制度懇談会   座長
  • 2011年 - 現在   代用臓器・再生医学研究会   常任世話人
  • 2008年 - 現在   札幌IBDフォーラム   幹事
  • 2008年 - 現在   公益財団法人 腸内細菌学会   編集委員会アドバイザー   日本腸内細菌学会
  • 2007年 - 現在   公益財団法人 腸内細菌学会   評議員   日本腸内細菌学会
  • 2006年 - 現在   日本食品免疫学会   研究委員会委員   日本食品免疫学会
  • 2002年 - 現在   日本消化器病学会   学会評議員
  • 2001年 - 現在   日本消化器内視鏡学会   学術評議員   日本消化器内視鏡学会

社会貢献活動

  • 母子の健康・腸内の環境
    期間 : 2020年02月14日 - 2020年02月14日
    役割 : 講師
    主催者・発行元 : 北海道大学/日立北大ラボ
    イベント・番組・新聞雑誌名 : Society 5.0北海道の地方創生と未来
  • 腸から健康になる話-腸内環境を整えて元気でいよう
    期間 : 2019年10月16日 - 2019年10月16日
    役割 : 講師
    主催者・発行元 : 幌向地域ふれあい協議会
    イベント・番組・新聞雑誌名 : 幌向地域ふれあい健康講座
  • 腸内環境が拓く健康と疾病のパラダイムシフト
    期間 : 2018年01月15日 - 2018年01月15日
    役割 : 講師
    主催者・発行元 : 電子情報技術産業協会
    イベント・番組・新聞雑誌名 : ヒューマンケア技術分科会講演会
  • 腸はからだの司令塔:なぜ病気になるのか?
    期間 : 2017年10月06日 - 2017年10月06日
    役割 : 講師
    主催者・発行元 : 岩見沢市 健康と福祉を高める市民会議
    イベント・番組・新聞雑誌名 : 岩見沢市健康と福祉を高めるセミナー
  • 腸内細菌が健康と病気を決める
    期間 : 2017年09月26日 - 2017年09月26日
    役割 : 講師
    主催者・発行元 : 岩見沢市光陵中学校地区町内会
    イベント・番組・新聞雑誌名 : 保健推進講演会
  • 腸の様々なはたらきについて―腸からみた健康と疾病―
    期間 : 2017年09月19日 - 2017年09月19日
    役割 : 講師
    主催者・発行元 : ヘルスイノベーションカレッジ
    イベント・番組・新聞雑誌名 : ネットワーク勉強会
  • 食と健康のサイエンスを知ろう
    期間 : 2017年07月07日 - 2017年07月07日
    役割 : 講師
    主催者・発行元 : 札幌市カルチャーナイト
    イベント・番組・新聞雑誌名 : カルチャーナイト15周年記念 札幌の文化再発見シリーズIII
  • 腸から健康になろう!“うんち”が語る過去・現在・未来
    期間 : 2016年05月20日 - 2016年05月20日
    役割 : 講師
    主催者・発行元 : 岩見沢市保健推進会
    イベント・番組・新聞雑誌名 : 岩見沢市保健推進会総会研修会

学術貢献活動

  • 第24回腸内細菌学会学術集会会長
    期間 : 2020年06月11日 - 2020年06月12日
    役割 : 企画立案・運営等
    種別 : 学会・研究会等
    主催者・責任者 : 公益財団法人腸内細菌学会


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