Screening for gut microbiota-derived metabolites that stimulate intestinal stem cells

2016 Fiscal Year Annual Research Report

• Project/Area Number: 16K15422
• Research Institution: The University of Tokyo
• Principal Investigator: 藤城 光弘 東京大学, 医学部附属病院, 准教授 (70396745)
• Co-Investigator(Kenkyū-buntansha): 池田 祐一 東京大学, 医学部附属病院, 特任准教授 (10744419) ; 熊谷 英敏 東京大学, 医学部附属病院, 特任助教 (20281008) ; 山下 裕玄 東京大学, 医学部附属病院, 講師 (50599397) ; 森田 啓行 東京大学, 医学部附属病院, 講師 (60323573) ; 浅岡 良成 東京大学, 医学部附属病院, 助教 (90431858)
• Project Period (FY): 2016-04-01 – 2017-03-31
• Keywords: Wntシグナル / 腸管幹細胞 / 常在性腸内細菌叢 / 生理活性代謝産物

Outline of Annual Research Achievements

LGR5とZNRF3/RNF43（Wnt受容体を基質とする細胞膜型E3 ligase）は細胞膜上で複合体を形成し、その複合体が Wntシグナル増強作用を有する分泌蛋白質R-spondinの受容体として機能する。LGR5が腸管幹細胞マーカーであることから、R-spondin-LGR4/5/6-ZNRF3/RNF43系は腸管幹細胞において重要な働きをしていると推察される。申請者らは、このR-spondin-LGR4/5/6-ZNRF3/RNF43系を直接的に制御する物質のスクリーニングを可能にする独自のアッセイ系を樹立し、R-spondin-LGR4/5/6-ZNRF3/RNF43系の制御を介してWntシグナルを増強する物質を健常者腸内細菌叢由来代謝産物より探索することを計画した。
スクリーニングの出発試料である健常者由来大腸内視鏡排液の収集準備を適宜すすめると同時に、パイロット実験として本学薬学部創薬機構所有の低分子化合物コアライブラリー（約一万種類の代表的な化合物群よりなる）をスクリーニングしたところ、R-spondinの作用を増強する興味深い化合物を2つ同定できた。この結果は、独自に樹立したアッセイ系が生理活性物質探索に耐えうる優れたスクリーニングシステムであることを示唆している。また併行して慶応大学薬学部長谷研究室との共同研究において、無菌マウス、SPFマウス、SPFマウスの糞便を移植された無菌マウス（糞便移植から3日後、6日後、9日後、16日後、23日後にサンプル採取）の盲腸内容物をメタボロミクス解析したところ、常在性腸内細菌叢依存的なメタボライトを54種類同定することにも成功した。今後は健常者由来大腸内視鏡排液から抽出した低分子画分のみならずこれら同定されたメタボライトの生理活性も本アッセイ系を用いて検定していく予定である。

Research Products

• [Journal Article] Guidelines for endoscopic managements of non-variceal upper gastrointestinal bleeding. (2016)
  • Author(s): Fujishiro M, Iguchi M, Kakushima N, Kato M, Sakata Y, Hoteya S, Kataoka M, Shimaoka S, Yahagi N, Fujimoto K.
  • Journal Title: Dig Endosc. Volume: 28 Pages: 363-378
  • DOI: 10.1111/den.12639.
  • Peer Reviewed / Open Access
• [Journal Article] Re-bleeding After Endoscopic Hemostasis for Peptic Ulcer Bleeding: Is eNough SAID or Are Other Factors Important? (2016)
  • Author(s): Fujishiro M, Ikeda Y.
  • Journal Title: Dig Dis Sci. Volume: 61 Pages: 1424-1425
  • DOI: 10.1007/s10620-016-4098-1
  • Peer Reviewed
• [Journal Article] Successful closure of a large perforation during colorectal endoscopic submucosal dissection by application of polyglycolic acid sheets and fibrin glue. (2016)
  • Author(s): Sakaguchi Y, Tsuji Y, Yamamichi N, Fujishiro M, Koike K.
  • Journal Title: Gastrointest Endos. Volume: 84 Pages: 374-375
  • DOI: 10.1016/j.gie.2016.03.787.
  • Peer Reviewed
• [Journal Article] Registration Committee for Esophageal Cancer of the Japan Esophageal Society. Comprehensive Registry of Esophageal Cancer in Japan, 2009. (2016)
  • Author(s): Tachimori Y, Ozawa S, Numasaki H, Fujishiro M, Matsubara H, Oyama T, Shinoda M, Toh Y, Udagawa H, Uno T
  • Journal Title: Esophagus. Volume: 13 Pages: 110-137
  • DOI: 10.1007/s10388-016-0531-y.
  • Peer Reviewed / Open Access
• [Journal Article] Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens. (2016)
  • Author(s): Matsusaka K, Ishikawa S, Nakayama A, Ushiku T, Nishimoto A, Urabe M, Kaneko N, Kunita A, Kaneda A, Aburatani H, Fujishiro M, Seto Y, Fukayama M.
  • Journal Title: PLoS One. Volume: 11 Pages: e0154430
  • DOI: 10.1371/journal.pone.0154430.
  • Peer Reviewed / Open Access
• [Journal Article] Triamcinolone Injection and Shielding with Polyglycolic Acid Sheets and Fibrin Glue for Postoperative Stricture Prevention after Esophageal Endoscopic Resection: A Pilot Study. (2016)
  • Author(s): Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y, Takeuchi C, Yakabi S, Saito I, Shichijo S, Minatsuki C, Asada-Hirayama I, Yamaguchi D, Niimi K, Ono S, Kodashima S, Yamamichi N, Koike K.
  • Journal Title: Am J Gastroenterol. Volume: 111 Pages: 581-583
  • DOI: 10.1038/ajg.2016.60.
  • Peer Reviewed
• [Journal Article] Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV. (2016)
  • Author(s): Onoyama H, Kamiya M, Kuriki Y, Komatsu T, Abe H, Tsuji Y, Yagi K, Yamagata Y, Aikou S, Nishida M, Mori K, Yamashita H, Fujishiro M, Nomura S, Shimizu N, Fukayama M, Koike K, Urano Y, Seto Y.
  • Journal Title: Sci Rep. Volume: 6 Pages: 26399
  • DOI: 10.1038/srep26399.
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic ultrasound-guided fine-needle aspiration skill acquisition of gastrointestinal submucosal tumor by trainee endoscopists: A pilot study. (2016)
  • Author(s): Niimi K, Goto O, Kawakubo K, Nakai Y, Minatsuki C, Asada-Hirayama I, Mochizuki S, Ono S, Kodashima S, Yamamichi N, Isayama H, Fujishiro M, Koike K.
  • Journal Title: Endosc Ultrasound. Volume: 5 Pages: 157-164
  • DOI: 10.4103/2303-9027.183970.
  • Peer Reviewed
• [Journal Article] Bleeding after endoscopic submucosal dissection: Risk factors and preventive methods. (2016)
  • Author(s): Kataoka Y, Tsuji Y, Sakaguchi Y, Minatsuki C, Asada-Hirayama I, Niimi K, Ono S, Kodashima S, Yamamichi N, Fujishiro M, Koike K
  • Journal Title: World J Gastroenterol. Volume: 22 Pages: 5927-5935
  • DOI: 10.3748/wjg.v22.i26.5927.
  • Peer Reviewed / Open Access
• [Journal Article] Congress report: Exchange of opinions in Tokyo, 2016 between Japan Gastroenterological Endoscopy Society (JGES) and counterparts from abroad. (2016)
  • Author(s): Fujishiro M, Yasuda I.
  • Journal Title: Dig Endosc. Volume: 28 Pages: 642-644
  • DOI: 10.1111/den.12703.
  • Peer Reviewed
• [Journal Article] Current Practices in the Management of Antithrombotic Therapy During the Periendoscopic Period for Patients With Cardiovascular Disease. (2016)
  • Author(s): Ono S, Saito I, Ikeda Y, Fujishiro M, Komuro I, Koike K.
  • Journal Title: Int Heart J. Volume: 57 Pages: 530-534
  • DOI: 10.1536/ihj.16-057.
  • Peer Reviewed / Open Access
• [Journal Article] Updated evidence on endoscopic resection of early gastric cancer from Japan. (2016)
  • Author(s): Fujishiro M, Yoshida S, Matsuda R, Narita A, Yamashita H, Seto Y.
  • Journal Title: Gastric Cancer. Volume: 20 Pages: 39-44.
  • DOI: 10.1007/s10120-016-0647-8.
  • Peer Reviewed
• [Journal Article] Safety and effectiveness of endovenous laser ablation combined with ligation for severe saphenous varicose veins in Japanese patients. (2016)
  • Author(s): Izumi M, Ikeda Y, Yamashita H, Asaoka Y, Fujishiro M, Shin M, Abo Y
  • Journal Title: Int Heart J. Volume: 57 Pages: 87-90
  • DOI: 10.1536/ihj.15-282.
  • Peer Reviewed / Open Access
• [Journal Article] Cacao polyphenols ameliorate autoimmune myocarditis in mice. (2016)
  • Author(s): Zempo H, Suzuki J, Watanabe R, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M
  • Journal Title: Hypertens Res. Volume: 39 Pages: 203-209
  • DOI: 10.1038/hr.2015.136.
  • Peer Reviewed
• [Journal Article] Angiotensin II receptor blocker irbesartan attenuates cardiac dysfunction induced by myocardial infarction in the presence of renal failure. (2016)
  • Author(s): Watanabe R, Suzuki J, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M
  • Journal Title: Hypertens Res. Volume: 39 Pages: 237-244
  • DOI: 10.1038/hr.2015.141.
  • Peer Reviewed
• [Journal Article] Toll-like receptor 4 signaling plays a critical role in Porphyromonas gingivalis accelerated neointimal formation after arterial injury in mice. (2016)
  • Author(s): Kobayashi N, Suzuki J, Aoyama N, Sato H, Akimoto S, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Izumi Y, Isobe M
  • Journal Title: Hypertens Res. Volume: 39 Pages: 717-722
  • DOI: 10.1038/hr.2016.58.
  • Peer Reviewed
• [Journal Article] Porphyromonas gingivalis, a periodontal pathogen, enhances myocardial vulnerability, thereby promoting post-infarct cardiac rupture. (2016)
  • Author(s): Shiheido Y, Maejima Y, Suzuki JI, Aoyama N, Kaneko M, Watanabe R, Sakamaki Y, Wakayama K, Ikeda Y, Akazawa H, Ichinose S, Komuro I, Izumi Y, Isobe M
  • Journal Title: J Mol Cell Cardiol. Volume: 99 Pages: 123-137
  • DOI: 10.1016/j.yjmcc.2016.03.017.
  • Peer Reviewed
• [Journal Article] Periodontitis may deteriorate sinus of valsalva dilatation in marfan syndrome patients. (2016)
  • Author(s): Suzuki J, Imai Y, Aoki M, Fujita D, Takeda N, Aoyama N, Wakayama K, Ikeda Y, Kumagai H, Akazawa H, Izumi Y, Isobe M, Komuro I, Hirata Y
  • Journal Title: Int Heart J. Volume: 57 Pages: 456-460
  • DOI: 10.1536/ihj.15-395.
  • Peer Reviewed / Open Access
• [Journal Article] Current therapies and investigational drugs for peripheral arterial disease. (2016)
  • Author(s): Suzuki J, Shimamura M, Suda H, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Isobe M, Komuro I, Morishita R
  • Journal Title: Hypertens Res. Volume: 39 Pages: 183-191
  • DOI: 10.1038/hr.2015.134.
  • Peer Reviewed
• [Journal Article] Understanding vascular diseases: Lessons from premature aging syndromes. (2016)
  • Author(s): Ikeda Y, Kumagai H, Motozawa Y, Suzuki J, Akazawa H, Komuro I
  • Journal Title: Can J Cardiol. Volume: 32 Pages: 650-658
  • DOI: 10.1016/j.cjca.2015.12.003.
  • Peer Reviewed
• [Journal Article] Periodontitis and myocardial hypertrophy. (2016)
  • Author(s): Suzuki J, Sato H, Kaneko M, Yoshida A, Aoyama N, Akimoto S, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Izumi Y, Isobe M, Komuro I
  • Journal Title: Hypertens Res. Volume: 40 Pages: 324-328
  • DOI: 10.1038/hr.2016.146.
  • Peer Reviewed
• [Journal Article] Growth differentiation factor 15 (GDF15) as a reliable biomarker for cardiovascular risk assessment. (2016)
  • Author(s): Ikeda Y, Kumagai H, Motozawa Y, Suzuki J
  • Journal Title: Int Heart J. Volume: 57 Pages: 1-2
  • DOI: 10.1536/ihj.15-324.
  • Peer Reviewed / Open Access
• [Journal Article] Early endoscopic management for early bowel obstruction after gastrectomy: a case report. (2016)
  • Author(s): Higashizono K, Aikou S, Yagi K, Mori K, Yamashita H, Nomura S, Seto Y.
  • Journal Title: Surg Case Rep. Volume: 2 Pages: 35
  • DOI: 10.1186/s40792-016-0164-3.
  • Peer Reviewed
• [Journal Article] Low density of CD204-positive M2 type tumor-associated macrophages in Epstein-Barr virus-associated gastric cancer: a clinicopathological study with digital image analysis. (2016)
  • Author(s): Ichimura T, Abe H, Morikawa T, Yamashita H, Ishikawa S, Ushiku T, Seto Y, Fukayama M.
  • Journal Title: Hum Pathol. Volume: 56 Pages: 74-80
  • DOI: 10.1016/j.humpath.
  • Peer Reviewed
• [Journal Article] Radical esophagectomy for a 92-year-old woman with granulocyte colony-stimulating factor-producing esophageal squamous cell carcinoma: a case report. (2016)
  • Author(s): Kitani M, Yamagata Y, Tanabe A, Yagi K, Aikou S, Kiyokawa T, Nishida M, Yamashita H, Mori K, Nomura S, Seto Y.
  • Journal Title: World J Surg Oncol. Volume: 14 Pages: 264
  • DOI: 10.1186/s12957-016-1023-1
  • Peer Reviewed / Open Access
• [Journal Article] Utility of cystatin C for estimating glomerular filtration rate in patients with muscular dystrophy: A good agreement with inulin clearance. (2016)
  • Author(s): Kimura K, Morita H, Daimon M, Horio M, Kawata T, Nakao T, Hirokawa M, Kitao R, Watanabe D, Komori T, Nagata T, Takeda S, Komaki H, Segawa K, Nakajima T, Takenaka K, Komuro I.
  • Journal Title: Int Heart J. Volume: 57 Pages: 386-388
  • DOI: 10.1536/ihj.15-461.
  • Peer Reviewed / Open Access
• [Journal Article] Fukutin gene mutations that cause left ventricular noncompaction. (2016)
  • Author(s): Amiya E, Morita H, Hatano M, Nitta D, Hosoya Y, Maki H, Motozawa Y, Sato N, Ishiura H, Numakura S. Shintani Y, Kinugawa K, Takeda N, Shimizu J, Tsuji S, Komuro I.
  • Journal Title: Int J Cardiol. Volume: 222 Pages: 727-729
  • DOI: 10.1016/j.ijcard.2016.08.011.
  • Peer Reviewed
• [Journal Article] Heart failure complicated by alveolar hemorrhage due to vascular collapse and amyloid deposits in wild-type transthyretin amyloidosis. (2016)
  • Author(s): Kido Y, Takahashi M, Fukuma N, Kawata T, Tanaka A, Hayashi A, Shibahara J, Daimon M, Morita H, Akazawa H, Komuro I.
  • Journal Title: Cardiology Volume: 135 Pages: 216-220
  • DOI: 10.1159/000446513
  • Peer Reviewed
• [Journal Article] Therapeutic strategy for heart failure in Becker muscular dystrophy. (2016)
  • Author(s): Kimura K, Morita H, Nakamura A, Takenaka K, Daimon M.
  • Journal Title: Int Heart J. Volume: 57 Pages: 527-529
  • DOI: 10.1536/ihj.16-311.
  • Peer Reviewed / Open Access
• [Journal Article] A strategy for genomic research on common cardiovascular diseases aiming at the realization of precision medicine; Personal insights and perspectives. (2016)
  • Author(s): Morita H, Komuro I.
  • Journal Title: Circ Res. Volume: 119 Pages: 900-903
  • DOI: 10.1161/CIRCRESAHA.116.309802.
  • Peer Reviewed
• [Journal Article] Neuromuscular electrical stimulation in patients with acute myocardial infarction. (2016)
  • Author(s): Nakao T, Morita H.
  • Journal Title: Int Heart J. Volume: 57 Pages: 659-660
  • DOI: 10.1536/ihj.16-498
  • Peer Reviewed / Open Access
• [Journal Article] Impact of oral treatment on physical function in older patients hospitalized for heart failure: A randomized clinical trial. (2016)
  • Author(s): Ueda K, Kasao M, Shimamura M, Haruta H, Nitta S, Kaneko M, Uemura Y, Morita H, Komuro I, Shirai T.
  • Journal Title: PLoS ONE Volume: 11 Pages: e0167933
  • DOI: 10.1371/journal.pone.0167933.
  • Open Access
• [Journal Article] The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. (2016)
  • Author(s): Minami T, Tateishi R, Nakagomi R, Fujiwara N, Sato M, Enooku K, Nakagawa H, Asaoka Y, Kondo Y, Shiina S, Koike K
  • Journal Title: J Hepatol. Volume: 65 Pages: 1272-1273
  • DOI: 10.1016/j.jhep.2016.07.043.
  • Peer Reviewed
• [Journal Article] A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. (2016)
  • Author(s): Ikenoue T, Terakado Y, Nakagawa H, Hikiba Y, Fujii T, Matsubara D, Noguchi R, Zhu C, Yamamoto K, Kudo Y, Asaoka Y, Yamaguchi K, Ijichi H, Tateishi K, Fukushima N, Maeda S, Koike K, Furukawa Y.
  • Journal Title: Sci Rep. Volume: 6 Pages: 23899
  • DOI: 10.1038/srep23899.
  • Peer Reviewed / Open Access