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

• Project/Area Number: 16K15422
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Fujishiro Mitsuhiro 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
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• 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 / 内科 / 消化器内科 / 下部消化管 / 再生医学 / 生理活性

Outline of Final Research Achievements

This study is being conducted to identify gut microbiota-derived metabolites that stimulate intestinal stem cells. Utilizing a novel assay system targeting R-spondin-LGR4/5/6-ZNRF3/RNF43 axis, we first screened a small-molecule compound library and identified 2 unique compounds that enhance R-spondin activities. This proof-of-concept experiment suggests that this newly established assay is well suited for biochemical purification of bioactive metabolites from crude microbiota-derived extracts. We also conducted comprehensive metabolomic analysis and identified 54 metabolites from fecal extracts of germ-free mice that had received fecal microbiota transplantation (FMT). The biological activities of these metabolites are currently being examined.

Research Products

• [Journal Article] Periodontitis and myocardial hypertrophy (2017)
  • Author(s): Suzuki J, Sato H, Kaneko M, Yoshida A, Aoyama N, Akimoto S, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, IzumiY, Isobe M, Komuro I
  • Journal Title: Hypertens Res Volume: [Epub ahead of print] Issue: 4 Pages: 324-328
  • DOI: 10.1038/hr.2016.146
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Issue: 4 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 Issue: 6 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 Issue: 2 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 Issue: 2 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 Issue: 4 Pages: e0154430-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 Issue: 4 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 Issue: 1 Pages: 26399-26399
  • 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 Issue: 3 Pages: 157-164
  • DOI: 10.4103/2303-9027.183970
  • Peer Reviewed / Open Access
• [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 Issue: 26 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 Issue: 6 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: International Heart Journal Volume: 57 Issue: 5 Pages: 530-534
  • DOI: 10.1536/ihj.16-057
  • NAID: 130005266608
  • ISSN: 1349-2365, 1349-3299
  • 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 Issue: S1 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: International Heart Journal Volume: 57 Issue: 1 Pages: 87-90
  • DOI: 10.1536/ihj.15-282
  • NAID: 130005120984
  • ISSN: 1349-2365, 1349-3299
  • 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 Issue: 4 Pages: 203-209
  • DOI: 10.1038/hr.2015.136
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 4 Pages: 237-244
  • DOI: 10.1038/hr.2015.141
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Toll-like receptor 4 signaling has a critical role in Porphyromonas gingivalis-accelerated neointimal formation after arterial injury in mice. (2016)
  • Author(s): Kobayashi N, Suzuki JI, 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 Issue: 10 Pages: 717-722
  • DOI: 10.1038/hr.2016.58
  • Peer Reviewed
• [Journal Article] Projections from single NUCB2/nesfatin-1 neuron in paraventricular nucleus to different brain regions involved in feeding (2016)
  • Author(s): Maejima Y, Kumamoto K, Takenoshita S, Shimomura K
  • Journal Title: Ｂｒａｉｎ Ｓｔｒｕｃｔｕｒｅ ａｎｄ Ｆｕｎｃｔｉｏｎ Volume: ｉｎ ｐｒｅｓｓ Pages: 123-137
  • DOI: 10.1016/j.yjmcc.2016.03.017
  • Peer Reviewed / Acknowledgement Compliant
• [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: International Heart Journal Volume: 57 Issue: 4 Pages: 456-460
  • DOI: 10.1536/ihj.15-395
  • NAID: 130006895913
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Issue: 4 Pages: 183-191
  • DOI: 10.1038/hr.2015.134
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 5 Pages: 1-9
  • DOI: 10.1016/j.cjca.2015.12.003
  • Peer Reviewed
• [Journal Article] Growth Differentiation Factor 15 (GDF15) as a Reliable Biomarker for Cardiovascular Risk Assessment (2016)
  • Author(s): Ikeda Y1, Kumagai H, Motozawa Y, Suzuki J
  • Journal Title: International Heart Journal Volume: 57 Issue: 1 Pages: 1-2
  • DOI: 10.1536/ihj.15-324
  • NAID: 130005120988
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Early endoscopic management for early bowel obstruction after gastrectomy: a case report (2016)
  • Author(s): K. Higashizono, S. Aikou, K. Yagi, K. Mori, H. Yamashita, S. Nomura, Y. Seto
  • Journal Title: Surg Case Rep Volume: 2 Issue: 1 Pages: 35-35
  • DOI: 10.1186/s40792-016-0164-3
  • Peer Reviewed / Open Access
• [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
  • 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 Issue: 1 Pages: 264-264
  • 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 (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: International Heart Journal Volume: 57 Issue: 3 Pages: 386-388
  • DOI: 10.1536/ihj.15-461
  • NAID: 130005153700
  • ISSN: 1349-2365, 1349-3299
  • 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: International Journal of Cardiology 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 Issue: 4 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: International Heart Journal Volume: 57 Issue: 5 Pages: 527-529
  • DOI: 10.1536/ihj.16-311
  • NAID: 130005266584
  • ISSN: 1349-2365, 1349-3299
  • 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: Circulation Research Volume: 119 Issue: 8 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: International Heart Journal Volume: 57 Issue: 6 Pages: 659-660
  • DOI: 10.1536/ihj.16-498
  • NAID: 130005172026
  • ISSN: 1349-2365, 1349-3299
  • 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 Issue: 12 Pages: e0167933-e0167933
  • DOI: 10.1371/journal.pone.0167933
  • Peer Reviewed / 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 Issue: 6 Pages: 1272-1273
  • DOI: 10.1016/j.jhep.2016.07.043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: 印刷中 Issue: 1 Pages: 23899-23899
  • DOI: 10.1038/srep23899
  • Peer Reviewed / Open Access / Int'l Joint Research