The effects of Dysbiosis on intestinal stem cells, inflammation, and cancer

• Project/Area Number: 17K09347
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Shimpoh Takayuki 東京大学, 医学部附属病院, 登録研究員 (90791591)
• Co-Investigator(Kenkyū-buntansha): 早河 翼 東京大学, 医学部附属病院, 助教 (60777655)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 炎症性腸疾患 / Dysbiosis / Notch / 消化管幹細胞 / E-cadherin / 樹状細胞 / Notch経路 / 腸炎 / 大腸癌 / 幹細胞 / 内科 / 細菌 / 細胞・組織 / トランスレーショナルリサーチ / 免疫学

Outline of Final Research Achievements

We tested the positivity of E.coli with pks island sequence, and found that pks+ E.coli is increased in colorectal cancer patients, but decreased in IBD patients, compared to healthy control.
We demonstrated that Tgfbr2-deficient dendritic cells have elevated expression of E-cadherin, and these DCs can directly bind to intestinal epithelial cells and activate Notch signaling, which contribute to the pathogenesis of colitis.
Notch activation in intestinal secretory progenitors lead to dedifferentiation into stem-like cells, and dedifferentiated progenitors can act as a tumor-initiating cells in the mouse intestine.

Academic Significance and Societal Importance of the Research Achievements

E.coli中に含まれるpks island遺伝子の有無を大腸洗浄液中から非侵襲的に検出する方法を確立した。
樹状細胞と上皮の相互作用をIn vitroでモニタリング可能な樹状細胞と上皮オルガノイドの共培養系を構築した。
今回マウスモデルと臨床サンプルで同定した樹状細胞と上皮Notch経路、およびDysbiosisとの関連機構は、ヒトIBDの病態を理解する上で重要な知見であると考えられる。

Research Products

• [Journal Article] GRP30-expressing gastric chief cells do not differentiate but are eliminated via PDK-dependent cell competition during development of metaplasia. (2020)
  • Author(s): 1.Hata M, Kinoshita H, Hayakawa Y, Konishi M, Tsuboi M, Oya Y, Hayata Y, Nakagawa H, Tateishi K, Fujiwara H, Hirata Y, Worthley DL, Muranishi Y, Furukawa T, Kon S, Tomita H, Wang TC, Koike K.
  • Journal Title: Gastroenterology Volume: 158 Issue: 6 Pages: 1650-1666
  • DOI: 10.1053/j.gastro.2020.01.046
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche (2020)
  • Author(s): Middelhoff Moritz、Nienheiser Henrik、Valenti Giovanni、Maurer H. Carlo、Hayakawa Yoku、Takahashi Ryota、Kim Woosook、Jiang Zhengyu、Malagola Ermanno、Cuti Krystle、Tailor Yagnesh、Zamechek Leah B.、Renz Bernhard W.、Quante Michael、Yan Kelley S.、Wang Timothy C.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 111-111
  • DOI: 10.1038/s41467-019-13850-7
  • Peer Reviewed / Open Access
• [Journal Article] Role of Muscarinic Acetylcholine Signaling in Gastrointestinal Cancers (2019)
  • Author(s): Konishi Mitsuru、Hayakawa Yoku、Koike Kazuhiko
  • Journal Title: Biomedicines Volume: 7 Issue: 3 Pages: 58-58
  • DOI: 10.3390/biomedicines7030058
  • Peer Reviewed / Open Access
• [Journal Article] BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice (2019)
  • Author(s): Hayakawa Yoku、Tsuboi Mayo、Asfaha Samuel、Kinoshita Hiroto、Niikura Ryota、Konishi Mitsuru、Hata Masahiro、Oya Yukiko、,,,Koike Kazuhiko、Wang Timothy C.
  • Journal Title: Gastroenterology Volume: 156 Issue: 4 Pages: 1066-1081.e16
  • DOI: 10.1053/j.gastro.2018.11.024
  • Peer Reviewed
• [Journal Article] Alpha-Blockers As Colorectal Cancer Chemopreventive: Findings from a Case?Control Study, Human Cell Cultures, and In Vivo Preclinical Testing (2019)
  • Author(s): Suzuki Nobumi、Niikura Ryota、Ihara Sozaburo、Hikiba Yohko、Kinoshita Hiroto、Higashishima Naoko、Hayakawa Yoku、Yamada Atsuo、Hirata Yoshihiro、Nakata Ryo、Okamoto Makoto、Sano Munetaka、Kushiyama Akifumi、Ichinose Mari、Woods Susan L.、Worthley Daniel、Iwamoto Yasuhiko、Koike Kazuhiko
  • Journal Title: Cancer Prevention Research Volume: 12 Issue: 3 Pages: 185-194
  • DOI: 10.1158/1940-6207.capr-18-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease (2018)
  • Author(s): Ihara Sozaburo、Hirata Yoshihiro、Hikiba Yohko、Yamashita Aya、Tsuboi Mayo、Hata Masahiro、Konishi Mitsuru、Suzuki Nobumi、Sakitani Kosuke、Kinoshita Hiroto、Hayakawa Yoku、Nakagawa Hayato、Ijichi Hideaki、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: Journal of Crohn's and Colitis Volume: 12 Pages: 1219-1231
  • DOI: 10.1093/ecco-jcc/jjy088
  • Peer Reviewed
• [Journal Article] The Tuft Cell-ILC2 Circuit Integrates Intestinal Defense and Homeostasis (2018)
  • Author(s): Hayakawa Yoku、Wang Timothy C.
  • Journal Title: Cell Volume: 174 Issue: 2 Pages: 251-253
  • DOI: 10.1016/j.cell.2018.06.037
  • Peer Reviewed
• [Journal Article] Prevalence of pks-positive Escherichia coli in Japanese patients with or without colorectal cancer. (2017)
  • Author(s): Shimpoh T, Hirata Y, Ihara S, Suzuki N, Kinoshita H, Hayakawa Y, Ota Y, Narita A, Yoshida S, Yamada A, Koike K.
  • Journal Title: Gut Pathog Volume: Jun 12;9 Issue: 1 Pages: 35-35
  • DOI: 10.1186/s13099-017-0185-x
  • Peer Reviewed
• [Presentation] MIST1+ SECRETORY PROGENITOR CELLS CAN GIVE RISE TO CANCER IN THE INTESTINE AND COLON. (2018)
  • Author(s): HAYAKAWA YOKU
  • Organizer: Digestive Disease Week 2018
  • Int'l Joint Research