Suppression of radiation-induced gastrointestinal disorders through the regulation of intestinal flora by the tumor suppressor p53

• Project/Area Number: 19K22525
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: TANIKAWA CHIZU 東京大学, 医科学研究所, 助教 (30422421)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: p53 / 腸内細菌叢 / 消化管障害 / microbiome

Outline of Research at the Start

p53はヒトがんの約半数で変異が生じる最も重要ながん抑制遺伝子である。p53ノックアウトマウスは放射線照射に対して重症の腸管症候群を示すことが知られているが、その機序はこれまで不明であった。我々は放射線照射前後のマウス糞便中のマイクロバイオーム解析の結果、p53が腸内細菌叢を制御することを発見した。本研究では、p53による腸内細菌叢制御に関わる標的遺伝子の探索、および腸内細菌の代謝産物解析を通じて、p53による消化管障害および消化器がん発症制御機構の解明を目指す。さらに標的遺伝子の多型と、消化器がんや炎症性消化管疾患の発症リスクとの関連も検討する。

Outline of Final Research Achievements

p53 is the most frequently mutated tumor-suppressor that functions as a transcription factor. p53-deficient mice are sensitive to radiation-inducible gastrointestinal disorders, however its molecular mechanism has not been elucidated. We found a novel role of p53 in intestinal flora control. The gut microbiota and its metabolite, short-chain fatty acids, were altered in the feces of p53-deficient mice after irradiation. We screened the p53 target genes in the mouse small intestine and found that p53 strongly induces some acute phase proteins.

Academic Significance and Societal Importance of the Research Achievements

近年の次世代シークエンス技術の進歩によりマイクロバイオーム研究は著しい発展を遂げ、腸内細菌叢の変化は肥満や炎症性腸疾患だけでなく、自閉症や肝がん、大腸がん等様々な疾患との関連が示されている。一方p53と腸内細菌叢の関連はこれまで報告されていなかった。本研究により、p53による腸内細菌叢の制御が明らかになったことで、消化器がん・炎症性腸疾患の新たな制御メカニズムが示唆された。さらに消化管障害に関与するp53下流遺伝子群は分泌タンパク質であることから、その投与により、高リスク群に対して腸内細菌叢やその代謝産物である短鎖脂肪酸を標的とした予防的介入または治療の可能性が開かれると期待される。

Research Products

• [Journal Article] The simplified Kyoto classification score is consistent with the ABC method of classification as a grading system for endoscopic gastritis (2021)
  • Author(s): Nishizawa Toshihiro、Toyoshima Osamu、Kondo Ryo、Sekiba Kazuma、Tsuji Yosuke、Ebinuma Hirotoshi、Suzuki Hidekazu、Tanikawa Chizu、Matsuda Koichi、Koike Kazuhiko
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 68 Issue: 1 Pages: 101-104
  • DOI: 10.3164/jcbn.20-41
  • NAID: 130007965311
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism in <i>Prostate Stem Cell Antigen</i> is associated with endoscopic grading in Kyoto classification of gastritis (2021)
  • Author(s): Toyoshima Osamu、Nishizawa Toshihiro、Sekiba Kazuma、Matsuno Tatsuya、Kondo Ryo、Watanabe Hidenobu、Suzuki Hidekazu、Tanikawa Chizu、Koike Kazuhiko、Matsuda Koichi
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 68 Issue: 1 Pages: 73-77
  • DOI: 10.3164/jcbn.20-67
  • NAID: 130007965305
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Endoscopy-based Kyoto classification score of gastritis related to pathological topography of neutrophil activity (2020)
  • Author(s): Toyoshima Osamu、Nishizawa Toshihiro、Yoshida Shuntaro、Sakaguchi Yoshiki、Nakai Yousuke、Watanabe Hidenobu、Suzuki Hidekazu、Tanikawa Chizu、Matsuda Koichi、Koike Kazuhiko
  • Journal Title: World Journal of Gastroenterology Volume: 26 Issue: 34 Pages: 5146-5155
  • DOI: 10.3748/wjg.v26.i34.5146
  • Peer Reviewed / Open Access
• [Journal Article] Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases (2020)
  • Author(s): Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Yamaji T, et al
  • Journal Title: Nature Genetics Volume: 52 Issue: 7 Pages: 669-679
  • DOI: 10.1038/s41588-020-0640-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease (2020)
  • Author(s): Curry Joshua N.、Saurette Matthew、Askari Masomeh、Pei Lei、Filla Michael B.、Beggs Megan R.、Rowe Peter S.N.、Fields Timothy、Sommer Andre J.、Tanikawa Chizu、Kamatani Yoichiro、Evan Andrew P.、Totonchi Mehdi、Alexander R. Todd、Matsuda Koichi、Yu Alan S.L.
  • Journal Title: Journal of Clinical Investigation Volume: 130 Issue: 4 Pages: 1948-1960
  • DOI: 10.1172/jci127750
  • Peer Reviewed
• [Journal Article] Identification of a novel uterine leiomyoma GWAS locus in a Japanese population (2020)
  • Author(s): Sakai Kensuke、Tanikawa Chizu、Hirasawa Akira、Terao Chikashi、Kamatani Yoichiro、Takahashi Atsushi、Momozawa Yukihide、Hirata Makoto、Kubo Michiaki、Matsuda Koichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1024-1024
  • DOI: 10.1038/s41598-020-58066-8
  • NAID: 120006872359
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians (2019)
  • Author(s): Lu Yingchang、Tanikawa Chizu、Matsuo Keitaro、Kamatani Yoichiro、Matsuda Koichi、Zheng Wei
  • Journal Title: Cancer Epidemiology Biomarkers & Prevention Volume: 29 Issue: 2 Pages: 477-486
  • DOI: 10.1158/1055-9965.epi-19-0755
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of two novel breast cancer loci through large-scale genome-wide association study in the Japanese population (2019)
  • Author(s): Low Siew-Kee、Chin Yoon Ming、Ito Hidemi、Matsuo Keitaro、et al.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 17332-17332
  • DOI: 10.1038/s41598-019-53654-9
  • NAID: 120006875665
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic variants of calcium and vitamin D metabolism in kidney stone disease (2019)
  • Author(s): Howles Sarah A.、Wiberg Akira、Goldsworthy Michelle、Bayliss Asha L.、Gluck Anna K.、Ng Michael、Grout Emily、Tanikawa Chizu、Kamatani Yoichiro、Terao Chikashi、Takahashi Atsushi、Kubo Michiaki、Matsuda Koichi、Thakker Rajesh V.、Turney Benjamin W.、Furniss Dominic
  • Journal Title: Nature Communications Volume: 10 Issue: 1
  • DOI: 10.1038/s41467-019-13145-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4. (2019)
  • Author(s): Liu, Y.Y., Tanikawa, C., Ueda, K., and Matsuda, K.
  • Journal Title: International journal of oncology Volume: 54 Pages: 1907-1920
  • DOI: 10.3892/ijo.2019.4786
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population (2019)
  • Author(s): Tanikawa Chizu、...、Ogishima Soichi、...、Matsuda Koichi
  • Journal Title: Journal of the American Society of Nephrology Volume: 印刷中 Issue: 5 Pages: 855-864
  • DOI: 10.1681/asn.2018090942
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Polymorphic Variant in p19Arf Confers Resistance to Chemically Induced Skin Tumors by Activating the p53 Pathway (2019)
  • Author(s): Saito M, Okumura K, Isogai E, Araki K, Tanikawa C, Matsuda K, Kamijo T, Kominami R, Wakabayashi Y.
  • Journal Title: Journal of Investigative Dermatology Volume: in press Issue: 7 Pages: 30032-6
  • DOI: 10.1016/j.jid.2018.12.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer. (2018)
  • Author(s): Lu Y, Kweon SS, Tanikawa C, Jia WH, Xiang YB, Cai Q, Zeng C, Schmit SL, Shin A, Matsuo K, Jee SH, Kim DH, Kim J, Wen W, Shi J, Guo X, Li B, Wang N, Zhang B, Li X, Shin MH, Li HL, Ren Z, Oh JH, Oze I, Ahn YO, Jung KJ, Conti DV, Schumacher FR, Rennert G, Je
  • Journal Title: Gastroenterology Volume: 156 Issue: 5 Pages: 1455-1466
  • DOI: 10.1053/j.gastro.2018.11.066
  • Peer Reviewed / Open Access / Int'l Joint Research