Gut microbiota and therapeutic intervention in non-B,non-C hepatocellular carcinoma

• Project/Area Number: 17K09418
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya University
• Principal Investigator: HONDA TAKASHI 名古屋大学, 医学系研究科, 講師 (10378052)
• Co-Investigator(Kenkyū-buntansha): 後藤 秀実 名古屋大学, 医学系研究科, 教授 (10215501) ; 廣岡 芳樹 藤田医科大学, 医学部, 教授 (50324413) ; 石上 雅敏 名古屋大学, 医学部附属病院, 講師 (90378042)
• 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: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 肝癌 / 腸内細菌 / 非B非C型 / NASH / 非B非Ｃ / 肝臓学

Outline of Final Research Achievements

In the mouse model of liver cancer, network analysis showed the bacteria in the gut have unique interaction with each other. We identified some different types of bacteria have been associated with tumorigenesis and fibrogenesis.
Patients with hepatocellular carcinoma (HCC) had increased genus Actiomyces compared to those without HCC. In the patients with non-B,non-C HCC, genus Veillonella increased compared to those without HCC. There is a possibility that there is a difference in gut microbiota such as oral indigenous bacteria between patients with and without HCC.

Academic Significance and Societal Importance of the Research Achievements

肝癌の原因はHCV、HBVウイルスなどによるものが大多数であったが、ウイルスのコントロールが可能となってきたことから、それ以外の非B非Ｃ型肝癌が最近増加している。
肝発癌促進因子として腸内細菌による肝臓への影響が考えられてきている。
本研究においてマウスモデルにおける腸内細菌と肝遺伝子発現に関するネットワーク解析により腸内細菌は相互に関係し、腫瘍形成や線維化と関連する複数の細菌が存在することを同定した。またヒト肝疾患からの解析では口腔内常在菌などの腸内細菌叢の違いが肝発癌症例と非肝癌症例との違いに関与している可能性が示唆された。

Research Products

• [Journal Article] Microbiota profile is different for early and invasive colorectal cancer; and is consistent throughout the colon (2020)
  • Author(s): Tao Pu LZC Yamamoto K; Honda T; Nakamura M; Yamamura T; Hattori S; Burt AD; Singh R; Hirooka Y,Fujishiro M
  • Journal Title: J Gastroenterol Hepatol. Volume: 35 Issue: 3 Pages: 433-437
  • DOI: 10.1111/jgh.14868
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of weight change and lifestyle modifications on the development or remission of nonalcoholic fatty liver disease (2020)
  • Author(s): Yoshioka N, Ishigami M, Watanabe Y, Sumi H, Doisaki M, Yamaguchi T, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Haruta J, and Fujishiro M
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 481-481
  • DOI: 10.1038/s41598-019-57369-9
  • Peer Reviewed / Open Access
• [Journal Article] Correlation of serum zinc levels with pathological and laboratory findings in patients with nonalcoholic fatty liver disease. (2020)
  • Author(s): Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M.
  • Journal Title: Eur J Gastroenterol Hepatol. Volume: - Issue: 6 Pages: 748-753
  • DOI: 10.1097/meg.0000000000001587
  • Peer Reviewed / Open Access
• [Journal Article] Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma. (2020)
  • Author(s): Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M.
  • Journal Title: Hepatol Res. Volume: 50 Issue: 3 Pages: 374-381
  • DOI: 10.1111/hepr.13452
  • Peer Reviewed / Open Access
• [Journal Article] Relationship Between Adverse Events and Microbiomes in Advanced Hepatocellular Carcinoma Patients Treated With Sorafenib. (2020)
  • Author(s): Yamamoto K, Kuzuya T, Honda T, Ito T, Ishizu Y, Nakamura M, Miyahara R, Kawashima H, Ishigami M, Fujishiro M.
  • Journal Title: Anticancer Res. Volume: 40 Issue: 2 Pages: 665-676
  • DOI: 10.21873/anticanres.13996
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Utility and limitations of noninvasive fibrosis markers for predicting prognosis in biopsy-proven Japanese non-alcoholic fatty liver disease patients. (2019)
  • Author(s): Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Nishimura D, Toyoda H, Kumada T, Goto H, Hirooka Y.
  • Journal Title: J Gastroenterol Hepatol. Volume: 34 Issue: 1 Pages: 207-214
  • DOI: 10.1111/jgh.14448
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment (2019)
  • Author(s): Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Hirooka Y, Fujishiro M.
  • Journal Title: Hepatol Res. Volume: 49 Issue: 9 Pages: 1054-1065
  • DOI: 10.1111/hepr.13358
  • Peer Reviewed / Open Access
• [Journal Article] Influence of proton pump inhibitors on microbiota in chronic liver disease patients (2019)
  • Author(s): Yamamoto K, Ishigami M, Honda T, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Hayashi K, Goto H, Hirooka Y.
  • Journal Title: Hepatology International Volume: 13 Issue: 2 Pages: 234-244
  • DOI: 10.1007/s12072-019-09932-9
  • Peer Reviewed
• [Journal Article] Antifibrotic Effects of 1,25(OH)2D3 on Nonalcoholic Steatohepatitis in Female Mice (2019)
  • Author(s): Ma L, Ishigami M, Honda T, Yokoyama S, Yamamoto K, Ishizu Y, Kuzuya T, Hayashi K, Hirooka Y, Goto H.
  • Journal Title: Dig Dis Sci. Volume: ー Issue: 9 Pages: 2581-2590
  • DOI: 10.1007/s10620-019-05560-3
  • Peer Reviewed
• [Presentation] Association between gut microbiota and hepatocellular carcinoma in patients with chronic liver disease (2019)
  • Author(s): Honda T, Ishigami M, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Fujishiro M
  • Organizer: EASL2019
  • Int'l Joint Research
• [Presentation] The early clinical response at 2 weeks of lenvatinib therapy for patients with advanced HCC (2019)
  • Author(s): Kuzuya T, Ito T, Ishigami M , Ishizu Y, Honda T, Fujishiro M
  • Organizer: EASL2019
  • Int'l Joint Research
• [Presentation] Serum Zinc levels as a prognostic factor for extra-hepatic carcinogenesis in Japanese patients with non-alcoholic liver disease (2019)
  • Author(s): Ito T, Ishigami M, Ishizu Y, Kuzuya T,Honda T, Fujishiro M
  • Organizer: EASL2019
  • Int'l Joint Research
• [Presentation] The optimal cut-off points of FIB-4 index for predicting the incidences of HCC and extra-hepatic malignancies in biopsyproven Japanese NAFLD patients (2019)
  • Author(s): Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Fujishiro M
  • Organizer: EASL2019
  • Int'l Joint Research
• [Presentation] 慢性肝疾患例における肝発癌症例に関連する腸内細菌叢の検討 (2019)
  • Author(s): 本多 隆、石上雅敏、廣岡芳樹
  • Organizer: 第105回消化器病学会総会
• [Presentation] Changes of microbiota after hepatitis C virus eradication (2019)
  • Author(s): Honda T, Ishigami M, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Fujishiro M
  • Organizer: AASLD2019
  • Int'l Joint Research
• [Presentation] Indication for HCC treatment in recent era-proposal of the new priority for liver transplantation in patients with HCC (2019)
  • Author(s): Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Fujishiro M
  • Organizer: AASLD2019
  • Int'l Joint Research
• [Presentation] C型肝炎による肝発癌に関連する腸内細菌叢の検討 (2018)
  • Author(s): 本多 隆、廣岡芳樹、後藤秀実
  • Organizer: 消化器病学会総会
• [Presentation] Association between microbiome and hepatitis C virus-infected patients with hepatocellular carcinoma (2018)
  • Author(s): Takashi Honda, Masatoshi Ishigami, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Yoshiki Hirooka
  • Organizer: ILCA2018
  • Int'l Joint Research
• [Presentation] C型肝炎ウイルス駆除による腸内細菌叢への影響 (2018)
  • Author(s): 本多 隆、石上雅敏、廣岡芳樹
  • Organizer: JDDW2018
• [Presentation] Comparison of Gut Microbiota and Predicted Functional Metagenome in Hepatitis C Patients with and without Advanced Fibrosis Categorized By FIB4-Index (2018)
  • Author(s): Kenta Yamamoto, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Yoshiki Hirooka
  • Organizer: AASLD2018
  • Int'l Joint Research
• [Presentation] 血小板数とC型肝炎患者における腸内細菌叢及び予測機能遺伝子に関する検討 (2018)
  • Author(s): 山本 健太, 本多 隆, 石上 雅敏
  • Organizer: 日本肝臓学会東部会
• [Presentation] 次世代シーケンサーによる肝発癌に関与する腸内細菌叢の検討 (2017)
  • Author(s): 本多 隆、廣岡芳樹、田中 卓、山本健太、安藤祐資、伊藤隆徳、安田 諭、野村 彩、加藤幸一郎、石津洋二、葛谷貞二、林 和彦、石上雅敏、後藤秀実
  • Organizer: 第103回消化器病学会総会
• [Presentation] 非B非C肝癌における肝発癌に関連する腸内細菌叢の検討 (2017)
  • Author(s): 本多 隆、石上雅敏、山本健太、田中 卓、横山晋也、石津洋二、葛谷貞二、林 和彦、廣岡芳樹、後藤秀実
  • Organizer: JDDW2017 (第21回日本肝臓学会大会)
• [Presentation] Effects of 1,25 (OH) 2D3 on Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice. (2017)
  • Author(s): M. L. Yun, T. Honda, A. Nomura, T. Ito, S. Yasuda, Y. Ishizu, T. Kuzuya, K. Hayashi, M. Ishigami, H. Goto.
  • Organizer: JDDW 2017 International Poster Session