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

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K09418
• Research Institution: Nagoya University
• Principal Investigator: 本多 隆 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• Co-Investigator(Kenkyū-buntansha): 後藤 秀実 名古屋大学, 医学系研究科, 教授 (10215501) [Withdrawn] ; 廣岡 芳樹 藤田医科大学, 医学部, 教授 (50324413) [Withdrawn] ; 石上 雅敏 名古屋大学, 医学部附属病院, 講師 (90378042)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
• Keywords: 腸内細菌 / NASH / 非B非Ｃ / 肝癌

Outline of Annual Research Achievements

マウス実験でCholine-sufficient high-fatを20週投与した（CSHF）とCholine-deficient high-fatを20週投与した(CDHF)と3週齢にDenを投与し、8週齢からCDHFを20週投与した(DEN＋CDHF)の3群を比較した。DEN＋CDHFで87.5％、CDHFで22.2%に肝腫瘍がみられが、CSHFではみられなかった。肝Cdkn1a(p21)遺伝子発現はCDHFにおいてCSHF及びCDHF＋DENと比べ増加していた。腸内細菌はBacteroides、Clostridium属などは肝線維化と相関しており、Akkermansia属などは逆相関していた、またBifidobacterium属は肝腫瘍と逆相関していた。CDHF投与により線維化とp21過剰発現がみられたが、DEN投与でp21過剰発現が抑制され腫瘍が高率にみられた。ネットワーク解析により細菌は相互に関係し腫瘍形成や線維化を促進或いは阻害していた。
一方慢性肝炎患者248名中で維化進展及び腸内細菌に影響を及ぼす因子でマッチングした肝癌症例(HCC) 79例とnonHCC79例を比較した。サブ解析で非B非C(NBNC)肝癌で肝硬変症例を除いたNBNCHCC7例とNBNCnonHCC22例を比較した。占拠率がHCC＞nonHCC＞control及び逆の順となる細菌を抽出した。HCCとnonHCC間でβ多様性に差が見られた。HCCではnonHCCと比較しActiomyces、Enterococcus属などが増加し、Odoribacter属などが減少していた。NBNCHCCではNBNCnonHCCと比較してVeillonella属などが増加し、Odoribcter属が減少していた。これらから口腔内常在菌などの腸内細菌の違いが肝発癌例と非癌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] 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 Pages: 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: - Pages: -
  • 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 Pages: 374-381
  • DOI: 10.1111/hepr.13452. Epub 2019 Dec 22
  • 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 Pages: 665-676
  • DOI: 10.21873/anticanres.13996.
  • Peer Reviewed / Open Access
• [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 Pages: 207-214
  • DOI: 10.1111/jgh.14448. Epub 2018 Sep 18.
  • 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 Pages: 1054-1065
  • DOI: 10.1111/hepr.13358. Epub 2019 May 29.
  • Peer Reviewed / Open Access
• [Journal Article] Microbiota profile is different for early and invasive colorectal cancer; and is consistent throughout the colon (2019)
  • 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 Pages: 433-437
  • DOI: 10.1111/jgh.14868. Epub 2019 Oct 23.
  • Peer Reviewed / Open Access
• [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