Evaluation of the role of gut-microbiota in NASH-associated HCC pathogenesis

• Project/Area Number: 17K09434
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Yokohama City University
• Principal Investigator: IMAJO KENTO 横浜市立大学, 附属病院, 助教 (30600192)
• Co-Investigator(Kenkyū-buntansha): 斉藤 聡 横浜市立大学, 附属病院, 准教授 (00275041) ; 留野 渉 横浜市立大学, 医学研究科, 客員講師 (00644957) ; 本多 靖 横浜市立大学, 附属病院, 助教 (00784844) ; 米田 正人 横浜市立大学, 附属病院, 講師 (10423831) ; 小川 祐二 横浜市立大学, 医学部, 助教 (20644959) ; 中島 淳 横浜市立大学, 医学研究科, 教授 (30326037) ; 結束 貴臣 横浜市立大学, 附属病院, 助教 (30738620)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: NASH由来肝細胞癌 / 非アルコール性脂肪肝炎由来肝細胞癌 / 非アルコール性脂肪肝炎 / 肝細胞癌 / 腸管透過性 / Faecalibacterium / 便メタゲノム解析

Outline of Final Research Achievements

This study was to investigate the role of gut-microbiota and endotoxin (ET) in the pathogenesis of non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC). By fecal metagenomic analysis, the occupation rate of Faecalibacterium was lower in the feces of NASH-associated HCC model mice than in non-HCC mice. This result was similar to that of human HCC patients. Moreover, administration of Fecalibacterium to these HCC model mice resulted in a decrease in the number and size of HCC. Although increased intestinal permeability is considered as a mechanism of progress of NASH-derived HCC, improvement was observed by administration of Fecalibacterium.

Academic Significance and Societal Importance of the Research Achievements

NASH由来肝細胞癌は増加の一途を辿っている。本研究は腸内細菌がNASH由来肝細胞癌に関わることのみならず、腸内細菌の是正がNASH由来肝細胞癌を抑制できる可能性を示唆するものである。将来的に肝細胞癌の予防や治療において、腸内細菌や腸管透過性へのアプローチといったこれまでとは全く異なる選択肢へとつながる可能性がある。

Research Products

• [Int'l Joint Research] UCSD(米国)
• [Journal Article] Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants (2019)
  • Author(s): Hsu C, Caussy C, Imajo K, Chen J, Singh S, Kaulback K, Le MD, Hooker J, Tu X, Bettencourt R, Yin M, Sirlin CB, Ehman RL, Nakajima A, Loomba R.
  • Journal Title: Clin Gastroenterol Hepatol. 2019 Mar;17(4):630-637.e8. Volume: ;17(4) Issue: 4 Pages: 630-637
  • DOI: 10.1016/j.cgh.2018.05.059
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Optimizing Use of Nonalcoholic Fatty Liver Disease Fibrosis Score, Fibrosis-4 Score, and Liver Stiffness Measurement to Identify Patients With Advanced Fibrosis (2019)
  • Author(s): Chan WK, Treeprasertsuk S, Goh GB, Fan JG, Song MJ, Charatcharoenwitthaya P, Duseja A, Dan YY, Imajo K, Nakajima A, Ho KY, Goh KL, Wong VW.
  • Journal Title: Clin Gastroenterol Hepatol. 2019 Nov;17(12):2570-2580.e37. Volume: 17(12) Issue: 12 Pages: 2570-2580
  • DOI: 10.1016/j.cgh.2019.03.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HOMA-IR: An independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease. (2019)
  • Author(s): Fujii H, Yoneda M, et al.
  • Journal Title: J Gastroenterol Hepatol. Volume: in press Issue: 8 Pages: 1-6
  • DOI: 10.1111/jgh.14595
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Three-dimensional analysis of pancreatic fat by fat-water magnetic resonance imaging provides detailed characterization of pancreatic steatosis with improved reproducibility (2019)
  • Author(s): Kato Shingo、Iwasaki Akito、Kurita Yusuke、Arimoto Jun、Yamamoto Toh、Hasegawa Sho、Sato Takamitsu、Imajo Kento、Hosono Kunihiro、Kobayashi Noritoshi、Yoneda Masato、Higurashi Takuma、Kubota Kensuke、Utsunomiya Daisuke、Nakajima Atsushi
  • Journal Title: PLOS ONE Volume: 14 Issue: 12 Pages: e0224921-e0224921
  • DOI: 10.1371/journal.pone.0224921
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Faecalibacterium prausnitzii 経口投与によるLeaky gut syndrome改善とNASH治療の可能性 (2019)
  • Author(s): 小林貴、結束貴臣、今城健人、中島淳
  • Organizer: 第38回 アルコール医学生物学研究会学術集会 一般演題 5，2019年.
• [Presentation] 「食事内容の変化がもたらすLeaky gut SyndromeやNASHに対するFaecalibacteriumu prausnitziiの治療効果」 (2019)
  • Author(s): 小林貴、結束貴臣、今城、中島淳
  • Organizer: 一般演題１ 第9回肥満と消火器疾患研究会，石川(ホテル日航金沢)，2019年5月8日.
• [Presentation] NASH における Faecalibacterium prausnitzii 減少の機序と菌体成分による治療の可能性. (2019)
  • Author(s): 小林貴、結束貴臣、今城、中島淳
  • Organizer: 第105回日本消化器病学会総会 ワークショップ2(WS2-12) 消化器領域における腸内細菌研究と臨床応用，石川（ANA クラウンプラザホテル金沢）2019年5月9日．
• [Presentation] Increased levelsof bile acid in faces plays an important role in pathophysiology of nonalcoholic stestohepatitis. (2019)
  • Author(s): 18.Kessoku T, Kobayashi T, Imajo K, Honda Y, Ogawa Y, Kato S, Higurashi T, Yoneda M, Yousuke Oikawa, Yoshiki Tanaka, Shunji Nakajima, Usuda H, Wada K, Saito S, Nakajima A:
  • Organizer: The international liver congress 2019 Poster,Vienna(Austria), April 12 2019.
  • Invited
• [Presentation] A direct comparative study among magnetic resonance elastography, vibration controlled transient elastography and shear wave elastography in patients with nonalcoholic fatty liver disease. (2019)
  • Author(s): 19.Kento Imajo, Takaomi Kessoku, Takashi Kobayashi, Yasushi Honda, Yuji Ogawa, Masato Yoneda, Hiroyuki Kirikosho, Satoru Saito, Atsushi Nakajima :
  • Organizer: The international liver congress 2019 Poster,Vienna(Austria), April 13 2019.
  • Invited
• [Presentation] Elevated hepatic iron overload obtained by magnetic resonance imaging reflects hepatic inflammation and ballooning in patients with non-alcoholic fatty liver disease. (2019)
  • Author(s): 69.K. Imajo, K. Suzuki, Y. Honda, Y. Ogawa, M. Yoneda, T. Kessoku, S. Saito, A Nakajima.
  • Organizer: IBD and Liver: East Meets West Poster Session Liver, Kyoto,2018(Kyoto Hotel Okura), September 8.
  • Invited
• [Presentation] 高果糖や高コレステロール食がもたらすLeaky gut syndromeに対するFaecalibacterium prausnitzii治療の検討 (2018)
  • Author(s): 結束貴臣、今城健人、中島淳
  • Organizer: JDDW 2018
• [Presentation] Faecalibacterium improves pathogenesis of nonalcoholic steatohepatitis via controlling Treg induced gut-permeability (2018)
  • Author(s): 結束貴臣、今城健人、中島淳
  • Organizer: EASL 2018
  • Int'l Joint Research
• [Presentation] 非アルコール性脂肪肝炎とその関連病態に対するFaecalibacterium prausnitziiの効果 (2018)
  • Author(s): 結束貴臣、今城健人
  • Organizer: 日本消化器病学会総会
• [Presentation] Faecalibacterium improves pathogenesis of nonalcoholic steatohepatitis via controlling Treg induced gut-permeability (2018)
  • Author(s): Takaomi Kessoku, Kento Imajo
  • Organizer: European Association for the Study of the Liver 2018
  • Int'l Joint Research