Elucidation of liver disease formation by bacterial species analysis detected in human portal blood

• Project/Area Number: 19K08451
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Watanabe Tsunamasa 聖マリアンナ医科大学, 医学部, 准教授 (20338528)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腸内細菌叢 / 肝疾患 / 門脈血 / 腸内細菌 / 門脈 / 門脈血液 / 次世代シークエンス

Outline of Research at the Start

腸内環境からみた新たな肝疾患治療戦略立案の科学的根拠を見出すことを目的とし、これまでに食道胃静脈瘤治療時に血管カテーテルから無菌的に採取した門脈血液内に細菌DNAが存在することを確認してきた。
本研究では独自の方法で採取したヒト門脈血液を用いて、これまでの成果を飛躍的に発展させることを目的に門脈内に侵入する腸内細菌のメタゲノム解析を行い、同時に門脈血中の細菌由来代謝産物のメタボローム解析により肝病態に影響を与える生理活性因子を同定し、腸内細菌叢、門脈血中の細菌、門脈血中の生理活性物質、肝病態の形成ならびに進展との関係を明らかにする。

Outline of Final Research Achievements

To find a scientific basis for a new treatment strategy for liver disease from the viewpoint of the intestinal environment, a total of 28 cases of human portal vein blood were collected by a unique method. Furthermore, we performed intestinal flora metagenomic analysis by next-generation sequencing, including feces and portal vein blood collected from the same individual at the same time. The results revealed that bacterial DNA was detected in the portal blood flow in about half of the cases, and that the bacterial flora detected in the portal blood and feces in the same case was not the equal. Even for the same liver disease, the bacterial species detected in the portal vein blood differed from each case, and a consistent tendency could not be obtained and a clear association with the disease could not be found.

Academic Significance and Societal Importance of the Research Achievements

近年、増加傾向にあるアルコール性肝疾患や非アルコール性脂肪性肝炎において、肝病態進展と腸内細菌叢の関連が指摘されているが、ヒトにおいて腸管粘膜を通過し門脈を通って肝臓に流入する細菌について検討した報告は少なく、今回独自の方法により採取した門脈血を用いて腸内細菌叢メタゲノム解析を試みた。肝疾患患者の約半数で閉鎖系の門脈血流に細菌が流入している可能性を見出したが、個体差が大きいことも明らかとなった。今後は、肝疾患患者の腸内細菌叢の改変による治療介入の可能性について、さらなる検討が必要と考えられた。

Research Products

• [Journal Article] Mac‐2‐binding protein glycan isomer predicts all malignancies after sustained virological response in chronic hepatitis C (2022)
  • Author(s): Kawata Kazuhito、Watanabe Tsunamasa、Tsubota Akihito
  • Journal Title: Hepatology Communications Volume: - Issue: 8 Pages: 1-15
  • DOI: 10.1002/hep4.1941
  • Peer Reviewed / Open Access
• [Journal Article] Serum miR-192-5p levels predict the efficacy of pegylated interferon therapy for chronic hepatitis B (2022)
  • Author(s): Nagura Yoshihito、Matsuura Kentaro、Iio Etsuko、Fujita Koji、Inoue Takako、Matsumoto Akihiro、Tanaka Eiji、Nishiguchi Shuhei、Kang Jong-Hon、Matsui Takeshi、Enomoto Masaru、Ikeda Hiroki、Watanabe Tsunamasa、Okuse Chiaki、Tsuge Masataka、Atsukawa Masanori、Tateyama Masakuni、Kataoka Hiromi、Tanaka Yasuhito
  • Journal Title: PLOS ONE Volume: 17 Issue: 2 Pages: e0263844-e0263844
  • DOI: 10.1371/journal.pone.0263844
  • Peer Reviewed
• [Journal Article] Time‐course changes in liver functional reserve after successful sofosbuvir/velpatasvir treatment in patients with decompensated cirrhosis (2021)
  • Author(s): Atsukawa Masanori、Watanabe Tsunamasa、Iwakiri Katsuhiko
  • Journal Title: Hepatology Research Volume: 52 Issue: 3 Pages: 235-246
  • DOI: 10.1111/hepr.13739
  • Peer Reviewed
• [Journal Article] Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis (2021)
  • Author(s): Chuma Makoto、Hattori Nobuhiro、Watanabe Tsunamasa、Maeda Shin
  • Journal Title: Hepatology Research Volume: 52 Issue: 3 Pages: 269-280
  • DOI: 10.1111/hepr.13732
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study (2021)
  • Author(s): Suzuki Fumitaka、Watanabe Tsunamasa、Kumada Hiromitsu
  • Journal Title: BMC Gastroenterology Volume: 21 Issue: 1
  • DOI: 10.1186/s12876-021-02008-9
  • Peer Reviewed
• [Journal Article] Prediction of esophagogastric varices associated with oxaliplatin administration (2021)
  • Author(s): Satta Yosuke、Shigefuku Ryuta、Watanabe Tsunamasa、Mizukami Takuro、Tsuda Takashi、Suzuki Tatsuya、Ehira Takuya、Hattori Nobuhiro、Kiyokawa Hirofumi、Nakahara Kazunari、Ikeda Hiroki、Matsunaga Kotaro、Takahashi Hideaki、Matsumoto Nobuyuki、Okuse Chiaki、Suzuki Michihiro、Sunakawa Yu、Yasuda Hiroshi、Itoh Fumio
  • Journal Title: JGH Open Volume: 5 Issue: 11 Pages: 1289-1297
  • DOI: 10.1002/jgh3.12668
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics and Prognosis of De Novo Hepatocellular Carcinoma After Sustained Virologic Response (2021)
  • Author(s): Toyoda Hidenori、Watanabe Tsunamasa、Tanaka Junko
  • Journal Title: Hepatology Communications Volume: 5 Issue: 7 Pages: 1290-1299
  • DOI: 10.1002/hep4.1716
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of Sequential Therapy With Tenofovir Alafenamide After Long-term Entecavir (2021)
  • Author(s): Nguyen Mindie H.、Watanabe Tsunamasa、Enomoto Masaru
  • Journal Title: American Journal of Gastroenterology Volume: 116 Issue: 6 Pages: 1264-1273
  • DOI: 10.14309/ajg.0000000000001157
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice (2021)
  • Author(s): Toyoda Hidenori、Watanabe Tsunamasa、Nguyen Mindie H.
  • Journal Title: Hepatology Volume: 74 Issue: 2 Pages: 656-666
  • DOI: 10.1002/hep.31793
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cytokines and Chemokines Involved in Hepatitis B Surface Antigen Loss in Human Immunodeficiency Virus/Hepatitis B Virus Coinfected Patients (2021)
  • Author(s): Urata Noboru、Watanabe Tsunamasa、Hirashima Noboru、Yokomaku Yoshiyuki、Imamura Junji、Iwatani Yasumasa、Shimada Masaaki、Tanaka Yasuhito
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 4 Pages: 833-833
  • DOI: 10.3390/jcm10040833
  • Peer Reviewed / Open Access
• [Journal Article] Safety and Efficacy of Lenvatinib Treatment in Child-Pugh A and B Patients with Unresectable Hepatocellular Carcinoma in Clinical Practice: A Multicenter Analysis (2020)
  • Author(s): Ogushi Katsuaki、Chuma Makoto、Uojima Haruki、Hidaka Hisashi、Numata Kazushi、Kobayashi Satoshi、Hirose Shunji、Hattori Nobuhiro、Fujikawa Tomoaki、Nakazawa Takahide、Wada Naohisa、Iwasaki Shuichiro、Fukushima Taito、Sano Yusuke、Ueno Makoto、Kawano Kuniyuki、Tsuruya Kota、Shomura Masako、Watanabe Tsunamasa, et al.
  • Journal Title: Clinical and Experimental Gastroenterology Volume: Volume 13 Pages: 385-396
  • DOI: 10.2147/ceg.s256691
  • Peer Reviewed / Open Access
• [Journal Article] Real-World Clinical Application of 12-Week Sofosbuvir/Velpatasvir Treatment for Decompensated Cirrhotic Patients with Genotype 1 and 2: A Prospective, Multicenter Study (2020)
  • Author(s): Atsukawa Masanori、Tsubota Akihito、Kondo Chisa、Toyoda Hidenori、Nakamuta Makoto、Takaguchi Koichi、Watanabe Tsunamasa、et al.
  • Journal Title: Infectious Diseases and Therapy Volume: 9 Issue: 4 Pages: 851-866
  • DOI: 10.1007/s40121-020-00329-y
  • Peer Reviewed / Open Access
• [Journal Article] The effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients with refractory factors in the real world: a comprehensive analysis of a prospective multicenter study (2020)
  • Author(s): Nozaki, A. Atsukawa, M. Ogawa, S. Itokawa, N. Arai, T. Ikegami, T. Tsubota, A. Genda, T. Okubo, H. Mikami, S. Morishita, A. Moriya, A. Tani, J. Tachi, Y. Hotta, N. Ishikawa, T. Okanoue, T. Tanaka, Y. Kumada, T. Iwakiri, K. Maeda, S. K. T. K. Liver Study Group
  • Journal Title: Hepatol Int Volume: - Issue: 2 Pages: 225-238
  • DOI: 10.1007/s12072-020-10019-z
  • Peer Reviewed / Open Access
• [Journal Article] Marked heterogeneity in the diagnosis of compensated cirrhosis of patients with chronic hepatitis C virus infection in a real-world setting: A large, multicenter study from Japan (2020)
  • Author(s): Toyoda H, Atsukawa M, Watanabe T..., Tsubota A, et al
  • Journal Title: J Gastroenterol Hepatol Volume: - Issue: 8 Pages: 1420-1425
  • DOI: 10.1111/jgh.14982
  • Peer Reviewed
• [Journal Article] Analysis of factors associated with the prognosis of cirrhotic patients who were treated with tolvaptan for hepatic edema (2020)
  • Author(s): Atsukawa M, Tsubota A, Takaguchi K, Toyoda H, Iwasa M, Ikegami T, Chuma M, Nozaki A, Uojima H, Hiraoka A, Fukunishi S, Yokohama K, Tada T, Kato K, Abe H, Tani J, Okubo H, Watanabe T, et al.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 7 Pages: 1229-1237
  • DOI: 10.1111/jgh.14965
  • Peer Reviewed
• [Journal Article] Efficacy and safety of ombitasvir/paritaprevir/ritonavir and ribavirin for chronic hepatitis patients infected with genotype 2a in Japan. (2019)
  • Author(s): Atsukawa M, Tsubota A, Toyoda H, Takaguchi K, Nakamuta M, Watanabe T, Tada T, Tsutsui A, Ikeda H, Abe H, Kato K, Uojima H, Ikegami T, Asano T, Kondo C, Koeda M, Okubo T, Arai T, Iwashita-Nakagawa A, Itokawa N, Kumada T, Iwakiri K
  • Journal Title: Hepatol Res Volume: 49 Issue: 4 Pages: 369-376
  • DOI: 10.1111/hepr.13292
  • Peer Reviewed
• [Journal Article] The efficacy and safety of glecaprevir plus pibrentasvir in 141 patients with severe renal impairment: a prospective, multicenter study. (2019)
  • Author(s): Atsukawa M, Tsubota A, Toyoda H, Takaguchi K, Nakamuta M, Watanabe T, Michitaka K, Ikegami T, Nozaki A, Uojima H, Fukunishi S, Genda T, Abe H, Hotta N, Tsuji K, Ogawa C, Tachi Y, Shima T, Shimada N, Kondo C, Akahane T, Aizawa Y, Tanaka Y, Kumada T, Iwakiri K
  • Journal Title: Aliment Pharmacol Ther Volume: 49 Issue: 9 Pages: 1230-1241
  • DOI: 10.1111/apt.15218
  • Peer Reviewed
• [Journal Article] Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10 688 Patients in Japan (2019)
  • Author(s): Toyoda H, Atsukawa M, Uojima H, Nozaki A, Tamai H, Takaguchi K, Fujioka S, Nakamuta M, Tada T, Yasuda S, Chuma M, Senoh T, Tsutsui A, Yamashita N, Hiraoka A, Michitaka K, Shima T, Akahane T, Itobayashi E, Watanabe T, et al.
  • Journal Title: Open Forum Infectious Diseases Volume: 6 Issue: 5
  • DOI: 10.1093/ofid/ofz185
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of 8‐week glecaprevir/pibrentasvir treatment in direct‐acting antiviral‐naive noncirrhotic HCV genotype 1 and 2 infected patients in a real‐world setting in Japan (2019)
  • Author(s): Ikeda H, Watanabe T, Iio E, Tsubota A, Hiraoka A, Nozaki A, Okubo H, Tachi Y, Moriya A, Oikawa T, Matsumoto Y, Tsuruoka S, Tani J, Kikuchi K, Iwakiri K, Tanaka Y, Kumada T, et al.
  • Journal Title: Journal of Viral Hepatitis Volume: 26 Issue: 11 Pages: 1266-1275
  • DOI: 10.1111/jvh.13170
  • Peer Reviewed
• [Journal Article] Real‐world experience of 12‐week direct‐acting antiviral regimen of glecaprevir and pibrentasvir in patients with chronic hepatitis C virus infection (2019)
  • Author(s): Toyoda H, Atsukawa M, Watanabe T, et al
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 5 Pages: 855-861
  • DOI: 10.1111/jgh.14874
  • Peer Reviewed