Metagenomic analysis of intestinal microbiota in hematologic malignancies and development of disease risk and prognostic models.

• Project/Area Number: 20K17401
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Osaka University
• Principal Investigator: Shinsuke Kusakabe 大阪大学, 大学院医学系研究科, 助教 (50747186)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腸内細菌叢 / 同種造血幹細胞移植 / 腸球菌 / 慢性GVHD / 晩期合併症 / 造血幹細胞移植 / 造血細胞移植 / メタゲノム解析

Outline of Research at the Start

再発・難治性血液悪性疾患では造血幹細胞移植が唯一の根治的治療である。しかし、感染症や移植片対宿主病(GVHD)など合併症により、治療関連死は20-40%に及び、QOL低下や二次発癌の発症が長期生存患者において問題となっている。造血幹細胞移植の予後改善には、合併症の制御が必要不可欠である。近年、腸内細菌叢の異常と移植合併症との関連性が複数の研究で報告されている。今回(1)経時的な菌叢の解析、(2)移植後20年目までの長期の検体解析をおこない、長期の経時的なデータから菌叢の変化と予後の関連性を検証し、合併症の発症時期や重症度を予測法、腸内細菌叢に影響の少ない移植関連治療法を開発することを目指す。

Outline of Final Research Achievements

Abnormalities in the intestinal microbiota have been reported to be associated with various complications and transplantation outcomes in the field of HSCT. We collected fecal samples from allogeneic hematopoietic stem cell transplant recipients over time and analyzed the correlation between abnormalities in the intestinal microbiota and complications after transplantation. In 2020 we reported that gut microbiota abnormalities persisted over 1 year after the transplantation in allogeneic transplantation recipients and that the relative abundance of Enterococcus at 1 month after the transplantation was associated with post-transplant survival. In 2021, in collaboration with the Department of Hematology, Tokyo Metropolitan Komagome Hospital, we reported the association between abnormalities of gut microbiota and chronic GVHD.In 2022, we reported the association between the gut persistent abnormalities of gut microbiota and complications in long-term post-transplant survivors.

Academic Significance and Societal Importance of the Research Achievements

2020年の論文では腸球菌の増加が移植後生存の予測因子になりうることを示した。2021年の論文では移植後の腸内細菌叢の多様性が慢性GVHDの発症予測因子になりうることを示した。これらの成果は、移植後の生存、合併症の予測モデルを構築するうえで重要な情報となる。また、2022年の論文では移植後長期生存者における腸内細菌叢の異常を報告した。移植後の晩期合併症はこれまでほとんど研究データがなく、発症予測、予防や治療に難渋することが多かったが、本研究の知見をもとに病態解明のための新たな道筋が開けるものと考える。

Research Products

• [Journal Article] Prolonged gut microbial alterations in post‐transplant survivors of allogeneic haematopoietic stem cell transplantation (2022)
  • Author(s): Hino Akihisa、Fukushima Kentaro、Kusakabe Shinsuke、Ueda Tomoaki、Sudo Takao、Fujita Jiro、Motooka Daisuke、Takeda Aya K.、Shinozaki Natsuko O.、Watanabe Satoshi、Yokota Takafumi、Shibayama Hirohiko、Nakamura Shota、Hosen Naoki
  • Journal Title: British Journal of Haematology Volume: - Issue: 4 Pages: 725-737
  • DOI: 10.1111/bjh.18574
  • Peer Reviewed
• [Journal Article] Low diversity of gut microbiota in the early phase of post-bone marrow transplantation increases the risk of chronic graft-versus-host disease. (2021)
  • Author(s): Konishi T, Kusakabe S, Hino A, Inamoto K, Yoshifuji K, Kiridoshi Y, Takeshita K, Sasajima S, Toya T, Igarashi A, Najima Y, Kobayashi T, Doki N, Motooka D, Nakamura S, Suyama M, Suda W, Shiota A, Atarashi K, Hattori M, Honda K, Yokota T, Ohashi K, Shibayama H, Fukushima K, Kakihana K.
  • Journal Title: Bone Marrow Transplant Volume: 56 Issue: 7 Pages: 1728-1731
  • DOI: 10.1038/s41409-021-01249-2
  • Peer Reviewed
• [Journal Article] High numbers of programmed cell death-1-positive tumor infiltrating lymphocytes correlate with early onset of post-transplant lymphoproliferative disorder (2021)
  • Author(s): Saito Hideaki、Miyoshi Hiroaki、Shibayama Hirohiko、Toda Jun、Kusakabe Shinsuke、Ichii Michiko、Fujita Jiro、Fukushima Kentaro、Maeda Tetsuo、Mizuki Masao、Oritani Kenji、Seto Masao、Yokota Takafumi、Kanakura Yuzuru、Hosen Naoki、Ohshima Koichi
  • Journal Title: International Journal of Hematology Volume: - Issue: 1 Pages: 53-64
  • DOI: 10.1007/s12185-021-03129-3
  • Peer Reviewed
• [Journal Article] Pre- and post-serial metagenomic analysis of gut microbiota as a prognostic factor in patients undergoing haematopoietic stem cell transplantation. (2020)
  • Author(s): Kusakabe S, Fukushima K, Maeda T, Motooka D, Nakamura S, Fujita J, Yokota T, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Br J Haematol Volume: 188 Issue: 3 Pages: 438-449
  • DOI: 10.1111/bjh.16205
  • Peer Reviewed / Open Access
• [Journal Article] Enterococcus: A predictor of ravaged microbiota and poor prognosis after allogeneic hematopoietic stem cell transplantation. (2020)
  • Author(s): Kusakabe S, Fukushima K, Yokota T, Hino A, Fujita J, Motooka D, Nakamura S, Shibayama H, Kanakura Y.
  • Journal Title: Biol Blood Marrow Transplant Volume: 26 Issue: 5 Pages: 1028-1033
  • DOI: 10.1016/j.bbmt.2020.01.019
  • Peer Reviewed / Open Access