Crosstalk between hematopoiesis and intestinal flora

• Project/Area Number: 17K19641
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine and related fields
• Research Institution: Hokkaido University
• Principal Investigator: Teshima Takanori 北海道大学, 医学研究院, 教授 (40284096)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 腸内細菌 / がん化学療法 / 造血幹細胞移植 / 緊急造血 / IL-17 / 造血 / G-CSF / 好中球 / GVHD / 生着 / 腸内フロラ / 腸内フローラ

Outline of Final Research Achievements

We evaluated role of intestinal microbiota on adult emergent myelopoiesis. After hematopoietic stem cell transplantation (HSCT), engraftment was achieved following increase in serum levels of G-CSF and IL-17A. Production of these cytokine and engraftment was impaired in IL-17A-/- mice and RAG-/- mice, suggesting that T cells play a critical role on the cytokine production. Gut decontamination by oral antibiotics impaired cytokine production and engraftment, indicating that intestinal microbiota plays a critical role in adult emergent myelopoiesis.

Academic Significance and Societal Importance of the Research Achievements

胎生期の造血の開始には母から胎児へと引き継がれる腸内細菌が重要な役割を果たすことが証明されている。一方、出生後の緊急時の造血（がん治療や感染症などによって減少した血液を増加させること）と腸内細菌叢の関連は明らかにされていない。本研究によって、腸内細菌がＴリンパ球のサイトカインIL-17産生を促すことによって造血の回復を促進していることが世界で初めて明らかになった。この結果から、健康な腸内細菌を維持することががん治療においても大切であることが示された。

Research Products

• [Int'l Joint Research] QIMR Berghofer医学研究所(オーストラリア)
• [Int'l Joint Research] Queensland institute of Medical Research(オーストラリア)
• [Int'l Joint Research] Queensland Institute of Medical Research(Australia)
• [Journal Article] Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis. (2020)
  • Author(s): Yokoyama E, Hashimoto D, Hayase E, Ara T, Ogasawara R, Takahashi S, Ohigashi H, Tateno T, Hasegawa Y, Chen X, Teshima T.
  • Journal Title: Bone Marrow Transplant. Volume: 55 Issue: 4 Pages: 787-795
  • DOI: 10.1038/s41409-019-0733-8
  • Peer Reviewed / Open Access
• [Journal Article] Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation (2020)
  • Author(s): Peled Jonathan U.、Gomes Antonio L.C.、Devlin Sean M.、Littmann Eric R.、Taur Ying、Sung Anthony D.、Teshima Takanori、…van den Brink Marcel R.M.
  • Journal Title: New England Journal of Medicine Volume: 382 Issue: 9 Pages: 822-834
  • DOI: 10.1056/nejmoa1900623
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ocular instillation of vitamin A-coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD. (2019)
  • Author(s): Ohigashi, H., Hashimoto, D., Hayase, E., Takahashi, S., Ara, T., Yamakawa, T., Sugita, J., Onozawa, M., Nakagawa, M., Teshima, T.
  • Journal Title: Blood Adv. Volume: 3 Issue: 7 Pages: 1003-1010
  • DOI: 10.1182/bloodadvances.2018028431
  • Peer Reviewed / Open Access
• [Journal Article] Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation (2019)
  • Author(s): Toffalori Cristina、Zito Laura、Gambacorta Valentina、Riba Michela、Oliveira Giacomo、Bucci Gabriele、Teshima Takanori、…Vago Luca
  • Journal Title: Nature Medicine Volume: 25 Issue: 4 Pages: 603-611
  • DOI: 10.1038/s41591-019-0400-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease (2019)
  • Author(s): Matsuoka Satomi、Hashimoto Daigo、Kadowaki Masanori、Ohigashi Hiroyuki、Hayase Eiko、Yokoyama Emi、Hasegawa Yuta、Tateno Takahiro、Chen Xuanzhong、Aoyama Kazutoshi、Oka Hideyo、Onozawa Masahiro、Takeda Kiyoshi、Akashi Koichi、Teshima Takanori
  • Journal Title: Haematologica Volume: 105 Issue: 1 Pages: 226-234
  • DOI: 10.3324/haematol.2018.203380
  • Peer Reviewed / Open Access
• [Journal Article] Lactose drives Enterococcus expansion to promote graft-versus-host disease (2019)
  • Author(s): Stein-Thoeringer C. K.、Nichols K. B.、Lazrak A.、Docampo M. D.、Slingerland A. E.、Slingerland J. B.、Teshima T.、…van den Brink M. R. M.
  • Journal Title: Science Volume: 366 Issue: 6469 Pages: 1143-1149
  • DOI: 10.1126/science.aax3760
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intestinal Lymphatic Endothelial Cells Produce R-Spondin3 (2018)
  • Author(s): Ogasawara Reiki、Hashimoto Daigo、Kimura Shunsuke、Hayase Eiko、Ara Takahide、Takahashi Shuichiro、Ohigashi Hiroyuki、Yoshioka Kosuke、Tateno Takahiro、Yokoyama Emi、Ebata Ko、Kondo Takeshi、Sugita Junichi、Onozawa Masahiro、Iwanaga Toshihiko、Teshima Takanori
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41598-018-29100-7
  • Peer Reviewed / Open Access
• [Journal Article] The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): Hidaka Daisuke、Hayase Eiko、Shiratori Souichi、Hasegawa Yuta、Ishio Takashi、Tateno Takahiro、Okada Kohei、Goto Hideki、Sugita Junichi、Onozawa Masahiro、Nakagawa Masao、Kahata Kaoru、Endo Tomoyuki、Hashimoto Daigo、Teshima Takanori
  • Journal Title: Clinical Transplantation Volume: 32 Issue: 9
  • DOI: 10.1111/ctr.13361
  • Peer Reviewed
• [Journal Article] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease. (2018)
  • Author(s): Yamakawa T, Ohigashi H, Hashimoto D, Hayase E, Takahashi S, Miyazaki M, Minomi K, Onozawa M, Niitsu Y, Teshima T
  • Journal Title: Blood Volume: 131(13) Pages: 1476-1485
  • NAID: 120006595502
  • Peer Reviewed / Open Access
• [Journal Article] Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease. (2018)
  • Author(s): Takahashi S, Hashimoto D, Hayase E, Ogasawara R, Ohigashi H, Ara T, Yokoyama E, Ebata K, Matsuoka S, Hill G, Sugita J, Onozawa M, Teshima T
  • Journal Title: Blood Volume: [Epub ahead of print]
  • NAID: 120006626559
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microbiome-Host Interactions in Hematopoietic Stem-Cell Transplant Recipients. (2018)
  • Author(s): Andermann T, Peled J, Ho C, Reddy P, Riches M, Storb R,Teshima T, van den Brink M, Alousi A, Balderman S, Chiusolo P, Clark W, Holler E, Howard A, Kean L, Koh A, McCarthy P, McCarty J, Mohty M, Nakamura R, Rezvani K, Segal B, Shaw B, Shpall E, Sung A, Weber D, Whangbo J, Wingard J, Wood W, Perales MA, Jenq R, Bhatt A
  • Journal Title: Biol Blood Marrow Transplant Volume: [Epub ahead of print]
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease. (2017)
  • Author(s): Hayase E, Hashimoto D, Nakamura K, Noizat C, Ogasawara R, Takahashi S, Ohigashi H, Yokoi Y, Sugimoto R, Matsuoka S, Ara T, Yokoyama E, Yamakawa T, Ebata K, Kondo T, Hiramine R, Aizawa T, Ogura Y, Hayashi T, Mori H, Kurokawa K, Tomizuka K, Ayabe T, Teshima T.
  • Journal Title: J Exp Med Volume: 214 (12) Pages: 3507-3518
  • NAID: 120006394569
  • Peer Reviewed / Open Access
• [Journal Article] Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice. (2017)
  • Author(s): Kosugi-Kanaya M, Ueha S, Abe J, Shichino S, Shand FHW, Morikawa T, Kurachi M, Shono Y, Sudo N, Yamashita A, Suenaga F, Yokoyama A, Yong W, Imamura M, Teshima T, Matsushima K.
  • Journal Title: Front Immunol Volume: 8 Pages: 1842-1842
  • DOI: 10.3389/fimmu.2017.01842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 造血幹細胞移植後の腸内フローラの解析 (2020)
  • Author(s): 豊嶋崇徳
  • Organizer: 第53回日本無菌生物ノートバイオロジー学会総会
  • Invited
• [Presentation] Intestinal microbioata are associated with outcome of hematopoietc stem cell transplantation (2019)
  • Author(s): Takanori Teshima
  • Organizer: The 10th Asian Cellular Therapy Organization
  • Int'l Joint Research / Invited
• [Presentation] Restoration of gut microbial ecology (2019)
  • Author(s): Takanori Teshima
  • Organizer: 1st EBMT GVHD Summit
  • Int'l Joint Research / Invited
• [Presentation] Novel insights in target tissue injury in graft-versus-host disease (2018)
  • Author(s): Takanori Teshima
  • Organizer: Hematology/Oncology Seminar, Icahn School of Medicine at Mount Sinai
  • Int'l Joint Research / Invited
• [Presentation] Intestinal microbiota play a critical role in neutrophil engraftment posttransplant and recovery after chemotherapy by stimulating T cell production of IL-17A. (2017)
  • Author(s): Ebata K, Hashimoto D,Takahashi S,Hayase E,Ogasawara R,Teshima T
  • Organizer: 59th ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] Gastric stem cells are targeted in upper gastrointestinal GVHD. 59th ASH Annual Meeting, Dec 9-12, 2017, Atlanta, GA, USA. (2017)
  • Author(s): Hayase E, Hashimoto D,Takahashi S,Ohigashi H,Takahiro T,Ara T,Yokoyama E,Teshima T.
  • Organizer: 59th ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] パネト細胞増殖因子としてのR-Spondin1と抗菌ペプチドを用いた腸内エコロジーシステムの制御法 (2017)
  • Author(s): 早瀬英子, 橋本大吾，中村公則，平峰里奈，相沢智康，近藤健，小椋義俊，林哲也，森宙史，黒川顕，綾部 時芳，豊嶋崇徳
  • Organizer: 第二回北大・部局横断シンホ_シ_ウム『免疫・癌・感染』
• [Presentation] 同種造血幹細胞移植後の腸管GVHD発症と抗菌薬投与の関連 (2017)
  • Author(s): 日高大輔, 早瀬英子, 白鳥聡一, 石尾崇, 立野貴大, 岡田耕平, 後藤秀樹, 杉田純一, 小野澤真弘, 中川雅夫, 加畑馨, 藤本勝也, 遠藤知之, 近藤健, 橋本大吾, 豊嶋崇徳
  • Organizer: 第79回日本血液学会学術集会