Microbiota-derived lactate and dietary responses of colonocytes; molecular bases for the manipulation of cell turnover by changing eating behavior to avoid cancer risk

• Project/Area Number: 15H04503
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Food science
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Dohi Taeko 国立研究開発法人国立国際医療研究センター, 消化器疾患研究部, 部長 (60250221)
• Research Collaborator: KAWAMURA Yuki I 国立国際医療研究センター研究所, 肝炎・免疫研究センター消化器疾患研究部, 室長
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 絶食 / 乳酸 / 大腸 / 肥満 / 大腸上皮細胞 / 菌叢 / 大腸癌 / 高脂肪食 / 食品 / 脂肪酸 / 摂食応答 / 細胞回転

Outline of Final Research Achievements

Turnover of gastrointestinal epithelial cells arrests at fasting, while refeeding induces transient hyperproliferation by the action of lumenal lactate produced by commensal microbiota. In this study, we found that this physiological response of colonocytes to fasting-refeeding was disturbed in high fat diet-fed obese mice, which resulted in the increased risk of carcinogenesis. However, we also showed that manipulation of colonocyte turnover with delivery of lactate into the colon lumen and setting appropriate fasting period was able to reduce colonic inflammation, promote epithelial repair, and reduce the risk of carcinogenesis.

Research Products

• [Journal Article] Intermittent fasting prompted recovery from dextran sulfate sodium-induced colitis in mice (2017)
  • Author(s): Okada T, Otsubo T, Hagiwara T, Inazuka F, Kobayashi E, Fukuda S, Inoue T, Higuchi K, Kawamura YI and Dohi T.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 61 Issue: 2 Pages: 100-107
  • DOI: 10.3164/jcbn.17-9
  • NAID: 130006038887
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice (2017)
  • Author(s): Sezaki, T. Hirata, Y. Hagiwara, T. Kawamura, Y. I. Okamura, T. Takanashi, R. Nakano, K. Tamura-Nakano, M. Burkly, L. C. Dohi, T.
  • Journal Title: World J Gastroenterol Volume: 23 Issue: 13 Pages: 2294-2307
  • DOI: 10.3748/wjg.v23.i13.2294
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DNA Hypermethylation and silencing of PITX1 correlated with advanced stage and poor postoperative prognosis of esophageal squamous cell carcinoma (2017)
  • Author(s): Otsubo T, Yamada K, Hagiwara T, Oshima K, Iida K, Nishikata K, Toyoda T, Igari T, Nohara K, Yamashita S, Hattori M, Dohi T and Kawamura YI.
  • Journal Title: Ongotarget Volume: 8 Issue: 48 Pages: 84434-84448
  • DOI: 10.18632/oncotarget.21375
  • Peer Reviewed / Open Access
• [Journal Article] 腸内細菌をめぐって発癌と腸内細菌-大腸癌と腸内細菌 (2017)
  • Author(s): 土肥 多惠子
  • Journal Title: Intestine Volume: 21 Pages: 331-334
• [Journal Article] Intermittent fasting prompted recovery from dextran sulfate sodium-induced colitis in mice (2017)
  • Author(s): Toshihiko Okada Takeshi Otsubo Teruki Hagiwara Fumika Inazuka Eiko Kobayashi Shinji Fukuda Takuya Inoue Kazuhide Higuchi Yuki I. Kawamura Taeko Dohi
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 印刷中
  • NAID: 130006038887
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fatty acids in a high-fat diet potentially induce gastric parietal-cell damage and metaplasia in mice (2016)
  • Author(s): Hirata, Y. Sezaki, T. Tamura-Nakano, M. Oyama, C. Hagiwara, T. Ishikawa, T. Fukuda, S. Yamada, K. Higuchi, K. Dohi, T. Kawamura, Y. I.
  • Journal Title: J Gastroenterol Volume: - Issue: 8 Pages: 889-903
  • DOI: 10.1007/s00535-016-1291-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of IFN-lambda3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection (2016)
  • Author(s): Murata, K. Asano, M. Matsumoto, A. Sugiyama, M. Nishida, N. Tanaka, E. Inoue, T. Sakamoto, M. Enomoto, N. Shirasaki, T. Honda, M. Kaneko, S. Gatanaga, H. Oka, S. Kawamura, Y. I. Dohi, T. Shuno, Y. Yano, H. Mizokami, M.
  • Journal Title: Gut Volume: - Issue: 2 Pages: 362-371
  • DOI: 10.1136/gutjnl-2016-312653
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Histone Methyltransferase ESET Is Critical for T Cell Development (2016)
  • Author(s): Takikita, S. Muro, R. Takai, T. Otsubo, T. Kawamura, Y. I. Dohi, T. Oda, H. Kitajima, M. Oshima, K. Hattori, M. Endo, T. A. Toyoda, T. Weis, J. Shinkai, Y. Suzuki, H.
  • Journal Title: J Immunol Volume: 197 Issue: 6 Pages: 2269-2279
  • DOI: 10.4049/jimmunol.1502486
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interferon-gamma Constrains Cytokine Production of Group 2 Innate Lymphoid Cells (2016)
  • Author(s): Kudo, F. Ikutani, M. Seki, Y. Otsubo, T. Kawamura, Y. I. Dohi, T. Oshima, K. Hattori, M. Nakae, S. Takatsu, K. Takaki, S.
  • Journal Title: Immunology Volume: 147 Issue: 1 Pages: 21-29
  • DOI: 10.1111/imm.12537
  • Peer Reviewed
• [Presentation] 食道扁平上皮癌において免疫チェックポイントを制御する新規がん抑制遺伝子NCCRP1 (2017)
  • Author(s): 河村 由紀, 稲塚 歩佳, 山田 和彦、相馬 大介, 猪狩 亨, 土肥 多惠子
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 消化管発がんと腸内細菌叢--管腔内環境がもたらす上皮細胞の変化 (2017)
  • Author(s): 土肥多惠子、河村由紀
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] DNAメチル化亢進によるPITX1遺伝子発現抑制は食道扁平上皮癌の予後不良と関連する. (2017)
  • Author(s): 河村 由紀, 大坪 武史, 山田 和彦, 萩原 輝記, 大島 健志朗, 飯田 慶, 西方 公郎, 豊田 哲郎, 猪狩 亨, 野原 京子, 服部 正平, 土肥 多惠子.
  • Organizer: 生命科学系学会合同年次大会ConBio2017
• [Presentation] 栄養シグナルによるパイエル板の恒常性維持機構の解明 (2017)
  • Author(s): 野口 遼太郎, 永井 基慈, 越田 航平, 高橋 大輔, 河村 由紀, 土肥 多惠子, 長谷 耕二.
  • Organizer: 生命科学系学会合同年次大会ConBio2017
• [Presentation] Nutritional signals are essential for the regulation of cell dynamics and mucosal immune response in GALT (2017)
  • Author(s): Motoyoshi Nagai, Ryotaro Noguchi, Daisuke Takahashi, Yuki I Kawamura, Taeko Dohi, Koji Hase.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Activation of NK/group1-innate lymphoid cells in adipose tissues depends on the composition of fatty acids in high fat diet. (2017)
  • Author(s): Saito Y, Mori T, Kawamura YI, Dohi T, Takaki S.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 消化管の摂食応答から見た発癌－予防は可能か？ (2016)
  • Author(s): 土肥 多惠子
  • Organizer: 題5回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 高脂肪食が引き起こすマウス上部消化管病変 (2016)
  • Author(s): 平田 有基, 瀬崎 拓人, 中野 美和, 山田 和彦, 樋口 和秀, 河村 由紀, 土肥 多恵子
  • Organizer: JDDW2016
  • Place of Presentation: 神戸
• [Presentation] 消化管の絶食-摂食に対する応答とマイクロバイオータ (2016)
  • Author(s): 土肥 多惠子
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] High fat diet induces oxyntic gastritis and metaplasia in wild type mice (2015)
  • Author(s): Hirata Y, Sezaki T, Dohi T and Kawamura YI.
  • Organizer: 第44回免疫学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Fn14 disruption suppresses 5-Fluorouracil-induced-diarrhea by enhancing IL-33 and IL-13Rα2 expression. (2015)
  • Author(s): Sezaki T, Hirata Y, Kawamura YI, Dohi T.
  • Organizer: 第44回免疫学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] 食道扁平上皮癌のメチロームおよびトランスクリプトーム統合解析により見出されたデスモソーム関連分子periplakinの発現低下 (2015)
  • Author(s): 河村 由紀、大坪 武史、山田 和彦、猪狩 亨、土肥 多惠子
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
• [Book] 手術用シーラント剤・癒着防止剤の利便化向上を目指した製品開発 (2016)
  • Author(s): 土肥多惠子
  • Total Pages: 494
  • Publisher: 技術情報協会
• [Book] ヒトマイクロバイオーム研究最前線, 絶食―再摂食サイクルと腸内細菌叢 (2016)
  • Author(s): 土肥 多惠子
  • Total Pages: 11
  • Publisher: 株式会社 エヌ・ティー・エス
• [Book] 摂食による消化管粘膜の増殖応答 (2015)
  • Author(s): 土肥 多惠子
  • Total Pages: 4
  • Publisher: 先端医学社