Exploring the gut microbiota-derived immunomodulation factors

• Project/Area Number: 24380072
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Food science
• Research Institution: Keio University
• Principal Investigator: FUKUDA Shinji 慶應義塾大学, 政策・メディア研究科, 准教授 (80435677)
• Co-Investigator(Kenkyū-buntansha): HASE Koji 慶應義塾大学, 薬学部, 教授 (20359714)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2012: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: メタボロミクス / 統合オミクス / 腸内細菌 / 腸内代謝産物 / 短鎖脂肪酸 / 酪酸 / 炎症 / 制御性T細胞 / 腸内細菌叢 / メタボロゲノミクス / 腸内エコシステム / メタゲノミクス / メタボローム / エピゲノム / オミクス / 代謝産物 / 免疫修飾因子

Outline of Final Research Achievements

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. We show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. An integrated omics approach identified gut microbiota-derived butyrate epigenetically induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis in mice. Our findings provide new insight into the mechanisms by which host–microbe interactions establish immunological homeostasis in the gut.

Research Products

• [Journal Article] Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD. (2015)
  • Author(s): Mishima, E., Fukuda, S., (co-first author) et al.
  • Journal Title: Journal of the American Society of Nephrology Volume: 26
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Toward the comprehensive understanding of the gut ecosystem via metabolomics-based integrated omics approach. (2015)
  • Author(s): Aw, W. and Fukuda, S. (co-first and corresponding author)
  • Journal Title: Seminars in Immunopathology Volume: 37 Issue: 1 Pages: 5-16
  • DOI: 10.1007/s00281-014-0456-2
  • Peer Reviewed
• [Journal Article] Periodontal disease bacteria specific to tonsil in IgA nephropathy patients predicts the remission by the treatment (2014)
  • Author(s): Nagasawa, Y., Iio, K., Fukuda, S. (co-first author) et al.
  • Journal Title: PLoS ONE Volume: 9 Issue: 1 Pages: e81636-e81636
  • DOI: 10.1371/journal.pone.0081636
  • Peer Reviewed
• [Journal Article] Gut microbiome and metabolic diseases (2014)
  • Author(s): Fukuda, S. and Ohno, H.
  • Journal Title: Seminars in Immunopathology Volume: 36 Issue: 1 Pages: 103-114
  • DOI: 10.1007/s00281-013-0399-z
  • Peer Reviewed
• [Journal Article] メタボロミクスによる腸内エコシステムの理解 (2014)
  • Author(s): 福田真嗣
  • Journal Title: 医学のあゆみ Volume: 249 Pages: 13780-13785
• [Journal Article] Commensal microbe-derived butyrate induces colonic regulatory T cells (2013)
  • Author(s): Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda, Shinnosuke Murakami, Eiji Miyauchi, Shingo Hino, Koji Atarashi, Satoshi Onawa, Yumiko Fujimura, Trevor Lockett, Julie M. Clarke, David L. Topping, Masaru Tomita, Shohei Hori, Osamu Ohara, Tatsuya Morita, Haruhiko Koseki, J un Kikuchi, Kenya Honda, Koji Hase and Hiroshi Ohno
  • Journal Title: Nature Volume: 506 Issue: 7480 Pages: 446-450
  • DOI: 10.1038/nature12721
  • Peer Reviewed
• [Journal Article] Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota (2013)
  • Author(s): Koji Atarashi, Takeshi Tanoue, et al.
  • Journal Title: Nature Volume: 500 Issue: 7461 Pages: 232-236
  • DOI: 10.1038/nature12331
  • Peer Reviewed
• [Journal Article] 統合オミクスが解き明かす腸内細菌叢の機能 (2013)
  • Author(s): 福田真嗣、長谷耕二、大野博司
  • Journal Title: 実験医学 Volume: 32 Pages: 726-732
• [Journal Article] 統合オミクスによる腸エコシステムの全容理解に向けた取り組み (2013)
  • Author(s): 福田真嗣、大野博司
  • Journal Title: 細胞工学 Volume: 32 Pages: 1138-1142
• [Journal Article] Robustness of gut microbiota of healthy adults in response to probiotic intervention revealed by high-throughput pyrosequencing. (2013)
  • Author(s): Kim, SW.
  • Journal Title: DNA Research Volume: 20(in press) Issue: 3 Pages: 241-253
  • DOI: 10.1093/dnares/dst006
  • Peer Reviewed
• [Journal Article] Microbiota-derived lactate accelerates colon epithelial cell turnover in starvation-refed mice (2013)
  • Author(s): Okada T
  • Journal Title: Nat. Commun Volume: 4巻 Issue: 1 Pages: 1654-1654
  • DOI: 10.1038/ncomms2668
  • Peer Reviewed
• [Journal Article] Thermophile-fermented compost as a possible scavenging feed additive to prevent peroxidation. (2013)
  • Author(s): Miyamoto, H.
  • Journal Title: Journal of Bioscience and Bioengineering Volume: 115(in press) Issue: 2 Pages: 203-208
  • DOI: 10.1016/j.jbiosc.2013.01.024
  • Peer Reviewed
• [Journal Article] Identification of novel genes selectively expressed in the follicle-associated epithelium from the meta-analysis of transcriptomics data from multiple mouse cell and tissue populations. (2012)
  • Author(s): Kobayashi A, Donaldson DS, Kanaya T, Fukuda S, Baillie JK, Freeman TC, Ohno H, Williams IR, Mabbott NA.
  • Journal Title: DNA Res. Volume: 19(5) Issue: 5 Pages: 407-22
  • DOI: 10.1093/dnares/dss022
  • Peer Reviewed
• [Journal Article] Acetate-producing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters. (2012)
  • Author(s): Fukuda, S.
  • Journal Title: Gut Microbes Volume: 3 Issue: 5 Pages: 449-454
  • DOI: 10.4161/gmic.21214
  • Peer Reviewed
• [Journal Article] The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells (2012)
  • Author(s): Kanaya, T., Hase, K., Takahashi, D., Fukuda, S., Hoshino, K., Sasaki, I., Hemmi, H., Knoop, K. A., Kumar, N., Sato, M., Katsuno, T., Yokosuka, O., Toyooka, K., Nakai, K., Sakamoto, A., Kitahara, Y., Jinnohara, T., McSorley, S. J., Kaisho, T., Williams, I. R., and Ohno, H.
  • Journal Title: Nat Immunol Volume: 13 Issue: 8 Pages: 729-736
  • DOI: 10.1038/ni.2352
  • Peer Reviewed
• [Journal Article] Exposure to probiotic Lactobacillus acidophilus L-92 modulates gene expression profiles of epithelial Caco-2 cells. (2012)
  • Author(s): Yanagihara, S.
  • Journal Title: Journal of Medicinal Food Volume: 15 Issue: 6 Pages: 511-519
  • DOI: 10.1089/jmf.2012.0040
  • Peer Reviewed
• [Journal Article] 統合オミクスによる腸エコシステムの理解 (2012)
  • Author(s): 福田真嗣
  • Journal Title: 実験医学 Volume: 30 Pages: 3255-3260
• [Presentation] Shedding light on the function of gut microbiota, another organ in our body. (2015)
  • Author(s): Fukuda, S.
  • Organizer: The Immunology Institute Seminar at the Mount Sinai School of Medicine
  • Place of Presentation: Mount Sinai School of Medicine (New York, USA)
  • Year and Date: 2015-03-10
  • Invited
• [Presentation] Shedding light on the function of gut microbiota, another organ in our body. (2014)
  • Author(s): Fukuda, S.
  • Organizer: 14th Japanese-American Frontiers of Science (JAFoS)
  • Place of Presentation: Hotel New Otani (Tokyo)
  • Year and Date: 2014-12-04 – 2014-12-07
  • Invited
• [Presentation] もう一つの臓器： 腸内細菌叢の機能に迫る (2014)
  • Author(s): 福田真嗣
  • Organizer: 日本食物繊維学会第19 回学術集会
  • Place of Presentation: 大妻女子大学（東京）
  • Year and Date: 2014-11-29 – 2014-11-30
  • Invited
• [Presentation] Gut microbiota-derived metabolites shape host physiological homeostasis. (2014)
  • Author(s): 福田真嗣
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] トランスオミクスによる腸内エコシステムがもたらす免疫修飾機構の理解 (2014)
  • Author(s): 福田真嗣
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Elucidation of the beneficial effect of probiotics and prebiotics on host physiology via integrated omics approach. (2014)
  • Author(s): Fukuda, S.
  • Organizer: 1st International Conference on Beneficial Microbes (ICOBM)
  • Place of Presentation: PARKROYAL Penang Resort (Penang, Malaysia)
  • Year and Date: 2014-05-27 – 2014-05-29
  • Invited
• [Presentation] 統合オミクスによる宿主－腸内細菌間相互作用の理解 (2014)
  • Author(s): 福田真嗣
  • Organizer: 日本農芸化学会2014年度大会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Understanding the complex gut ecosystem via integrated omics approach (2014)
  • Author(s): 福田真嗣
  • Organizer: 第87回日本細菌学会総会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Multiple omics approach identified acetate produced by probiotic bifidobacteria to protect host from enterooathoeenic infection. (2012)
  • Author(s): Fukuda, S.
  • Organizer: International Conference and Exhibition of Probiotics
  • Place of Presentation: San Antonio, USA(招待講演)
• [Presentation] Understanding the gut ecosystem via multiple omics approach. (2012)
  • Author(s): Fukuda, S.
  • Organizer: The International Scientific Conference on Probiotics and Prebiotics 2012
  • Place of Presentation: Kosice, Slovakia(招待講演)
• [Presentation] マルチオミクスによる腸内共生システムの理解 (2012)
  • Author(s): 福田真嗣
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡(招待講演)
• [Presentation] 腸内エコシステムの理解に向けたマルチオーミクス解析技術の構築 (2012)
  • Author(s): 福田真嗣
  • Organizer: 第16回腸内細菌学会
  • Place of Presentation: 神戸(招待講演)
• [Presentation] 腸内細菌叢がもたらす生体修飾機構の理解
  • Author(s): 福田真嗣
  • Organizer: 第8回獣医アトピー・アレルギー・免疫学会
  • Place of Presentation: 東京
  • Invited
• [Book] 微生物機能学 (2012)
  • Author(s): 福田真嗣
  • Publisher: 三共出版