Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

• Project/Area Number: 17K15734
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Keio University
• Principal Investigator: Takahashi Daisuke 慶應義塾大学, 薬学部(芝共立), 助教 (40612130)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 酪酸 / 濾胞制御性T細胞数 / 間接リウマチ / 濾胞制御性T細胞 / 自己免疫疾患 / HDAC / 胚中心反応 / 関節リウマチ / 腸内細菌 / コラーゲン誘発性関節炎 / 濾胞性制御性T細胞 / 濾胞性制御性T細胞 (Tfr) / コラーゲン誘発関節炎 / 自己反応抗体

Outline of Final Research Achievements

We found that butyrate, one of the short-chain fatty acids produced by the gut commensal bacteria, significantly decreased in the intestinal tract of the early stages untreated rheumatoid arthritis patients compared to healthy people. Furthermore, we found that the treatment of the butyrate diet mitigated the development of an autoimmune rheumatoid arthritis model in mice. Butyrate increased the number of follicular regulatory T cells and suppressed the production of autoantibodies required for the development of arthritis. Moreover, we developed a new follicular regulatory T cell culture system and examined the mechanism of induction of follicular regulatory T cell differentiation by butyrate. Using the culture system, we found that butyrate promotes the differentiation of follicular regulatory T cells by inducing the expression of the transcriptional repressor Bcl-6, which is essential for the differentiation through its histone deacetylase inhibitory action.

Academic Significance and Societal Importance of the Research Achievements

本研究では、発症初期の未治療の関節リウマチ患者の腸管内の酪酸濃度が健常者と比較して顕著に低い事を明らかにしている。さらに、酪酸産生菌が顕著に減少することを見出した。これは、腸内の酪酸産生が減少することと関節リウマチの発症との関連性を示す成果である。実際マウス関節リウマチモデルを用いた検討から、酪酸産生菌により酪酸が産生される飼料を与えることで、関節炎の症状が著明に改善した。以上のことから、発症初期の関節リウマチ患者へ酪酸が産生される食事を予防的に提供することで、将来的な症状を抑制できると考えている。これを既存薬と合わせて使用し、効果的な関節リウマチ治療法に結び付くと期待している。

Research Products

• [Journal Article] Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon (2021)
  • Author(s): Nakamura Atsuo、Kurihara Shin、Takahashi Daisuke、Ohashi Wakana、Nakamura Yutaka、Kimura Shunsuke、Onuki Masayoshi、Kume Aiko、Sasazawa Yukiko、Furusawa Yukihiro、Obata Yuuki、Fukuda Shinji、Saiki Shinji、Matsumoto Mitsuharu、Hase Koji
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2105-2105
  • DOI: 10.1038/s41467-021-22212-1
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial HVEM promotes basement membrane synthesis and intraepithelial T cell survival and migration (2020)
  • Author(s): Daisuke Takahashi*, Qingyang Wang*, Goo-Young Seo* (*equal contribution), Jr-wen Shui, Zbigniew Mikulski, Paola Marcovecchio, Masumi Takahashi, Charles D. Surh, Hilde Cheroutre, Mitchell Kronenberg
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2020.09.30.317628
  • Open Access
• [Journal Article] Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression (2020)
  • Author(s): Atsuo Nakamura, Daisuke Takahashi*, Yutaka Nakamura, Takahiro Yamada, Mitsuharu Matsumoto* (*equal correspondence), Koji Hase
  • Journal Title: Arch Biochem Biophys Volume: 693 Pages: 108587-108587
  • DOI: 10.1016/j.abb.2020.108587
  • Peer Reviewed
• [Journal Article] Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells (2020)
  • Author(s): Daisuke Takahashi, Naomi Hoshina, Yuma Kabumoto, Yuichi Maeda, Akari Suzuki, Hiyori Tanabe, Junya Isobe, Takahiro Yamada, Kisara Muroi, Yuto Yanagisawa, Atsuo Nakamura, ... Koji Hase
  • Journal Title: EBioMedicine Volume: 58 Pages: 102913-102913
  • DOI: 10.1016/j.ebiom.2020.102913
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon. (2020)
  • Author(s): Junya Isobe, Shintarou Maeda, Yuuki Obata, Keito Iizuka, Yutaka Nakamura, Yumiko Fujimura, Tatsuki Kimizuka, Kouya Hattori, Yun-Gi Kim, Tatsuya Morita, Ikuo Kimura, Stefan Offermanns, Takahiro Adachi, Atsuhito Nakao, Hiroshi Kiyono, Daisuke Takahashi, Koji Hase
  • Journal Title: International Immunology Volume: 32 Issue: 4 Pages: 243-258
  • DOI: 10.1093/intimm/dxz078
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases (2019)
  • Author(s): Kobayashi Nobuhide、Takahashi Daisuke、Takano Shunsuke、Kimura Shunsuke、Hase Koji
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 2345-2345
  • DOI: 10.3389/fimmu.2019.02345
  • Peer Reviewed / Open Access
• [Presentation] Microbiota-derived Butyrate Limits the Autoimmune Response by promoting the Differentiation of Follicular Regulatory T cells (2019)
  • Author(s): Daisuke Takahashi, Koji Hase
  • Organizer: アメリカ免疫学会年次総会
  • Int'l Joint Research
• [Presentation] AP-1B-dependent sorting of basolateral membrane protein is required for maintenance of intestinal intraepithelial lymphocytes (2018)
  • Author(s): Daisuke Takahashi, Ryohtaroh Matsumoto, Koji Hase
  • Organizer: 日本免疫学会学術集会
• [Presentation] Microbial fermentation product butyrate Ameliorates Autoimmune Arthritis. (2018)
  • Author(s): Daisuke Takahashi, Trevor Lockett, Julie M Clarke, David L Topping, Koji Hase
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology
• [Patent(Industrial Property Rights)] 濾胞性制御性T細胞の製造方法 (2019)
  • Inventor(s): 長谷耕二、高橋大輔
  • Industrial Property Rights Holder: 学校法人慶應義塾
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-185826
  • Filing Date: 2019