The effects of Atg5-independent autophagy activator on DSS-induced colitis in mice

• Project/Area Number: 17K10632
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: Matsuda Chu 大阪大学, 医学系研究科, 准教授 (00379207)
• Co-Investigator(Kenkyū-buntansha): 水島 恒和 大阪大学, 医学系研究科, 寄附講座教授 (00527707) ; 西村 潤一 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 消化器外科副部長 (20379209) ; 清水 重臣 東京医科歯科大学, 難治疾患研究所, 教授 (70271020)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: オートファジー / 炎症性腸疾患

Outline of Final Research Achievements

Disturbed activation of autophagy is implicated in the pathogenesis of colitis via excessive immune response. We screened the autophagy activators from a library including natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2 % dextran sodium sulfate (DSS). Among the autophagy inducers, 3 compounds suppressed DSS-induced colitis. Among three, sample A ameliorate DSS-induced colitis by providing intestinal macrophage with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.
Furthermore, our results indicated that a mixture of tannins including ellagic acid, gallic acid and catechin acid have important role on colitis amelioration via autophagy activation in macrophage.

Academic Significance and Societal Importance of the Research Achievements

腸管に慢性的な炎症を呈することで知られる炎症性腸疾患(IBD)は、未だ発症原因が明らかではなく、発症原因の解明と、それに対応した治療法の開発が求められている。本検討では、オートファジーの誘導が、マクロファージにおけるサイトカイン産生調整を介して、腸炎緩和に寄与することを示唆する結果を得た。同定サンプルAは今後、ヒトサンプルを用いた解析、並びに安全性検討を経て、炎症性腸疾患の新規治療薬候補となり得る可能性がある。

Research Products

• [Journal Article] Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages (2019)
  • Author(s): Asuka Yasueda, Hisako Kayama, Michiko Murohashi, Junichi Nishimura, Koji Wakame, Ken-ichi Komatsu, Takayuki Ogino, Norikatsu Miyoshi, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Toru Kitagawa, Kiyoshi Takeda, Toshinori Ito, Yuichiro Doki, Hidetoshi Eguchi, Shigeomi Shimizu and Tsunekazu Mizushima,
  • Journal Title: Scientific Reports Volume: -
  • Peer Reviewed
• [Presentation] Autophagy induction of epithelium alleviate colitis in DSS model mice (2019)
  • Author(s): Asuka Yasueda, Shigeomi Shimizu, Junichi Nishimura, Michiko Murohashi, Takayuki Ogino, Yoshifumi Watanabe, Koji Wakame, Kenichi Komatsu, Norikatsu Miyoshi, Hidekazu Takahashi ,Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki,
  • Organizer: UEG WEEK 2019 Bercelona (Spain)
  • Int'l Joint Research
• [Presentation] オートファジー誘導物質による薬剤誘導性腸炎緩和効果の検討 (2019)
  • Author(s): 安枝明日香, 荻野崇之, 清水重臣, 西村潤一, 室橋道子, 渡部嘉文, 三吉範克,高橋秀和, 原口直紹, 畑泰司, 松田宙, 水島恒和, 森正樹, 土岐祐一郎
  • Organizer: 第56回日本消化器免疫学会総会