Investigation of the mechanisms for inhibitory effects on colonic inflammation and cancer of indigo naturalis including indole compounds

• Project/Area Number: 16K09326
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: Naganuma Makoto 慶應義塾大学, 医学部(信濃町), 准教授 (00265810)
• Co-Investigator(Kenkyū-buntansha): 金井 隆典 慶應義塾大学, 医学部(信濃町), 教授 (40245478)
• Research Collaborator: Toshiaki Teratani ; Mizuno Shinta
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: AhR リガンド / 生薬青黛 / 潰瘍性大腸炎 / 大腸癌 / 腸内細菌叢 / 青黛 / Aryl Hydrocarbon受容体 / 炎症性腸疾患

Outline of Final Research Achievements

In this research subject, indigo naturalis has the control of enteritis in a dose-dependent manner in both mouse colitis model and patients with ulcerative colitis. The mechanisms of anti-inflammatory effect were associated with inducing IL-22 which repaired mucosal damage and the up-regulation regulatory T cells. For the efficacy of indigo naturalis on microbiota, the abundance of Bifidobacterium was significantly changed after treatment of indigo naturalis in colitis model and UC patients.
In addition, using the mouse model for colitis associated cancer, the inhibitory effect of indigo naturalis on colon cancer was confirmed, and it was revealed that indigo naturalis has an inhibitory effect on colitis associated cancers independently of inflammation suppression.

Academic Significance and Societal Importance of the Research Achievements

青黛による抗炎症効果の作用機序が粘膜修復に関与するIL-22の亢進以外にも、青黛が調節性T細胞や腸内細菌叢に直接影響を及ぼし、炎症を抑制していることが明らかになった。また青黛が大腸癌の発症抑制に関与していることも示された。炎症性腸疾患患者において、既存治療抵抗・依存例は多く存在し、さらに慢性炎症の持続により大腸癌を発生することが社会的問題となっているが、今回の検討により機序不明であった青黛がマウスモデルおよび潰瘍性大腸炎患者において抗炎症効果を有し、その機序が明らかになったことは、今後新たな炎症性腸疾患の新規治療法の創薬探索に直結するものであると考えられた。

Research Products

• [Journal Article] Efficacy of Indigo naturalis in a Multicenter Randomized Controlled Trial of Patients with Ulcerative Colitis (2018)
  • Author(s): .Naganuma M, Sugimoto S, Mitsuyama K, Kobayashi T, Yoshimura N, Ohi H, Tanaka S, Andoh A, Ohmiya N, Saigusa K, Yamamoto T, Morohoshi Y, Ichikawa H, Matsuoka K, Hisamatsu T, Watanabe K, Mizuno S, Suda W, Hattori M, Fukuda S, Hirayama A, Abe T, Watanabe M, Hibi T, Suzuki Y, Kanai T
  • Journal Title: Gastroenterology. Volume: 4 Pages: 935-947
  • DOI: 10.1053/j.gastro.2017.11.024
  • Peer Reviewed / Open Access
• [Journal Article] Indole compounds may be promising medicines for ulcerative colitis. (2016)
  • Author(s): Sugimoto S, Naganuma M, Kanai T.
  • Journal Title: Journal of Gastroenterology Volume: 51(9) Pages: 853-61
  • DOI: 10.1007/s00535-016-1220-2
  • Peer Reviewed
• [Presentation] Indigo naturalis is effective in treatment-refractory patients with ulcerative colitis: Post-hoc analysis from INDIGO study. (2018)
  • Author(s): Naganuma M et al
  • Organizer: American Gastroenterological Association
  • Int'l Joint Research
• [Presentation] Recent evidences and future perspect of indigo naturalis for ulcerative colitis. (2018)
  • Author(s): Naganuma M et al
  • Organizer: Japan Digestive Disease Week 2018
  • Int'l Joint Research
• [Presentation] Indigo naturalis is effective for inducing clinical remission and mucosal healing in patients with ulcerative colitis. (INDIGO study). (2017)
  • Author(s): Naganuma M et al
  • Organizer: United European Gastroenterology Week
  • Int'l Joint Research