Identifications and functional analyses of beneficial bacteria-derived bioactive molecules

• Project/Area Number: 18K07927
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Asahikawa Medical College
• Principal Investigator: Fujiya Mikihiro 旭川医科大学, 医学部, 教授 (80322915)
• Co-Investigator(Kenkyū-buntansha): 上野 伸展 旭川医科大学, 医学部, 特任講師 (30436000) ; 小西 弘晃 旭川医科大学, 医学部, 特任助教 (30777181) ; 盛一 健太郎 旭川医科大学, 医学部, 准教授 (70455715)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: プロバイオティクス / 消化器癌 / 炎症性腸疾患 / 腸内細菌 / 認識機構 / フェリクローム / Heptelidic acid / ポリリン酸 / 大腸腫瘍 / 麹菌 / 乳酸菌 / ビフィズス菌 / 抗腫瘍 / 腸管保護

Outline of Final Research Achievements

We identified heptelidic acid as an anti-pancreatic tumor molecule from the conditioned media of Aspergillus oryzae. Heptelidic acid induced apoptosis through p38 MAPK activation. In ex vivo loop study, heptelidic acid permeated the intestinal wall, and might reach pancreatic tumor. Heptelidic acid also exerted an anti-tumor effect for melanoma cells through the inhibition of GAPDH. Lactobacillus brevis-derived polyphosphate enhanced mucosal healing through the activation of platelets. Lactobacillus casei-derived ferrichrome exerted an anti-tumor effect for the pancreatic tumor through the activation of p53.

Academic Significance and Societal Importance of the Research Achievements

腸管保護活性や抗腫瘍活性を持つ非特異的な細菌代謝産物(酪酸、酢酸など)の報告は多い。しかし、プロバイオティクス由来の特異的な活性分子を同定し、その作用機序を解明した研究は非常に少なく、我々の報告に加え、Lactobacillus rhamnosus GG由来のp40やp75、Lactobacillus casei ATCC 334 由来のm2163やm2386などに限られている。本研究は、多数のプロバイオティクスについて、菌由来活性分子の同定とその作用機序を解明する独創的な研究であり、その研究成果は菌由来分子を用いた新規治療薬開発へと発展する高い社会的意義を持つ。

Research Products

• [Int'l Joint Research] University of California, Davis(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, Davis(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, Davis(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Journal Article] Probiotic Aspergillus oryzae produces anti-tumor mediator and exerts anti-tumor effects in pancreatic cancer through the p38 MAPK signaling pathway. (2021)
  • Author(s): Konishi H, Isozaki S, Kashima S, Moriichi K, Ichikawa S, Yamamoto K, Yamamura C, Ando K, Ueno N, Akutsu H, Ogawa N, Fujiya M.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 11070-11070
  • DOI: 10.1038/s41598-021-90707-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polyphosphate, derived from the probiotic Lactobacillus brevis, modulates the intestinal microbiome and attenuates acute pancreatitis. (2021)
  • Author(s): Takauji S, Konishi H, Fujiya M, Ueno N, Tanaka H, Sato H, Isozaki S, Kashima S, Moriichi K, Mizukami Y, Okumura T.
  • Journal Title: Dig Dis Sci Volume: - Issue: 11 Pages: 1-1
  • DOI: 10.1007/s10620-020-06747-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Probiotic derived polyphosphate accelerates intestinal epithelia wound healing through inducing platelet-derived mediators. (2021)
  • Author(s): Isozaki S, Konishi H, Fujiya M, Tanaka H, Murakami Y, Kashima S, Ando K, Ueno N, Moriichi K, Okumura T.
  • Journal Title: Mediators of Inflammation Volume: 2021:5582943 Pages: 1-14
  • DOI: 10.1155/2021/5582943
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bacteria-derived ferrichrome inhibits tumor progression in sporadic colorectal neoplasms and colitis-associated cancer. (2021)
  • Author(s): Iwama T, Fujiya M, Konishi H, Tanaka H, Murakami Y, Kunogi T, Sasaki T, Takahashi K, Ando K, Ueno N, Kashima S, Moriichi K, Tanabe H, Okumura T.
  • Journal Title: Cancer Cell Int Volume: 21 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s12935-020-01723-9
  • Peer Reviewed / Open Access
• [Journal Article] Probiotic-derived ferrichrome inhibits the growth of refractory pancreatic cancer cells. (2020)
  • Author(s): Kita A, Fujiya M, Konishi H, Tanaka H, Kashima S, Iwama T, Ijiri M, Murakami Y, Takauji S, Goto T, Sakatani A, Ando K, Ueno N, Ogawa N, Okumura T.
  • Journal Title: Int J Oncol Volume: 57 Issue: 3 Pages: 721-732
  • DOI: 10.3892/ijo.2020.5096
  • Peer Reviewed / Open Access
• [Presentation] 乳酸菌由来長鎖ポリリン酸は血小板活性化を介して腸管上皮の創傷治癒を促進する (2020)
  • Author(s): 磯崎 翔太郎、藤谷幹浩、小西弘晃、田中宏樹、村上雄紀、杉山雄哉、安藤勝祥、上野伸展、後藤拓磨、嘉島伸、高氏修平、盛一健太郎、田邊裕貴、水上裕輔、奥村利勝
  • Organizer: 第57回消化器免疫学会総会
• [Patent(Industrial Property Rights)] 血小板凝集剤 (2020)
  • Inventor(s): 藤谷幹浩、小西弘晃、田中宏樹、磯崎翔太郎、大野佳宏、尾川直樹
  • Industrial Property Rights Holder: 藤谷幹浩、小西弘晃、田中宏樹、磯崎翔太郎、大野佳宏、尾川直樹
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020