Development of personalized medcicine for inflammatory bowel disease based on control of epigenome

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18H02799
• Research Institution: Sapporo Medical University
• Principal Investigator: 仲瀬 裕志 札幌医科大学, 医学部, 教授 (60362498)
• Co-Investigator(Kenkyū-buntansha): 青井 貴之 神戸大学, 科学技術イノベーション研究科, 教授 (00546997) ; 鈴木 拓 札幌医科大学, 医学部, 教授 (20381254)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 炎症性腸疾患 / エピゲノム / iPS細胞 / 自然免疫 / 腸管上皮細胞 / オルガノイド

Outline of Annual Research Achievements

炎症性腸疾患(IBD)は再燃・寛解を繰りかえす原因不明の難治性疾患であるが、その発症原因は現在のところ明らかとなっていない。日本における患者数は増加の一途をたどっていることから、根治的治療の開発が望まれている。欧米では IBD患者の疾患感受性遺伝子として自然免疫に関する遺伝子異常が報告された。しかしながら、欧米で見出された IBD関連遺伝子の多くは日本では認められていない。遺伝的要因のみならず、後天的な免疫担当細胞における機能異常が IBD発症に関与している可能性が示唆される。癌、心疾患、アレルギー疾患などの多因子疾患は、エピゲノム変化が重要な役割を果たしていると考えられている。このような観点から、IBD発症においてもエピゲノム変化が大きく関して いる可能性が高いと推測される。このことを明らかにするためには、同一患者における自然免疫担当細のエピゲノム変化を正確に捉える必要がある。そこで本研究においては、以下の検討を進めてきた。
(1)日本人IBD患者から iPS 細胞を樹立する。(2)iPS 細胞から自然免疫担当細胞を分化誘導させる。(3)IBD発症後の患者から採取された自然免疫担当細胞とiPS細胞から分化誘導された細胞との間のエピゲノム変化を網羅的に比較検討することである。IBD患者において、発症機序が腸管上皮機能障害によるところが大きいと考えられる潰瘍性大腸炎(UC)患者の生検組織を用いてオルガノイド作製を行った。UC患者腸管上皮細胞からのオルガノイド樹立は確立し、腸管オルガノイドからiPS化、その細胞を腸管上皮に分化させることに成功した。UC患者のオルガノイドおよびiPS化後に分化した腸管上皮細胞からDNAを抽出して、エピゲノム変化を網羅的に解析した。その結果から、腸管上皮細胞の分化制御に関する転写因子にエピゲノム変化が認められていることが明らかとなった。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial. (2021)
  • Author(s): Kita T, Ashizuka S, Ohmiya N, Yamamoto T, Kanai T, Motoya S, Hirai F, Nakase H, Moriyama T, Nakamura M, Suzuki Y, Kanmura S, Kobayashi T, Ohi H, Nozaki R, Mitsuyama K, Yamamoto S, Inatsu H, Watanabe K, Hibi T, Kitamura K.
  • Journal Title: J Gastroenterol Volume: 56 Pages: 147-157
  • DOI: 10.1007/s00535-020-01741-4.
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal cancer in patients with Crohn’s disease: a systematic review and meta-analysis. (2021)
  • Author(s): Uchino M, Ikeuchi H, Hata K, Minagawa T, Horio Y, Kuwahara R, Nakamura S, Watanabe K, Saruta M, Fujii T, Kobayashi T, Sugimoto K, Hirai F, Esaki M, Hiraoka S, Matsuoka K, Shinzaki S, Matsuura M, Inoue N, Nakase H, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol Volume: 36 Pages: 329-336
  • DOI: 10.1111/jgh.15229.
  • Peer Reviewed
• [Journal Article] Does anti-tumor necrosis factor alpha prevent the recurrence of Crohn's disease? Systematic review and meta-analysis (2021)
  • Author(s): Uchino M, Ikeuchi H, Hata K, Minagawa T, Horio Y, Kuwahara R, Nakamura S, Watanabe K, Saruta M, Fujii T, Kobayashi T, Sugimoto K, Hirai F, Esaki M, Hiraoka S, Matsuoka K, Shinzaki S, Matsuura M, Inoue N, Nakase H, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol Volume: - Pages: -
  • DOI: 10.1111/jgh.15288.
  • Peer Reviewed
• [Journal Article] In vivo gene expression profile of human intestinal epithelial cells: from the viewpoint of drug metabolism and pharmacokinetics. (2021)
  • Author(s): Takayama K, Ito K, Matsui A, Yamashita T, Kawakami K, Hirayama D, Kishimoto W, Nakase H, Mizuguchi H.
  • Journal Title: Drug Metab Dispos Volume: 49 Pages: 221-232
  • DOI: 10.1124/dmd.120.000283.
  • Peer Reviewed
• [Journal Article] Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease (2021)
  • Author(s): Suzuki K, Kakuta Y, Naito T, Takagawa T, Hanai H, Araki H, Sasaki Y, Sakuraba H, Sasaki M, Hisamatsu T, Motoya S, Matsumoto T, Onodera M, Ishiguro Y, Nakase H, et al.
  • Journal Title: Inflamm Bowel Dis Volume: - Pages: -
  • DOI: 10.1093/ibd/izab004.
  • Peer Reviewed
• [Journal Article] The characteristics of gastrointestinal symptoms for in patients with severe COVID-19: A systematic review and meta-analysis (2021)
  • Author(s): Hayashi Y, Wagatsuma K, Nojima M, Yamakawa T, Ichimiya T, Yokoyama Y, Kazama T, Hirayama D, Nakase H
  • Journal Title: J Gastroenterol Volume: - Pages: -
  • DOI: 10.1007/s00535-021-01778-z
  • Peer Reviewed / Open Access
• [Journal Article] Down-regulation of RalGTPase-activating protein promotes colitis-associated cancer via NLRP3 inflammasome activation. (2020)
  • Author(s): Iida T, Hirayama D, Minami N, Matsuura M, Wagatsuma K, Kawakami K, Nagaishi K, Nojima M, Ikeuchi H, Hirota S, Shirakawa R, Horiuchi H, Nakase H.
  • Journal Title: Cell Mol Gastroenterol Hepatol Volume: 9 Pages: 277-293
  • DOI: 10.1016/j.jcmgh.2019.10.003.
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of inflammatory bowel disease from the immunological perspective. (2020)
  • Author(s): Nakase H.
  • Journal Title: Immunol Med Volume: 43 Pages: 79-86.
  • DOI: 10.1080/25785826.2020.1751934.
  • Peer Reviewed / Open Access
• [Journal Article] CγP3A5 genotype as a potential pharmacodynamic biomarker for tacrolimus therapy in ulcerative colitis in Japanese patients. (2020)
  • Author(s): Yamamoto Y, Nakase H, Matsuura M, Maruyama S, Masuda S.
  • Journal Title: Int J Mol Sci. Volume: 21 Pages: 4347.
  • DOI: 10.3390/ijms21124347.
  • Peer Reviewed / Open Access
• [Journal Article] Long-term follow-up of targeted biopsy yield (LOFTY Study) in ulcerative colitis surveillance colonoscopy. (2020)
  • Author(s): Hata K, Ishihara S, Ajioka Y, Mitsuyama K, Watanabe K, Hanai H, Kunisaki R, Nakase H, Matsuda K, Iwakiri R, Hida N, Tanaka S, Takeuchi Y, Shinozaki M, Ogata N, Moriichi K, Hirai F, Sugihara K, Hisamatsu T, Suzuki Y, Watanabe M, Hibi T.
  • Journal Title: J Clin Med Volume: 18 Pages: E2286.
  • DOI: 10.3390/jcm9072286.
  • Peer Reviewed / Open Access
• [Journal Article] Expert opinions on the current therapeutic management of inflammatory bowel disease during the COVID-19 pandemic: Japan IBD COVID-19 taskforce, intractable diseases, the health and labor sciences research. (2020)
  • Author(s): akase H, Matsumoto T, Matsuura M, Iijima H, Matsuoka K, Ohmiya N, Ishihara S, Hirai F, Wagatsuma K, Yokoyama Y, Hisamatsu T.
  • Journal Title: Digestion Volume: - Pages: 1-9
  • DOI: 10.1159/000510502.
  • Peer Reviewed / Open Access
• [Journal Article] MEFV gene-related enterocolitis account for some cases diagnosed as inflammatory bowel disease unclassified. (2020)
  • Author(s): Saito D, Hibi N, Ozaki R, Kikuchi O, Sato T, Tokunaga S, Minowa S, Ikezaki O, Mitsui T, Miura M, Sakuraba A, Hayashida M, Miyoshi J, Matsuura M, Nakase H, Hisamatsu T.
  • Journal Title: Digestion Volume: 101 Pages: 785-793
  • DOI: 10.1159/000502640.
  • Peer Reviewed
• [Journal Article] Immunological mechanisms in inflammation-associated colon carcinogenesis. (2020)
  • Author(s): Hirano T, Hirayama D, Wagatsuma K, Yamakawa T, Yokoyama Y, Nakase H.
  • Journal Title: Int J Mol Sci Volume: 21 Pages: 3062.
  • DOI: 10.3390/ijms21093062.
  • Peer Reviewed / Open Access
• [Journal Article] Current diagnostic and therapeutic approaches to cytomegalovirus infections in ulcerative colitis patients based on clinical and basic research data. (2020)
  • Author(s): Yokoyama Y, Yamakawa T, Hirano T, Kazama T, Hirayama D, Wagatsuma K, Nakase H.
  • Journal Title: Int J Mol Sci Volume: 21 Pages: 2438.
  • DOI: 10.3390/ijms21072438.
• [Journal Article] The shining DIAMOND for evidence-based treatment strategies for Crohn’s disease. (2020)
  • Author(s): Nakase H, Matsumoto T, Watanabe K, Hisamatsu T.
  • Journal Title: J Gastroenterol Volume: 55 Pages: 824-832
  • DOI: 10.1007/s00535-020-01702-x.
  • Peer Reviewed
• [Journal Article] Contradictory effects of NLRP3 inflammasome regulatory mechanisms in colitis. (2020)
  • Author(s): Wagatsuma K, Nakase H.
  • Journal Title: Int J Mol Sci Volume: 21 Pages: 8145.
  • DOI: 10.3390/ijms21218145.
  • Peer Reviewed / Open Access
• [Journal Article] Automatic, computer-aided determination of endoscopic and histological inflammation in patients with mild to moderate ulcerative colitis based on red density. (2020)
  • Author(s): Bossuyt P, Nakase H, Vermeire S, de Hertogh G, Eelbode T, Ferrante M, Hasegawa T, Willekens H, Ikemoto Y, Makino T, Bisschops R.
  • Journal Title: GUT Volume: 69 Pages: 1778-1786
  • DOI: 10.1136/gutjnl-2019-320056.
  • Peer Reviewed
• [Journal Article] Artificial intelligence-assisted endoscopy changes the definition of mucosal healing in ulcerative colitis. (2020)
  • Author(s): Nakase H, Hirano T, Wagatsuma K, Ichimiya T, Yamakawa T, Yokoyama Y, Hayashi Y, Hirayama D, Kazama T, Yoshii S, Yamano HO.
  • Journal Title: Dig Endosc Volume: - Pages: -
  • DOI: 10.1111/den.13825
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy and autophagy-related diseases: a review. (2020)
  • Author(s): Ichimiya T, Yamakawa T, Hirano T, Yokoyama Y, Hayashi Y, Hirayama D, Wagatsuma K, Itoi T, Nakase H.
  • Journal Title: Int J Mol Sci Volume: 21 Pages: 8974.
  • DOI: 10.3390/ijms21238974.
  • Peer Reviewed / Open Access
• [Journal Article] Exploratory study of the effectiveness of granulocyte and monocyte adsorptive apheresis before initiation of steroids in patients with active ulcerative colitis (EXPECT study): A multicenter prospective clinical trial. (2020)
  • Author(s): Kakimoto K, Matsuura M, Takumi Fukuchi, Hongo H, Kimura T, Aoyama N, Okuda Y, Aomatsu K, Kamata N, Yokoyama Y, Mizuno C, Inoue T, Miyazaki T, Nakamura S, Higuchi K, Nakase H.
  • Journal Title: Crohn’s & Colitis 360. Volume: 2 Pages: -
  • Peer Reviewed / Open Access
• [Journal Article] Long-Term Clinical Effectiveness of Ustekinumab in Patients With Crohn’s Disease: A Retrospective Cohort Study. (2020)
  • Author(s): Itoh T, Maemoto A, Katsurada T, Tanaka H, Motoya S, Ueno N, Fujiya M, Ashida T, Hirayama D, Nakase H.
  • Journal Title: Crohn’s & Colitis 360. Volume: 2 Pages: -
  • Peer Reviewed / Open Access
• [Presentation] ECCO-AOCC Forum 2020 :Optimal strategies for drug therapy: Which one, when, and how? (2020)
  • Author(s): Hiroshi Nakase
  • Organizer: Asian Organization for Crohn’s and Colitis
  • Int'l Joint Research / Invited
• [Presentation] Japan IBD COVID-19 Taskforce の現在、そして今後の課題 Panel discussion 3. COVID-19 パンデミック下でのIBD診療 (2020)
  • Author(s): 仲瀬裕志
  • Organizer: 第11回炎症性腸疾患学会 学術集会
  • Invited
• [Presentation] 今しっておきたいIBDと感染症 (JSIBD教育セミナー) (2020)
  • Author(s): 仲瀬裕志
  • Organizer: 第11回炎症性腸疾患学会 学術集会
  • Invited
• [Presentation] いつ知るの？今でしょ！IBDとCOVID－19(JSIBD MS教育セミナー) (2020)
  • Author(s): 仲瀬裕志
  • Organizer: 第11回炎症性腸疾患学会 学術集会
  • Invited