Regulation of intractable intestinal inflammation via the exposome based on glycoimmunology

• Project/Area Number: 19K08394
• 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: Osaka University
• Principal Investigator: Shinzaki Shinichiro 大阪大学, 医学系研究科, 講師 (60546860)
• Co-Investigator(Kenkyū-buntansha): 井上 隆弘 大阪大学, 医学部附属病院, 准教授 (30648184) ; 林 義人 大阪大学, 医学系研究科, 助教 (80647123) ; 飯島 英樹 大阪大学, 医学系研究科, 特任准教授 (90444520)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 炎症性腸疾患 / エクスポソーム / ストレス / 糖鎖免疫 / 季節 / 腸内細菌

Outline of Research at the Start

原因不明の難治性疾患である炎症性腸疾患に環境因子（エクスポソーム）が関わる可能性に着目し、エクスポソームによる糖鎖免疫を介した腸炎発症や制御機構の解明を目指す。基礎的検討において、エクスポソームの変化が腸管由来の糖鎖を介した腸内環境や腸管上皮・免疫細胞に及ぼす影響につき、マウス腸炎モデルやストレスモデル等を用いた解析を行う。また、エクスポソームの変化が炎症性腸疾患患者の病態に及ぼす影響を、生検組織や便検体等の臨床検体を用いて、その臨床経過と比較検討する。

Outline of Final Research Achievements

Environmental factors (exposomes) such as mental stress and seasons are involved in the onset and exacerbation of inflammatory bowel disease, an intractable disease with an unknown cause, but the details are still unknown. In this study, we aimed to elucidate the mechanism by which exposomes are involved in the onset and exacerbation of intestinal inflammation via glycoimmunology.
We conducted a basic study to elucidate the mechanisms underlying mental stress-related exacerbation of intestinal inflammation by using stress-loaded and/or depressed mice with experimental colitis model, and examined the pathways involved in the intestinal inflammation. In addition, we focused on the seasonality of disease exacerbations in patients with inflammatory bowel disease, and identified intestinal bacteria involved in the improvement of seasonal exacerbations.

Academic Significance and Societal Importance of the Research Achievements

原因不明の難治性疾患である炎症性腸疾患において、その発症や増悪に環境因子（エクスポソーム）が関わるとされている。今回の検討において、腸炎の増悪に関わるエクスポソームとして精神的ストレスおよび季節による腸内細菌変化が同定された。これらの成果により、エクスポソームを自己調節することで疾患の増悪を制御できることを示唆するとともに、エクスポソームに着目した薬剤等による疾患コントロールが可能となることが期待される。

Research Products

• [Journal Article] Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease (2022)
  • Author(s): Amano T, Shinzaki S, Asakura A, Tashiro T, Tani M, Otake Y, Yoshihara T, Yoshii S, Tsujii Y, Hayashi Y, Inoue T, Iijima H, Takehara T, et al.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 5324-5324
  • DOI: 10.1038/s41598-022-09455-8
  • Peer Reviewed
• [Journal Article] Exacerbation of non‐steroidal anti‐inflammatory drug‐induced enteropathy in C‐C chemokine receptor type 7‐deficient mice (2022)
  • Author(s): Yamaguchi Toshio、Iijima Hideki、Yoshihara Takeo、Tani Mizuki、Otake Yuriko、Iwatani Shuko、Amano Takahiro、Tashiro Taku、Kurahashi Tomohide、Inoue Takanori、Tsujii Yoshiki、Hayashi Yoshito、Inoue Takahiro、Motooka Daisuke、Nakamura Shota、Shinzaki Shinichiro、Takehara Tetsuo
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 8 Pages: 1561-1570
  • DOI: 10.1111/jgh.15868
  • Peer Reviewed
• [Journal Article] Concomitant use of an immunomodulator with ustekinumab as an induction therapy for Crohn's disease: A systematic review and meta-analysis (2021)
  • Author(s): Takeo Yoshihara, Shinichiro Shinzaki, Takahiro Amano, Hideki Iijima, Tetsuo Takehara, Nagamu Inoue, Motoi Uchino, Motohiro Esaki, Taku Kobayashi, Masayuki Saruta, Ken Sugimoto, Shiro Nakamura, Keisuke Hata, Fumihito Hirai, Sakiko Hiraoka, Toshimitsu Fujii, Minoru Matsuura, Katsuyoshi Matsuoka, Kenji Watanabe, et al
  • Journal Title: J Gastroenterol Hepatol Volume: 15 Issue: 7 Pages: 1744-1753
  • DOI: 10.1111/jgh.15401
  • Peer Reviewed
• [Journal Article] Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study (2021)
  • Author(s): Shinzaki S, Matsuoka K, Tanaka H, Takeshima F, Kato S, Torisu T, Ohta Y, Watanabe K, Nakamura S, Yoshimura N, Kobayashi T, Shiotani A, Hirai F, Hiraoka S, Watanabe M, Matsuura M, Nishimoto S, Mizuno S, Iijima H, Takehara T, Naka T, Kanai T, Matsumoto T.
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 6 Pages: 560-569
  • DOI: 10.1007/s00535-021-01793-0
  • Peer Reviewed / Open Access
• [Journal Article] Leucine-Rich Alpha-2 Glycoprotein May Be Predictive of the Adalimumab Trough Level and Antidrug Antibody Development for Patients with Inflammatory Bowel Disease: A Sub-Analysis of the PLANET Study (2021)
  • Author(s): Yanai Shunichi、Shinzaki Shinichiro、Matsuoka Katsuyoshi、Mizuno Shinta、Iijima Hideki、Naka Tetsuji、Kanai Takanori、Matsumoto Takayuki
  • Journal Title: Digestion Volume: 102 Issue: 6 Pages: 929-937
  • DOI: 10.1159/000517339
  • Peer Reviewed
• [Journal Article] Detection of fucosylated haptoglobin using the 10-7G antibody as a biomarker for evaluating endoscopic remission in ulcerative colitis (2021)
  • Author(s): Motooka Kei、Morishita Koichi、Ito Nami、Shinzaki Shinichiro、Tashiro Taku、Nojima Satoshi、Shimizu Kayoko、Date Mutsuhiro、Sakata Natsumi、Yamada Momoko、Takamatsu Shinji、Kamada Yoshihiro、Iijima Hideki、Mizushima Tsunekazu、Morii Eiichi、Takehara Tetsuo、Miyoshi Eiji
  • Journal Title: World Journal of Gastroenterology Volume: 27 Issue: 2 Pages: 162-175
  • DOI: 10.3748/wjg.v27.i2.162
  • Peer Reviewed / Open Access
• [Journal Article] Oligosaccharide‐dependent anti‐inflammatory role of galectin‐1 for macrophages in ulcerative colitis (2020)
  • Author(s): Iwatani Shuko、Shinzaki Shinichiro、Amano Takahiro、Otake Yuriko、Tani Mizuki、Yoshihara Takeo、Tsujii Yoshiki、Hayashi Yoshito、Inoue Takahiro、Okuzaki Daisuke、Mizushima Tsunekazu、Miyoshi Eiji、Iijima Hideki、Takehara Tetsuo
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 35 Issue: 12 Pages: 2158-2169
  • DOI: 10.1111/jgh.15097
  • Peer Reviewed
• [Journal Article] Psychologic stress and disease activity in patients with inflammatory bowel disease: A multicenter cross-sectional study (2020)
  • Author(s): Araki M, Shinzaki S, Yamada T, Arimitsu S, Komori M, Shibukawa N, Mukai A, Nakajima S, Kinoshita K, Kitamura S, Murayama Y, Ogawa H, Yasunaga Y, Oshita M, Fukui H, Masuda E, Tsujii M, Kawai S, Hiyama S, Inoue T, Tanimukai H, Iijima H, Takehara T.
  • Journal Title: PLOS ONE Volume: 15 Issue: 5 Pages: e0233365-e0233365
  • DOI: 10.1371/journal.pone.0233365
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic Alterations in Peyer's Patches in Patients With Ulcerative Colitis: A Prospective, Multicenter Study. (2020)
  • Author(s): Hiyama S, Iijima H, Sakakibara Y, Yamada T, Mukai A, Otake Y, Yamaguchi T, Araki M, Kawai S, Tsujii Y, Inoue T, Hayashi Y, Shinzaki S, Takehara T.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 7 Pages: 1143-1149
  • DOI: 10.1111/jgh.14933
  • Peer Reviewed
• [Journal Article] Novel mass spectrometry-based comprehensive lipidomic analysis of plasma from patients with inflammatory bowel disease. (2020)
  • Author(s): Iwatani S, Iijima H, Otake Y, Amano T, Tani M, Yoshihara T, Tashiro T, Tsujii Y, Inoue T, Hayashi Y, Takeda K, Hayashi A, Fujita S, Shinzaki S, Takehara T.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 8 Pages: 1355-1364
  • DOI: 10.1111/jgh.15067
  • Peer Reviewed
• [Journal Article] Usefulness of intestinal real-time virtual sonography in patients with inflammatory bowel disease. (2019)
  • Author(s): Kawai S, Iijima H, Shinzaki S, Hiyama S, Yamaguchi T, Araki M, Iwatani S, Shiraishi E, Mukai A, Inoue T, Tsujii Y, Hayashi Y, Tsujii M, Takehara T.
  • Journal Title: J Gastroenterol Hepatol. Volume: 34(10) Issue: 10 Pages: 1743-1743
  • DOI: 10.1111/jgh.14670
  • Peer Reviewed
• [Presentation] Importance of MDT activities in the Care of Patients with Inflammatory Bowel Disease. (2021)
  • Author(s): Shinzaki S.
  • Organizer: 9th annual meeting of Asian Organization for Crohn’s and Colitis
  • Int'l Joint Research / Invited
• [Presentation] 高齢潰瘍性大腸炎患者に対する抗TNF製剤初回投与の安全性と有効性：多施設共同後ろ向き観察研究 (2021)
  • Author(s): 天野孝広、新崎信一郎、朝倉亜希子、田代拓、大竹由利子、谷瑞季、良原丈夫、井上隆弘、中原征則、飯島英樹、竹原徹郎
  • Organizer: 第17回日本消化管学会総会学術集会
• [Presentation] Usefulness of serum LRG as a biomarker for evaluating endoscopic activity of ileal Crohn’s disease in clinical remission. (2021)
  • Author(s): Taku Tashiro, Shinichiro Shinzaki, Akiko Asakura, Takahiro Amano, Mizuki Tani, Yuriko Otake, Takeo Yoshihara, Shunsuke Yoshii, Yoshiki Tsujii, Takahiro Inoue, Yoshito Hayashi, Hideki Iijima and Tetsuo Takehara.
  • Organizer: Digestive Disease Week 2021
  • Int'l Joint Research
• [Presentation] クローン病の内視鏡的重症度評価における血清LRGの有用性 (2021)
  • Author(s): 田代拓、新崎信一郎、竹原徹郎
  • Organizer: 第107回日本消化器病学会総会
• [Presentation] 抑うつモデルマウスを用いた脳腸相関を介する腸管炎症増悪機構の検討 (2020)
  • Author(s): 良原 丈夫、新崎 信一郎、田代 拓、天野 孝広、谷 瑞季、大竹 由利子、岩谷 修子、辻井 芳樹、井上 隆弘、林 義人、渡部 健二、飯島 英樹、竹原 徹郎
  • Organizer: 第57回日本消化器免疫学会総会
• [Presentation] 新型コロナウイルスPandemicが炎症性腸疾患患者に及ぼす精神的影響と臨床症状との関連についての検討 (2020)
  • Author(s): 谷 瑞季、新崎信一郎、朝倉亜希子、田代 拓、天野孝広、大竹由利子、良原丈夫、吉井俊輔、辻井芳樹、林 義人、井上隆弘、飯島英樹、竹原徹郎
  • Organizer: 第11回日本炎症性腸疾患学会学術集会
• [Presentation] FECAL MICROBIOTA RELATED TO THE SEASONAL AGGRAVATION OF IBD (2020)
  • Author(s): Mizuki Tani, Shinichiro Shinzaki, Taku Tashiro, Takahiro Amano, Yuriko Otake, Takeo Yoshihara, Shuko Iwatani, Hideki Iijima and Tetsuo Takehara
  • Organizer: Digestive Disease Week 2020
  • Int'l Joint Research
• [Presentation] IBD 患者の便検体における季節性変化と増悪との関連 (2019)
  • Author(s): 谷 瑞季、新崎 信一郎、天野 孝広、大竹 由利子、良原 丈夫、岩谷 修子、荒木 学、辻井 芳樹、林 義人、井上 隆弘、飯島 英樹、竹原 徹郎
  • Organizer: 第56回日本消化器免疫学会総会
• [Presentation] 炎症性腸疾患患者の腸内細菌叢で見られる季節性変化 (2019)
  • Author(s): 谷 瑞季、新崎 信一郎、田代 拓、天野 孝広、大竹 由利子、良原 丈夫、岩谷 修子、荒木 学、辻井 芳樹、林 義人、 井上 隆弘、飯島 英樹、竹原 徹郎
  • Organizer: 第10回日本炎症性腸疾患学会学術集会