Identification of causative bacteria for ulcerative colitis by using model mice and Maldi mass-spectrometer.

• Project/Area Number: 18K08008
• 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: Kumamoto University
• Principal Investigator: Irie Atsushi 熊本大学, 大学院生命科学研究部(医), 講師 (30250343)
• Co-Investigator(Kenkyū-buntansha): 今村 隆寿 熊本大学, 大学院生命科学研究部(医), 准教授 (20176499)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 潰瘍性大腸炎 / 炎症性腸疾患 / 小胞体ストレス / HLA-DR / トランスジェニックマウス / 動物モデル / 疾患モデルマウス / 発光レポーター / 質量分析 / IgA / HLA / 腸内細菌

Outline of Final Research Achievements

We have established human leukocyte antigen HLA-DR4 transgenic mice of which homozygotes spontaneously develop ulcerative colitis-like inflammatory bowel disease. Previous studies have shown that the etiology of this disease involves endoplasmic reticulum stress due to overexpression of HLA-DR4 molecules and some gut microbiota. The purpose of this study was to identify the causative organism of the above-mentioned colitis. As a result of examination of the spectrum of antibiotics, it was shown that the presence of Helicobacter japonicus, a Helicobacter species, is involved in the onset of the colitis. It was shown that this bacterium was isolated from the feces of the mice, its onset was suppressed by its elimination by administration of antibiotics, and then when the bacterium was administered, the colitis developed in about two months.

Academic Significance and Societal Importance of the Research Achievements

潰瘍性大腸炎（UC）の病因として腸内細菌叢の関与が古くから疑われているが、関与する菌種、発症機構については未だ明らかではない。近年、大腸上皮細胞に生じる小胞体（ER）ストレスがUCの有力な原因として注目されているが、ヒトのUCの病態に類似する実験動物モデルが少ないことが、UCの病因病態の解明とその治療法の確立を困難なものとしてきた一因となっている。本研究の成果はUC起因菌の存在とERストレス発生のメカニズム、および大腸のどの部位から大腸炎が発症しどのように進展するのかを明らかにし、従前の研究では得られなかった動的UCの病態解明に資することを目指す。

Research Products

• [Journal Article] A novel coculture system for assessing respiratory sensitizing potential by IL-4 in T cells. (2022)
  • Author(s): Izuru Mizoguchi, Yasuhiro Katahira, Shinya Inoue, Eri Sakamoto, Aruma Watanabe, Yuma Furusaka, Atsushi Irie, Satoru Senju, Yasuharu Nishimura, Shusaku Mizukami, Kenji Hirayama, Sou Nakamura, Koji Eto, Hideaki Hasegawa, Takayuki Yoshimoto
  • Journal Title: ALTEX Volume: - Pages: 204-216
  • DOI: 10.14573/altex.2111181
  • Peer Reviewed / Open Access
• [Journal Article] Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD‐L1 expression by C5a (2020)
  • Author(s): Imamura Ryuji、Kitagawa Saki、Kubo Tatsuko、Irie Atsushi、Kariu Toru、Yoneda Masakazu、Kamba Tomomi、Imamura Takahisa
  • Journal Title: The Prostate Volume: 81 Issue: 3 Pages: 147-156
  • DOI: 10.1002/pros.24090
  • Peer Reviewed
• [Journal Article] Identification of a Promiscuous Epitope Peptide Derived From HSP70. (2019)
  • Author(s): Matsui H, Hazama S, Tamada K, Udaka K, Irie A, Nishimura Y, Miyakawa T, Doi S, Nakajima M, Kanekiyo S, Tokumitsu Y, Shindo Y, Tomochika S, Yoshida S, Iida M, Suzuki N, Takeda S, Yamamoto S, Yoshino S, Ueno T, Nagano H
  • Journal Title: J Immunother Volume: 42 Issue: 7 Pages: 244-250
  • DOI: 10.1097/cji.0000000000000274
  • Peer Reviewed / Open Access
• [Journal Article] Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4+ T cells expressing converged T-cell receptor genes in vitro (2018)
  • Author(s): Tsuruta Miki、Ueda Shohei、Yew Poh Yin、Fukuda Isao、Yoshimura Sachiko、Kishi Hiroyuki、Hamana Hiroshi、Hirayama Masatoshi、Yatsuda Junji、Irie Atsushi、Senju Satoru、Yuba Eiji、Kamba Tomomi、Eto Masatoshi、Nakayama Hideki、Nishimura Yasuharu
  • Journal Title: OncoImmunology Volume: 7 Issue: 4 Pages: 1415687-1415687
  • DOI: 10.1080/2162402x.2017.1415687
  • Peer Reviewed / Open Access
• [Presentation] Effective combination immunotherapy for chemoresistant mouse bladder cancer using peptide vaccines and PD-1 blockade. (2019)
  • Author(s): Ueda S, Irie A, Senju S, Eto M, Nishimura Y
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Imaging of ulcerative colitis diseased area-development by using model mice with luciferase reporter gene and inoculation of causative gut bacteria. (2019)
  • Author(s): Irie A, Imamura T, Kubo T, Michibata Y, Nishimura Y
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] ヘリコバクター種によりHLA-DR4トランスジェニックマウスに誘導される潰瘍性大腸炎の病態の解析 (2019)
  • Author(s): 入江厚, 今村隆寿, 久保多津子, 道端弥生, 西村泰治
  • Organizer: 第72回日本細菌学会九州支部総会
• [Presentation] Helicobacter species are involved in the pathogenesis of ulcerative colitis in the homozygotes of HLA-DR4 transgenic mice. (2018)
  • Author(s): Irie A, Imamura T, Kubo T, Shibuya I, Sogo S, Nishimura Y.
  • Organizer: 第４７回日本免疫学会学術集会
• [Presentation] A mouse model of combination immunotherapy for advanced and chemoresistant bladder cancer by using cancer-associated peptides vaccine and PD-1 blockade. (2018)
  • Author(s): Ueda S, Irie A, Senju S, Eto M, Nishimura Y.
  • Organizer: 第４７回日本免疫学会学術集会