Identification of inflammation-inducing bacteria from oral microbiota in inflammatory bowel disease

• Project/Area Number: 19K17413
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokai University
• Principal Investigator: IMAI Jin 東海大学, 医学部, 助教 (40725363)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 炎症性腸疾患 / クローン病 / 口腔内細菌 / IgA / 腸内細菌

Outline of Research at the Start

炎症性腸疾患(IBD）の根治療法確立にはさらなる病態解明が必須である。IBD患者の口腔内細菌叢のdysbiosisが腸管に影響し病態との関与が示唆されているが、その詳細は不明である。本研究では、IBD患者の検体(唾液/糞便)のメタゲノム解析と難治性や再燃回数などの臨床データとを比較し、一部の症例を経時的に1年間フォローして細菌叢を評価することで、口腔内細菌と疾患病態との関連を明らかにする。そして、IBD患者の唾液検体より口腔内細菌を分離し、無菌マウスに移植後、実験的腸炎増悪能を指標に炎症誘導性細菌を同定する。同時に、患者メモリーT細胞と同細菌を応答させ、細菌特異的な反応を評価する。

Outline of Final Research Achievements

We performed metagenomic analysis of saliva and fecal samples from patients with inflammatory bowel disease (IBD) and healthy controls to examine differences in the composition of microbiota between the subject and control groups. The results showed that the oral microbiota of IBD patients differed significantly from that of healthy controls. On the other hand, comparison with fecal samples did not lead to the identification of bacteria common to both oral and fecal samples. Furthermore, the patients were classified into two groups according to the presence or absence of periodontitis in IBD, the clinical course and microbiota were compared. Interestingly, Crohn's disease patients with periodontitis were found to use anti-TNF-a antibodies and immunosuppressive drugs more frequently. In the microbiral analysis, substantial differences were observed in the oral microbiota of IBD with and without periodontitis.

Academic Significance and Societal Importance of the Research Achievements

本研究において、IBDのうち、クローン病においては歯周病の存在は、その細菌叢の乱れから波及し腸管病態へ強く影響を与えている可能性が示唆された。今後、さらなる研究が進むことで、クローン病の診療のおいて口腔内ケアの重要性の科学データが蓄積され、今後注目されていくと考えられる。また、口腔内由来の炎症誘導を起こす細菌が新たな治療ターゲットとなりうると考えられる。

Research Products

• [Int'l Joint Research] ミシガン大学(米国)
• [Int'l Joint Research] ミシガン大学(米国)
• [Int'l Joint Research] University of Michigan(米国)
• [Journal Article] The pathogenic oral-gut-liver axis: new understandings and clinical implications (2021)
  • Author(s): Imai J, Kitamoto S, Kamada N
  • Journal Title: Expert Rev Clin Immunol Volume: 17(7) Issue: 7 Pages: 727-736
  • DOI: 10.1080/1744666x.2021.1935877
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A potential pathogenic association between periodontal disease and Crohn's disease (2021)
  • Author(s): Imai J, Ichikawa H, Kitamoto S, Golob JL, Kaneko M, Nagata J, Takahashi M, Gillilland MG 3rd, Tanaka R, Nagao-Kitamoto H, Hayashi A, Sugihara K, Bishu S, Tsuda S, Ito H, Kojima S, Karakida K, Matsushima M, Suzuki T, Hozumi K, Watanabe N, Giannobile WV, Shirai T, Suzuki H, Kamada N
  • Journal Title: JCI insight Volume: 6(23) Issue: 23
  • DOI: 10.1172/jci.insight.148543
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch signaling supports the appearance of follicular helper T cells in the Peyer's patches concomitantly with the reduction of regulatory T cells (2021)
  • Author(s): Yazawa M, Hosokawa H, Koizumi M, Hirano KI, Imai J, Hozumi K.
  • Journal Title: Int Immunol Volume: 33(9) Issue: 9 Pages: 469-478
  • DOI: 10.1093/intimm/dxab032
  • Peer Reviewed
• [Journal Article] Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium (2021)
  • Author(s): Hirano KI, Hosokawa H, Yahata T, Ando K, Tanaka M, Imai J, Yazawa M, Ohtsuka M, Negishi N, Habu S, Sato T, Hozumi K.
  • Journal Title: Front Immunol Volume: 13 Pages: 852427-852427
  • DOI: 10.3389/fimmu.2022.852427
  • Peer Reviewed / Open Access
• [Journal Article] Primary Sclerosing Cholangitis Complicated with Aphthoid Colitis Difficult to Diagnose from IgG4-Related Sclerosing Cholangitis (2021)
  • Author(s): Imai J, Ichikawa H, Kaneko M, Ito H, Takashimizu S, Shirai T, Tajiri T, Watanabe N, Suzuki H
  • Journal Title: Case Rep Gastroenterol Volume: 16(1) Issue: 1 Pages: 23-28
  • DOI: 10.1159/000521538
  • Peer Reviewed / Open Access
• [Journal Article] The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis (2020)
  • Author(s): Sho Kitamoto, Hiroko Nagao-Kitamoto, Yizu Jiao, Merritt G Gillilland, Atsushi Hayashi, Jin Imai, Kohei Sugihara, Mao Miyoshi, Jennifer C Brazil, Peter Kuffa, Brett D Hill, Syed M Rizvi, Fei Wen, Shrinivas Bishu, Naohiro Inohara, Kathryn A Eaton, Asma Nusrat, Yu L Lei, William V Giannobile, Nobuhiko Kamada
  • Journal Title: Cell Volume: 182(2) Issue: 2 Pages: 447-462
  • DOI: 10.1016/j.cell.2020.05.048
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice (2019)
  • Author(s): Imai J, Yahata T, Ichikawa H, Ibrahim AA, Yazawa M, Sumiyoshi H, Inagaki Y, Matsushima M, Suzuki T, Mine T, Ando K, Miyata T, Hozumi K.
  • Journal Title: Intestinal Research Volume: 18 Issue: 2 Pages: 219-228
  • DOI: 10.5217/ir.2019.00037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis. (2019)
  • Author(s): Imai J, Kitamoto S, Sugihara K, Nagao-Kitamoto H, Hayashi A, Morhardt TL, Kuffa P, Higgins PDR, Barnich N, Kamada N
  • Journal Title: Mucosal Immunology Volume: 12 Issue: 3 Pages: 632-643
  • DOI: 10.1038/s41385-019-0138-4
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 歯周病合併クローン病における口腔内・腸内細菌叢解析と臨床経過 (2020)
  • Author(s): 今井 仁, 鎌田 信彦, 北本 祥, 市川 仁志, 高橋 美穂, 白井 孝之, 穂積 勝人, 鈴木 秀和
  • Organizer: GI WEEK 2021
• [Presentation] クローン病における接着性侵入性大腸菌（AIEC）による腸管線維化誘導の検討 (2020)
  • Author(s): 今井 仁, 鈴木 秀和
  • Organizer: 第39回サイトプロテクション研究会
• [Presentation] 接着性侵入性大腸菌(AIEC)はIL-33/ST2シグナルを介し腸管線維化を誘導する (2019)
  • Author(s): 今井 仁, 鈴木 孝良, 鎌田 信彦
  • Organizer: 第27回日本消化器関連学会週間 JDDW
• [Presentation] 炎症性腸疾患と口腔内環境との関連性について (2019)
  • Author(s): 市川 仁志, 今井 仁, 金子 元基, 津田 真吾, 永田 順子, 白井 孝之, 高橋 美穂, 唐木田 一成, 高山 哲朗, 伊藤 裕幸, 小嶋 清一郎, 坂本 春生, 渡辺 勲史
  • Organizer: 第27回日本消化器関連学会週間 JDDW
• [Presentation] Adherent-invasive Escherichia coli colonization promotes intestinal fibrosis via activation of IL-33-ST2 signaling (2019)
  • Author(s): Jin Imai, Sho Kitamoto, Hiroko Nagao-Kitamoto, Atsushi Hayashi, Kohei Sugihara, Tina L. Morhardt, Peter Kuffa, Peter D. R. Higgins, Nicolas Barnich, Nobuhiko Kamada
  • Organizer: DDW (Digestive Disease Week) 2019
  • Int'l Joint Research
• [Book] 医学のあゆみ (2020)
  • Author(s): 今井 仁, 穂積 勝人, 鈴木 秀和
  • Total Pages: 5
  • Publisher: 医歯薬出版株式会社