Role of Reg protein on the mucosal barrier function in the inflammatory gastrointestinal diseases

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K09363
• Research Institution: Hyogo Medical University
• Principal Investigator: 福井 広一 兵庫医科大学, 医学部, 准教授 (60378742)
• Co-Investigator(Kenkyū-buntansha): 三輪 洋人 兵庫医科大学, 医学部, 教授 (80190833) ; 渡 二郎 兵庫医科大学, 医学部, 教授 (10311531) [Withdrawn] ; 大島 忠之 兵庫医科大学, 医学部, 准教授 (00381814)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 遺伝子 / 臨床 / 感染症 / 免疫学 / 再生医学

Outline of Annual Research Achievements

我々は、Reg 蛋白が炎症性消化管疾患において粘膜上皮細胞に過剰発現することを世界に先駆けて報告し、Reg 蛋白が炎症性消化管疾患の病態形成に関与することは示したがその役割は明らかでない。そこで我々は、Reg ファミリー蛋白が粘膜バリア機能や消化管炎症からの生体防御に有益な作用を有すると考えて本研究を進めた結果、Reg 蛋白がタイトジャンクション蛋白の発現を誘導して粘膜バリア機能の維持に関与することを明らかにした。消化管粘膜防御にはバリア機能だけはなく、消化管内に存在する腸内細菌との反応と病原抗原が侵入した際の消化管免疫も重要である。そこで本年度は、薬剤起因性腸炎や抗菌薬投与によって腸内細菌叢バランスを攪乱した dysbiosis モデルを作成し、その環境における Reg ファミリー蛋白の役割について検討した。薬剤（デキストラン硫酸）起因性腸炎では、Regファミリー蛋白の中で Reg IIIβと Reg IIIγが特異的に発現増強し、その発現には転写因子 STAT3 の活性化を誘導する IL-6, IL-17, IL-22 が関与することを明らかにした。他方、Vancomycin 投与による dysbiosis モデルでは、体重の増加と消化管運動の抑制が生じ、腸管組織における IFN-γの発現増強を認めた。さらに Regファミリー蛋白に関しては、Reg IIIγの発現が減弱し、M1/M2 マクロファージ比が増加して消化管粘膜の透過性が亢進する所見を得ている。これらの事実から、dysbiosis によって誘発された Reg IIIγ発現減弱が粘膜バリア機能の低下に関与し、粘膜固有層への抗原侵入が増加して消化管免疫のマクロファージの動態とその産生サイトカインのプロファイルに影響を与える可能性が示唆された。

Research Products

• [Journal Article] Lubiprostone induces claudin-1 and protects intestinal barrier function (2020)
  • Author(s): Nishii N, Oshima T, Li M, Eda H, Nakamura K, Tamura A, Ogawa T, Yamasaki T, Kondo T, Kono T, Tozawa K, Tomita T, Fukui H, Miwa H.
  • Journal Title: Pharmacology Volume: 105 Pages: 102-108
  • DOI: 10.1159/000503054.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylated STAT3 expression linked to SOCS3 methylation is associated with proliferative ability of gastric mucosa in patients with early gastric cancer (2020)
  • Author(s): Fukui H, Watari J, Zhang X, Ran Y, Tomita T, Oshima T, Hirota S, Miwa H.
  • Journal Title: Oncol Lett Volume: 19 Pages: 3542-3550
  • DOI: 10.3892/ol.2020.11462.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Colonic M1 macrophage is associated with the prolongation of gastrointestinal motility and obesity in mice treated with vancomycin (2019)
  • Author(s): Inoue Y, Fukui H, Xu X, Ran Y, Tomita T, Oshima T, Watari J, Miwa H.
  • Journal Title: Mol Med Rep Volume: 19 Pages: 2591-2598
  • DOI: 10.3892/mmr.2019.9920.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alteration of GLP-1/GPR43 expression and gastrointestinal motility in dysbiotic mice treated with vancomycin (2019)
  • Author(s): Xu X, Fukui H, Ran Y, Tomita T, Oshima T, Watari J, Miwa H.
  • Journal Title: Sci Rep Volume: 9 Pages: 4381
  • DOI: 10.1038/s41598-019-40978-9.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The link between type III Reg and STAT3-associated cytokines in inflamed colonic tissues (2019)
  • Author(s): Xu X, Fukui H, Ran Y, Wang X, Inoue Y, Ebisudani N, Nishimura H, Tomita T, Oshima T, Watari J, Kiyama H, Miwa H.
  • Journal Title: Mediators Inflamm Volume: 2019 Pages: 7859460
  • DOI: 10.1155/2019/7859460.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Duodenal low-grade inflammation and expression of tight junction proteins in functional dyspepsia (2019)
  • Author(s): Taki M, Oshima T, Li M, Sei H, Tozawa K, Tomita T, Fukui H, Watari J, Miwa H.
  • Journal Title: Neurogastroenterol Motil Volume: 31 Pages: e13576
  • DOI: 10.1111/nmo.13576.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DNA methylation silencing of microRNA gene methylator in the precancerous background mucosa with and without gastric cancer: Analysis of the effects of H. pylori eradication and long-term aspirin use (2019)
  • Author(s): Watari J, Ito C, Shimoda T, Tomita T, Oshima T, Fukui H, Das KM, Miwa H.
  • Journal Title: Sci Rep Volume: 9 Pages: 12559
  • DOI: 10.1038/s41598-019-49069-1.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chenodeoxycholic acid releases proinflammatory cytokines from small intestinal epithelial cells through the farnesoid X receptor (2019)
  • Author(s): Horikawa T, Oshima T, Li M, Kitayama Y, Eda H, Nakamura K, Tamura A, Ogawa T, Yamasaki T, Okugawa T, Kondo T, Kono T, Tozawa K, Tomita T, Fukui H, Watari J, Miwa H.
  • Journal Title: Digestion Volume: 100 Pages: 286-294
  • DOI: 10.1159/000496687.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A randomized double-blind placebo-controlled trial on the effect of magnesium oxide in patients with chronic constipation (2019)
  • Author(s): Mori S, Tomita T, Fujimura K, Asano H, Ogawa T, Yamasaki T, Kondo T, Kono T, Tozawa K, Oshima T, Fukui H, Kimura T, Watari J, Miwa H.
  • Journal Title: J Neurogastroenterol Motil Volume: 25 Pages: 563-575
  • DOI: 10.5056/jnm18194.
  • Peer Reviewed / Open Access
• [Presentation] Antibiotics treatment affects body metabolism and GI motility accompanied by the alteration of macrophage polarization in the colonic tissues (2019)
  • Author(s): Fukui H, Inoue Y, Ran Y, Kondo T, Kono T, Tozawa K, Tomita T, Oshima T, Watari J, Miwa H.
  • Organizer: nnual Meetings of the American Gastroenterology Association and American Association for the Study of Liver Disease at the Digestive Disease Week
  • Int'l Joint Research
• [Presentation] Alteration of colonic mucosal permeability under antibiotics-induced dysbiotic condition (2019)
  • Author(s): Ran Y, Fukui H, Xu X, Kondo T, Kono T, Tozawa K, Tomita T, Oshima T, Watari J, Miwa H.
  • Organizer: Annual Meetings of the American Gastroenterology Association and American Association for the Study of Liver Disease at the Digestive Disease Week
  • Int'l Joint Research
• [Presentation] Axis of Reg III/STAT3-associated cytokines in DSS-induced colitis in mice (2019)
  • Author(s): Fukui H, Nishimura H, Ogawa T, Kondo T, Kono T, Tozawa K, Tomita T, Oshima T, Miwa H.
  • Organizer: Asian Pacific Digestive Week
  • Int'l Joint Research
• [Presentation] Alteration of gut microbiota affects Reg IIIγ expression in the intestine (2019)
  • Author(s): Nishimura H, Fukui H, Ogawa T, Kondo T, Kono T, Tozawa K, Tomita T, Oshima T, Miwa H.
  • Organizer: Asian Pacific Digestive Week
  • Int'l Joint Research