炎症性消化管疾患における Reg 蛋白の消化管粘膜防御機序に関する研究

2017 Fiscal Year Research-status 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) ; 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

我々はこれまで，Reg 蛋白が消化管粘膜に対して再生促進作用を示し，炎症性消化管疾患の病態形成に役割を果たすことを明らかにした．さらには，Reg 蛋白がIL-22 シグナルの実効分子として消化管粘膜保護作用を促進する可能性も示唆した．
そこで本年度は，Reg 蛋白の粘膜バリア機能に対する作用に関する検討を行った．Reg 遺伝子改変マウスでは，NSAID 投与を受けた場合コントロール群に較べ有意に粘膜透過性が亢進することから，Reg 遺伝子が粘膜バリアの保護作用を有することが示された．その機序としては，Reg 遺伝子改変マウスでタイト結合蛋白である claudin 3 の発現が減弱していることから，Reg 蛋白刺激に誘導された claudin 3 が粘膜保護作用に関与している可能性が示唆された．実際我々は，in vitro 実験で，Reg 蛋白が転写因子 Sp1 のリン酸化を促進して claudin 3 蛋白の発現を誘導することを明らかにした．
次のステップとして我々は，腸内細菌と Reg 蛋白発現の関連とReg 蛋白の免疫担当細胞に対する作用を解明するため，germ free マウスに SPF マウスの糞便移植を行ったモデルと SPF マウスに抗菌薬を投与して dysbiosis 状態を惹起したモデルをした．興味深いことに，糞便移植を受けた germ free　マウスの消化管運動は促進し，消化管の内分泌細胞数や消化管ホルモンの産生に変化が見られた．一方，抗菌薬投薬による dysbiosis では消化管運動の抑制が認められ，こちらでも大腸内分泌細胞の動態に変化を認めている，現在，それらモデルの消化管組織におけるマクロファージなどの動態を解析中であり，Reg 蛋白がそれらの消化管機能や粘膜免疫にどのような役割を果たしているのか解析を進めている所である．

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Reg 蛋白が転写因子 Sp1 のリン酸化を促進して claudin 3 蛋白の発現を誘導することを明らかにし，その結果，粘膜透過性を抑制する可能性を示した．次の段階として，Reg 蛋白の粘膜免疫と消化管運動機能に関する役割について解析を進めており，本研究は概ね当初の計画通りに進展していると考えられる．

Strategy for Future Research Activity

消化管粘膜防御機序における腸内細菌と REG 蛋白の役割を検討するため，糞便移植を受けた germ free　マウスや抗菌薬投与を受けた dysbiosis マウスモデルを用い，腸内細菌と Reg 蛋白発現の関連およびReg 蛋白の免疫担当細胞に対する作用の解明を進める予定である．

Research Products

• [Journal Article] Involvement of gut microbiota in the association between gastrointestinal motility and 5-HT expression/M2 macrophage behavior in the gastrointestinal tract (2017)
  • Author(s): Yang M, Fukui H, Eda H, Kitayama Y, Hara K, Kodani M, Tomita T, Oshima T, Watari J, Miwa H.
  • Journal Title: Mol Med Rep Volume: 16 Pages: 3482-3488
  • DOI: doi: 10.3892/mmr.2017.6955.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Involvement of gut microbiota in the association between GLP-1/GLP-1 receptor expression and gastrointestinal motility. (2017)
  • Author(s): Yang M, Fukui H, Eda H, Xu X, Kitayama Y, Hara K, Kodani M, Tomita T, Oshima T, Watari J, Miwa H.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 312 Pages: G367-373
  • DOI: 10.1152/ajpgi.00232.2016.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of Helicobacter pylori infection on the link between GLP-1 expression and motility of the gastrointestinal tract (2017)
  • Author(s): Eda H, Fukui H, Uchiyama R, Kitayama Y, Hara K, Yang M, Kodani M, Tomita T, Oshima T, Watari J, Tsutsui H, Miwa H.
  • Journal Title: PLOS One Volume: 12 Pages: e0177232
  • DOI: 10.1371/journal.pone.0177232.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia (2017)
  • Author(s): Nakamura K, Tomita T, Oshima T, Asano H, Yamasaki T, Okugawa T, Kondo T, Kono T, Tozawa K, Ohda Y, Fukui H, Kazuhito F, Hirota S, Watari J, Miwa H.
  • Journal Title: J Gastroenterol Volume: 52 Pages: 602-610
  • DOI: 10.1007/s00535-016-1260-7.
  • Peer Reviewed
• [Journal Article] Genetic instability, CpG island methylator phenotype and proliferative activity are distinct differences between diminutive and small tubular adenoma of the colorectum (2017)
  • Author(s): Nando Y, Watari J, Hara K, Yamasaki T, Okugawa T, Kondo T, Kono T, Tozawa K, Tomita T, Ohda Y, Oshima T, Fukui H, Matsubara N, Tomita N, Hirota S, Miwa H.
  • Journal Title: Hum Pathol Volume: 60 Pages: 37-45
  • DOI: 10.1016/j.humpath.2016.09.022.
  • Peer Reviewed
• [Journal Article] Acotiamide improves stress-induced gastric accommodation (2017)
  • Author(s): Ikeo K, Oshima T, Sei H, Kondo T, Fukui H, Watari J, Miwa H.
  • Journal Title: Neurogastroenterol Motil Volume: 29 Pages: e12991
  • DOI: 10.1111/nmo.12991.
  • Peer Reviewed
• [Journal Article] Adenosine triphosphate induces P2Y2 activation and IL-8 release in human esophageal epithelial cells (2017)
  • Author(s): Wu L, Oshima T, Fukui H, Watari J, Miwa H.
  • Journal Title: J Gastroenterol Hepatol Volume: 32 Pages: 1341-1347
  • DOI: 10.1111/jgh.13672.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of vonoprazan, a potassium-competitive acid blocker, on the 13C-urea breath test in Helicobacter pylori-positive patients (2017)
  • Author(s): Takimoto M, Tomita T, Yamasaki T, Fukui S, Taki M, Okugawa T, Kondo T, Kono T, Tozawa K, Arai E, Ohda Y, Oshima T, Fukui H, Watari J, Miwa H.
  • Journal Title: Dig Dis Sci Volume: 62 Pages: 739-745
  • DOI: 10.1007/s10620-016-4439-0.
  • Peer Reviewed
• [Journal Article] A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial. (2017)
  • Author(s): Kondo T, Sei H, Yamasaki T, Tomita T, Ohda Y, Oshima T, Fukui H, Watari J, Miwa H.
  • Journal Title: J Gastroenterol Volume: 52 Pages: 1081-1089
  • DOI: 10.1007/s00535-017-1308-3.
  • Peer Reviewed
• [Journal Article] Prevalence of gastric motility disorders in patients with functional dyspepsia (2017)
  • Author(s): Asano H, Tomita T, Nakamura K, Yamasaki T, Okugawa T, Kondo T, Kono T, Tozawa K, Ohda Y, Oshima T, Fukui H, Fukushima K, Hirota S, Watari J, Miwa H.
  • Journal Title: J Neurogastroenterol Motil Volume: 23 Pages: 392-399
  • DOI: 10.5056/jnm16173.
  • Peer Reviewed
• [Journal Article] Claudin-2 expression is upregulated in the ileum of diarrhea predominant irritable bowel syndrome patients (2017)
  • Author(s): Ishimoto H, Oshima T, Sei H, Yamasaki T, Kondo T, Tozawa K, Tomita T, Ohda Y, Fukui H, Watari J, Miwa H.
  • Journal Title: J Clin Biochem Nutr Volume: 60 Pages: 146-150
  • DOI: 10.3164/jcbn.16-92.
  • Peer Reviewed
• [Journal Article] Intravenous corticotropin-releasing hormone administration increases esophageal electrical sensitivity in healthy individuals (2017)
  • Author(s): Yamasaki T, Tomita T, Takimoto M, Kondo T, Tozawa K, Ohda Y, Oshima T, Fukui H, Watari J, Miwa H.
  • Journal Title: Neurogastroenterol Motil Volume: 23 Pages: 526-532
  • DOI: 10.5056/jnm17067.
  • Peer Reviewed
• [Journal Article] Effect of long-term aspirin use on molecular alterations in precancerous gastric mucosa in patients with and without gastric cancer (2017)
  • Author(s): Michigami Y, Watari J, Ito C, Hara K, Yamasaki T, Kondo T, Kono T, Tozawa K, Tomita T, Oshima T, Fukui H, Morimoto T, Das KM, Miwa H.
  • Journal Title: Sci Rep Volume: 7 Pages: 13384
  • DOI: 10.1038/s41598-017-13842-x.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Role of microbiota in gut hormone and gastrointestinal motility (2017)
  • Author(s): Fukui H
  • Organizer: 2017 Academic Congress of Intestinal Diseases Tianjin・China
  • Invited
• [Presentation] Microbiota and gut hormones (2017)
  • Author(s): Fukui H, Miwa H.
  • Organizer: 5th Biennial Congress of the Asian Neurogastroenterology & Motility Association
  • Int'l Joint Research / Invited
• [Presentation] Relationship between intestinal motility and small intestinal inflammation after acute colitis. (2017)
  • Author(s): Fukui H, Kodani M, Tozawa K, Ohda Y, 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] Effect of gut microbiota on Reg IIIr expression in relation to intestinal immunity. (2017)
  • Author(s): Xin Xu, Fukui H, Eda H, Yamasaki T, Kondo T, Tozawa K, Ohda Y, Tomita T, Oshima T, Watari J, Miwa H.
  • Organizer: 5th Biennial Congress of Asian Neurogastroenterology and Motility Association
  • Int'l Joint Research
• [Presentation] Role of gut microbiota on GLP-1 receptor expression and gastrointestinal motility. (2017)
  • Author(s): Xin Xu, Fukui H, Eda H, Yamasaki T, Kondo T, Tozawa K, Ohda Y, Tomita T, Oshima T, Watari J, Miwa H.
  • Organizer: 5th Biennial Congress of Asian Neurogastroenterology and Motility Association
  • Int'l Joint Research
• [Presentation] Ratio of neutrophil to lymphocytes is useful to predict the prognosis of patients with paclitaxel plus ramucirumab treatment for unresectable advanced gastric cancer. (2017)
  • Author(s): Hara K, Fukui H, Tozawa K, Takimoto M, Nakamura K, Tamura A, Okugawa T, Tomita T, Ohda Y, 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] Effect of gut microbiota on GLP-1 receptor expression in relation to gastrointestinal motility. (2017)
  • Author(s): Xin Xu, Fukui H, Eda H, Yamasaki T, Kondo T, Tozawa K, Ohda Y, 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] 腸内細菌が GLP-1/GLP-1 receptor 発現と消化管運動に及ぼす影響について (2017)
  • Author(s): 福井広一，江田裕嗣，三輪洋人．
  • Organizer: 第 103 回日本消化器病学会総会