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

• Project/Area Number: 17K09363
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hyogo Medical University
• Principal Investigator: Fukui Hirokazu 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 遺伝子 / 再生医学 / 臨床 / 感染症 / 免疫学

Outline of Final Research Achievements

The expression of Reg protein is up-regulated by the STAT3-associated cytokines stimulation in gastrointestinal inflammatory diseases. Reg family proteins are expressed in the gastrointestinal epithelial cells and their expression levels are affected by the gut microbiome composition and the profile of macrophages in the intestinal mucosa. Antibiotics-induced dysbiosis caused the acceleration of intestinal mucosal permeability accompanied by the reduction of Reg and tight junction proteins expression. This finding suggests that the linkage between Reg protein and tight junction protein may play a role in the maintenance of mucosal barrier function.

Academic Significance and Societal Importance of the Research Achievements

消化管粘膜は粘膜バリア機能と消化管免疫システムで宿主を病原体侵入から防御する役割を担っている。本研究は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 Reg 蛋白が粘膜バリア機能を増強するだけでなく消化管免疫システムで中心的な役割を果たすマクロファージの性質変化にも関与していることを明らかにしたものである。近年、腸内細菌叢の変化に伴う消化管免疫異常と消化管粘膜のバリア機能異常が消化管疾患のみならず全身の疾患の誘因になる可能性が示唆されている。本研究は、この重要な異常を引き起こす機序の一端を明らかにした点で学術的意義があり、その成果が今後の医学の発展という社会的貢献につながると考えられる。

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 Issue: 1-2 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 Issue: 1 Pages: 4381-4381
  • 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): Xin Xu , Hirokazu Fukui , Ying Ran , Xuan Wang , Yoshihito Inoue , Nobuhiko Ebisudani, Heihachiro Nishimura, Toshihiko Tomita , Tadayuki Oshima , Jiro Watari , Hiroshi Kiyama , Hiroto Miwa
  • Journal Title: Mediators Inflamm Volume: 6 Pages: 7859460-7859460
  • 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: Neurogastroenterology & motility Volume: Epub ahead Issue: 10
  • 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 Issue: 1 Pages: 12559-12559
  • 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 Issue: 4 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 Issue: 4 Pages: 563-575
  • DOI: 10.5056/jnm18194
  • Peer Reviewed / Open Access
• [Journal Article] Role of gut microbiota-gut hormone axis in the pathophysiology of functional gastrointestinal disorders. (2018)
  • Author(s): Fukui H, Xu X, Miwa H.
  • Journal Title: J Neurogastroenterol Motil Volume: 24 Issue: 3 Pages: 367-386
  • DOI: 10.5056/jnm18071
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of probiotic Bifidobacterium bifidum G9-1 on the relationship between gut microbiota profile and stress sensitivity in maternally separated rats (2018)
  • Author(s): Fukui H, Oshima T, Tanaka Y, Oikawa Y, Makizaki Y, Ohno H, Tomita T, Watari J, Miwa H.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 12384-12384
  • DOI: 10.1038/s41598-018-30943-3
  • Peer Reviewed / Open Access
• [Journal Article] Association between gastrointestinal motility and macrophage/mast cell distribution in mice during the healing stage after DSS-induced colitis (2018)
  • Author(s): Kodani M, Fukui H, Tomita T, Oshima T, Watari J, Miwa H.
  • Journal Title: Mol Med Rep Volume: 17 Pages: 8167-8172
  • DOI: 10.3892/mmr.2018.8926
  • Peer Reviewed / Open Access
• [Journal Article] Filaggrin and tight junction proteins are crucial for IL-13-mediated esophageal barrier dysfunction (2018)
  • Author(s): Wu L, Oshima T, Li M, Tomita T, Fukui H, Watari J, Miwa H.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 315 Issue: 3 Pages: G341-G350
  • DOI: 10.1152/ajpgi.00404.2017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term effects of H. pylori eradication on epigenetic alterations related to gastric carcinogenesis (2018)
  • Author(s): Michigami Y, Watari J, Ito C, Nakai 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: 8 Issue: 1 Pages: 14369-14369
  • DOI: 10.1038/s41598-018-32717-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sex differences in associations among metabolic syndrome, obesity, related biomarkers, and colorectal adenomatous polyp risk in a Japanese population (2018)
  • Author(s): Nakai K, Watari J, Tozawa K, Tamura A, Hara K, Yamasaki T, Kondo T, Kono T, Tomita T, Ohda Y, Oshima T, Fukui H, Sakurai J, Kim Y, Hayakawa Y, Fujisawa T, Morimoto T, Miwa H.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 63 Issue: 2 Pages: 154-163
  • DOI: 10.3164/jcbn.18-11
  • NAID: 130007479962
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. (2018)
  • Author(s): Oshima T, Wu L, Li M, Fukui H, Watari J, Miwa H.
  • Journal Title: J Gastroenterol Volume: 53 Issue: 1 Pages: 84-94
  • DOI: 10.1007/s00535-017-1369-3
  • Peer Reviewed / Int'l Joint Research
• [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 Issue: 3 Pages: 3482-3488
  • 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 Issue: 4 Pages: G367-G373
  • DOI: 10.1152/ajpgi.00232.2016
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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 Issue: 5 Pages: e0177232-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 Issue: 5 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 Issue: 4
  • 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 Issue: 7 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 Issue: 3 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 Issue: 10 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 Issue: 3 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: Journal of Clinical Biochemistry and Nutrition Volume: 60 Issue: 2 Pages: 146-150
  • DOI: 10.3164/jcbn.16-92
  • NAID: 130005398540
  • ISSN: 0912-0009, 1880-5086
  • 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 Issue: 4 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 Issue: 1 Pages: 13384-13384
  • DOI: 10.1038/s41598-017-13842-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] Antibiotics treatment prolongs gastrointestinal transit time accompanied by increase of colonic GLP-1/GPR43 expression. (2018)
  • Author(s): Inoue Y, Fukui H, Xu X, Kondo T, Kono 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] Capsule endoscopic observation of small intestine in patients with familial adenomatous polyposis. (2018)
  • Author(s): Kono T, Fukui H, Katsuyuki T, Tomita T, Oshima T, Watari J, Miwa H.
  • Organizer: Asian Pacific Digestive Week
  • Int'l Joint Research
• [Presentation] Clinical outcome of patients after endoscopic resection for T1-stage colorectal cancer. (2018)
  • Author(s): Eda H, Fukui H, Kono T, Kitayama Y, Nakamura K, Tamura A, Ogawa T, Yamasaki T, Kondo T, Tozawa K, Tomita T, Oshima T, Watari J, Miwa H.
  • Organizer: Asian Pacific Digestive Week
  • Int'l Joint Research
• [Presentation] 母子分離ラットモデルにおける腸内細菌叢と消化管機能に関する検討 (2018)
  • Author(s): 福井広一，大島忠之，三輪洋人.
  • Organizer: 第104回日本消化器病学会総会
• [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