腸内細菌叢の攪乱と消化管微小炎症における Reg ファミリー蛋白の役割

• Project/Area Number: 21K08016
• 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: Hyogo Medical University
• Principal Investigator: 福井 広一 兵庫医科大学, 医学部, 教授 (60378742)
• Co-Investigator(Kenkyū-buntansha): 三輪 洋人 兵庫医科大学, 医学部, 教授 (80190833) ; 富田 寿彦 兵庫医科大学, 医学部, 准教授 (60388824)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2023: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 腸内細菌 / 免疫学 / 遺伝子 / 臨床 / 再生医学 / 感染症

Outline of Research at the Start

我々は Reg 蛋白が消化管粘膜の再生・修復を促進することを明らかにしたが、近年、抗菌ペプチドとして粘膜防御に役割を果たす可能性も示唆されている。本研究では、機能性消化管障害と寛解期の炎症性腸疾患に生じる過敏性腸症候群様症状の病態解明を念頭におき、種々の動物モデル (Reg 遺伝子改変マウス、抗菌薬および高脂肪食負荷による dysbiosis モデル、母子分離ストレスモデル) を用いて腸内細菌、粘膜バリア機能および免疫応答における Reg family 蛋白の機能解析を行い、腸内細菌叢の攪乱と消化管微小炎症における Reg family 蛋白の役割を明らかにすることを目的として研究を遂行する。

Outline of Annual Research Achievements

我々は世界に先駆けて，Reg ファミリー蛋白が炎症性消化管疾患の消化管粘膜において過剰発現することを報告し，その病態形成に重要な役割を果たすことを示した．さらにはその機能解析を進め，Reg ファミリー蛋白が IL-22/STAT3 シグナルにより増強し，腸管の自然免疫にも関与する可能性を示唆した．腸管の自然免疫は粘膜のバリア機能維持に極めて重要であるが，それらは腸内環境によって大きな影響を受けることが知られている．そこで我々は高脂肪食負荷や抗菌薬投与などによる dysbiosis モデルを用い，Reg ファミリー蛋白の機能解析を試みた．高脂肪食負荷によるdysbiosis モデルでは， 小腸において Reg IIIb と Reg IIIr の発現が減弱し，粘膜バリア機能に重要なタイト結合蛋白のうち occludin の発現が減弱した結果，粘膜の透過性が亢進して肝組織への LPS 侵入が促進されて肝組織における炎症性サイトカイン発現が増強して脂肪蓄積が促進することを明らかにした．また，バンコマイシン投与による dysbiosis モデルでは，腸内細菌叢の多様性が低下し，それに伴って腸管における Reg ファミリー蛋白発現とタイト結合蛋白 claudin 3, claudin 4 の発現が減弱し，実際に腸管粘膜の透過性の亢進も認められ，腸管組織における炎症性サイトカイン TNF-a や IFN-r の発現増強が認められた．近年，Reg ファミリー蛋白には抗菌ペプチドとしての作用がある可能性が示唆されているが，これらの結果から，dysbiosis 環境における Reg ファミリー蛋白の発現低下が腸管粘膜バリア機能の低下に寄与し，腸管の微小炎症に関与している可能性が示唆された．

Research Products

• [Journal Article] Pegfilgrastim for the management of neutropenia during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer patients. (2024)
  • Author(s): Yoshimoto T, Oshima T, Fukada T, Imamura N, Nakanishi T, Ebisutani N, Morishita D, Mieno M, Nakai K, Sei H, Kitayama Y, Eda H, Okugawa T, Tomita T, Fukui H, Shinzaki S.
  • Journal Title: Int J Clin Oncol Volume: 29 Issue: 2 Pages: 142-148
  • DOI: 10.1007/s10147-023-02438-3
  • Peer Reviewed
• [Journal Article] Regulatory T cells are increased and correlate with mast cells in eosinophilic esophagitis. (2024)
  • Author(s): Chen J, Oshima T, Tomita T, Fukui H, Shinzaki S.
  • Journal Title: J Neurogastroenterol Motil Volume: 30 Issue: 1 Pages: 29-37
  • DOI: 10.5056/jnm23040
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diarrhea-predominat irritable bowel syndrome-like symptoms in patients with quiescent Crohn's disease: Comprehensive analysis of clinical features and intestinal environment including the gut microbiome, organic acids, and intestinal permeability. (2023)
  • Author(s): Tomita T, Fukui H, Morishita D, Maeda A, Makizaki Y, Tanaka Y, Ohno H, Oshima T, Miwa H.
  • Journal Title: J Neurogastroenterol Motil Volume: 29 Issue: 1 Pages: 102-112
  • DOI: 10.5056/jnm22027
  • Peer Reviewed
• [Journal Article] Effect of Bifidobacterium bifidum G9-1 on the intestinal environment and diarrhea-predominant irritable bowel syndrome (IBS-D)-like symptoms in patients with quiescent Crohn's disease: A prospective pilot study. (2023)
  • Author(s): Tomita T, Fukui H, Okugawa T, Nakanishi T, Mieno M, Nakai K, Eda H, Kitayama Y, Oshima T, Shinzaki S, Miwa H.
  • Journal Title: J Clin Med Volume: 12 Issue: 10 Pages: 3368-3368
  • DOI: 10.3390/jcm12103368
  • Peer Reviewed / Open Access
• [Journal Article] Reg family proteins contribute to inflammation and pancreatic stellate cells activation in chronic pancreatitis (2023)
  • Author(s): Chen Wenting、Imasaka Mai、Lee Miyu、Fukui Hirokazu、Nishiura Hiroshi、Ohmuraya Masaki
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 12201-12201
  • DOI: 10.1038/s41598-023-39178-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-cardiac chest pain in Japan: prevalence, impact, and consultation behavior - a population-based study (2023)
  • Author(s): Chen J, Oshima T, Kondo T, Tomita T, Fukui H, Shinzaki S, Miwa H.
  • Journal Title: J Neurogastroenterol Motil. Volume: 29 Issue: 4 Pages: 446-454
  • DOI: 10.5056/jnm22184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gastric xanthelasma, microsatellite instability and methylation of tumor suppressor genes in the gastric mucosa: correlation and comparison as a predictive marker for the development of synchronous/metachronous gastric cancer (2022)
  • Author(s): Fukushima M, Fukui H, Watari J, Ito C, Hara K, Eda H, Tomita T, Oshima T, Miwa H.
  • Journal Title: J Clin Med Volume: 11 Issue: 1 Pages: 9-9
  • DOI: 10.3390/jcm11010009
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of serotonin type 3 receptor antagonist ramosetron on diarrhea-predominant irritable bowel syndrome (IBS-D)-like symptoms in patients with quiescent inflammatory bowel disease: A randomized, double-blind, placebo-controlled trial. (2022)
  • Author(s): Tomita T, Fukui H, Morishita D, Mori S, Oshima T, Shinzaki S, Miwa H.
  • Journal Title: J Clin Med Volume: 11 Issue: 23 Pages: 6822-6822
  • DOI: 10.3390/jcm11236882
  • Peer Reviewed / Open Access
• [Journal Article] Acid increases PGE₂ in the duodenal mucosa in rats (2022)
  • Author(s): Fujimura T, Kondo T, Kobayashi K, Duan S, Kanda H, Kono T, Fukushima M, Tomita T, Oshima T, Fukui H, Fujii Y, Konemura T, Okada H, Yamanaka H, Dai Y, Noguchi K, Miwa H.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 70 Issue: 1 Pages: 28-32
  • DOI: 10.3164/jcbn.21-59
  • NAID: 130008139100
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Microinflammation in the intestinal mucosa and symptoms of irritable bowel syndrome. (2022)
  • Author(s): Yoshimoto T, Oshima T, Huang X, Tomita T, Fukui H, Miwa H.
  • Journal Title: J Gastroenterol Volume: 57 Issue: 2 Pages: 62-69
  • DOI: 10.1007/s00535-021-01838-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Yokukansan suppresses gastric hypersensitivity and eosinophil-associated mcroinflammation in rats with functional dyspepsia. (2022)
  • Author(s): Duan S, Imamura N, Kondo T, Kanda H, Kogure Y, Okugawa T, Fukushima M, Tomita T, Oshima T, Fukui H, Noguchi K, Dai Y, Miwa H.
  • Journal Title: J Neurogastroenterol Motil Volume: 28 Issue: 2 Pages: 255-264
  • DOI: 10.5056/jnm21204
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Duodenal cholinergic tuft cell number is increased in functional dyspepsia. (2022)
  • Author(s): Huang X, Oshima T, Akiba Y, Yoshimoto T, Chen J, Taki M, Tomita T, Fukui H, Kaunitz JD, Miwa H.
  • Journal Title: Neurogastroenterol Motil Volume: 34 Issue: 10
  • DOI: 10.1111/nmo.14378
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Esophageal mucosal permeability as a surrogate measure of cure in eosinophilic esophagitis. (2022)
  • Author(s): Chen J, Oshima T, Huang X, Tomita T, Fukui H, Miwa H.
  • Journal Title: J Clin Med Volume: 11 Issue: 14 Pages: 4246-4246
  • DOI: 10.3390/jcm11144246
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of the b-catenin/REG Ia axis in the proliferation of sessile serrated adenoma/polyps associated with Fusobacterium nucleatum (2021)
  • Author(s): Nishimura H, Fukui H, Wang X, Ebisutani N, Nakanishi T, Tomita T, Oshima T, Hirota S, Miwa H.
  • Journal Title: Pathogens Volume: 10 Issue: 4 Pages: 434-434
  • DOI: 10.3390/pathogens10040434
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Probiotic Bifidobacterium bifidum G9-1 has a preventive effect on the acceleration of colonic permeability and M1 macrophage population in maternally separated rats. (2021)
  • Author(s): Wang X, Fukui H, Ran Y, Xu X, Ebisutani N, Nakanishi T, Tanaka Y, Maeda A, Makizaki Y, Tomita T, Oshima T, Miwa H.
  • Journal Title: Biomedicines Volume: 9 Issue: 6 Pages: 641-641
  • DOI: 10.3390/biomedicines9060641
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The potential role of REG family proteins in inflammatory and inflammation-associated diseases of the gastrointestinal tract (2021)
  • Author(s): Sun C, Wang X, Hui Y, Fukui H, Wang B, Miwa H.
  • Journal Title: Int J Mol Sci Volume: 22 Issue: 13 Pages: 7196-7196
  • DOI: 10.3390/ijms22137196
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of a high-fat diet on the small-intestinal environment and mucosal integrity in the gut-liver axis (2021)
  • Author(s): Nakanishi T, Fukui H, Wang X, Nishiumi S, Yokota H, Makizaki Y, Tanaka Y, Ohno H, Tomita T, Oshima T, Miwa H.
  • Journal Title: Cells Volume: 10 Issue: 11 Pages: 3168-3168
  • DOI: 10.3390/cells10113168
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutamine blocks interleukin-13-induced intestinal epithelial barrier dysfunction (2021)
  • Author(s): Li M, Oshima T, Ito C, Yamada M, Tomita T, Fukui H, Miwa H.
  • Journal Title: Digestion Volume: 102 Issue: 2 Pages: 170-179
  • DOI: 10.1159/000502953
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vitamin D receptor is overexpressed in the duodenum of patients with irritable bowel syndrome (2021)
  • Author(s): Miura K, Oshima T, Ito C, Horikawa T, Yamada M, Tomita T, Fukui H, Miwa H.
  • Journal Title: J Gastroenterol Hepatol Volume: 36 Issue: 4 Pages: 951-958
  • DOI: 10.1111/jgh.15225
  • Peer Reviewed
• [Journal Article] Senna Versus Magnesium Oxide for the Treatment of Chronic Constipation: A Randomized, Placebo-Controlled Trial. (2021)
  • Author(s): Morishita D, Tomita T, Mori S, Kimura T, Oshima T, Fukui H, Miwa H.
  • Journal Title: Am J Gastroenterol. Volume: 116 Issue: 1 Pages: 152-161
  • DOI: 10.14309/ajg.0000000000000942
  • Peer Reviewed
• [Journal Article] Eosinophil-associated microinflammation in the gastroduodenal tract contributes to gastric hypersensitivity in a rat model of early-life adversity (2021)
  • Author(s): Duan Shaoqi、Kondo Takashi、Miwa Hiroto、Yang Yanjing、Wang Shenglan、Kanda Hirosato、Kogure Yoko、Imamura Nobuko、Fujimura Tadahiro、Kono Tomoaki、Fukushima Masashi、Tozawa Katsuyuki、Tomita Toshihiko、Oshima Tadayuki、Fukui Hirokazu、Yamamoto Satoshi、Noguchi Koichi、Dai Yi
  • Journal Title: American Journal of Physiology-Gastrointestinal and Liver Physiology Volume: 320 Issue: 2 Pages: G206-G216
  • DOI: 10.1152/ajpgi.00313.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Butyrate alleviates cytokine-induced barrier dysfunction by modifying caudin-2 levels (2021)
  • Author(s): Huang X, Oshima T, Tomita T, Fukui H, Miwa H.
  • Journal Title: Biology-Basel Volume: 10 Issue: 3 Pages: 205-205
  • DOI: 10.3390/biology10030205
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 寛解期炎症性腸疾患における過敏性腸症候群症状に対するラモセトロンの臨床効果 (2023)
  • Author(s): 富田寿彦、福井広一、森下大輔、北山義隆、江田裕嗣、奥川卓也、大島忠之、新﨑信一郎、三輪洋人.
  • Organizer: 第25回日本神経消化器病学会
• [Presentation] 潰瘍性大腸炎に対するUpadacitinibの短期治療成績 (2023)
  • Author(s): 池ノ内真衣子、福井広一、横山恵子、賀来宏司、八木聡一、高木康宏、佐藤寿行、河合幹夫、上小鶴孝二、横山陽子、富田寿彦、新﨑信一郎．
  • Organizer: 第14回日本炎症性腸疾患学会学術集会
• [Presentation] 潰瘍性大腸炎に対するトファシチニブとフィルゴチニブの短期有効性および安全性 (2023)
  • Author(s): 422.八木聡一、福井広一、横山恵子、賀来宏司、高木康宏、池ノ内真衣子、佐藤寿行、河合幹夫、横山陽子、上小鶴孝二、富田寿彦、新﨑信一郎.
  • Organizer: 第14回日本炎症性腸疾患学会学術集会
• [Presentation] 寛解期クローン病患者における過敏性腸症候群様症状と腸内環境の関連について (2022)
  • Author(s): 富田俊彦，福井広一，三輪洋人．
  • Organizer: 第 64 回日本消化器学会大会
• [Presentation] 高脂肪食起因性脂肪肝発症における小腸内環境の変化について (2022)
  • Author(s): 中西貴士，福井広一，三重野将敏，鶴田晋也，岡村政道，吉原俊也，吉本崇典，中井啓介，北山嘉隆，原謙，江田裕嗣，奥川卓也，富田寿彦，大島忠之，三輪洋人
  • Organizer: 第 64 回日本消化器学会大会
• [Presentation] 社会的敗北ストレスマウスにおける腸内細菌叢の変化および大腸グアニリン/ウログアニリン発現と便性状の関連 (2021)
  • Author(s): 戎谷信彦、福井 広一、三輪 洋人．
  • Organizer: 第 107 回日本消化器病学会総会
• [Presentation] 精神的ストレスが guanylin/uroguanylin 発現と便性状に及ぼす影響について (2021)
  • Author(s): 戎谷信彦，福井広一，中西貴士，富田寿彦，大島忠之，三輪洋人．
  • Organizer: 第 23 回日本神経消化器学会