Gut-liver axis mediated by endotoxin and innate immunity

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nara Medical University
• Principal Investigator: FUKUI HIROSHI 奈良県立医科大学, 医学部, 教授 (80145838)
• Co-Investigator(Renkei-kenkyūsha): YOSHIJI Hitoshi 奈良県立医科大学, 医学科, 准教授 (40336855) ; FUJIMOTO Masao 奈良県立医科大学, 医学科, 講師 (60295805) ; NAMISAKI Tadashi 奈良県立医科大学, 医学科, 助教 (20526850)
• Project Period (FY): 2011 – 2013
• Keywords: エンドトキシン / 自然免疫 / Toll-like受容体 / 非アルコール性脂肪肝炎 / 腸管相関 / 難吸収性抗菌薬 / ウルソデオキシコール酸 / 急性肝不全

Research Abstract

The underling cause of nonalcoholic steatohepatitis is still unlear, but intestinal bacterial flora and endotoxin are important factors. We evaluated pathogenic roles of endotoxin, intestinal permeability and innate immunity on the development of liver fibrosis in rats fed choline-deficient and amino acid-defined (CDAA) diet. In these rats, marked fibrosis was associated with increased intestinal permeability, augmented development of Toll-like recrptor 4 (TLR4) mRNA, lipopolysaccharide binding protein (LBP) mRNA and TNF-alpha mRNA in the liver. Oral administrations of nonabsorbable antibiotics for selective bowel decontamination and ursodeoxycholic acids were demonstrated to suppress intestinal permeability and TLR4 mediated inflammation and finally inhibit progression of fibrosis. Regulation of gut-liver axis may become a new strategy for prevention of human steatohepatitis.

Research Products

• [Journal Article] Difficulty in evaluating intestinal permeability in patients with liver cirrhosis : What is the precipitating factor? (2013)
  • Author(s): Fukui H.
  • Journal Title: Hepatol Res. Volume: 43 Pages: 179-81
  • Peer Reviewed
• [Journal Article] The effect of inflammatory cytokines in alcoholic liver disease (2013)
  • Author(s): Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, Noguchi R, Yoshiji H, Fujimoto M, Fukui H.
  • Journal Title: Mediators Inflamm. Volume: 2013 Pages: 495156
  • Peer Reviewed
• [Journal Article] Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis (2013)
  • Author(s): Shirai Y, Yoshiji H, Noguchi R, Kaji K, Aihara Y, Douhara A, Moriya K, Namisaki T, Kawaratani H, Fukui H.
  • Journal Title: J Gastroenterol Hepatol Volume: 28 Pages: 723-30
  • Peer Reviewed
• [Journal Article] ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the Child-Turcotte-Pugh score and the Model for End-Stage Liver Disease score (2012)
  • Author(s): Takaya H, Uemura M, Fujimura Y, Matsumoto M, Matsuyama T, Kato S, Morioka C, Ishizashi H, Hori Y, Fujimoto M, Tsujimoto T, Kawaratani H, Toyohara M, Kurumatani N, Fukui H.
  • Journal Title: Hepatol Res. Volume: 42 Pages: 459-72
  • Peer Reviewed
• [Journal Article] Innate immune reactivity of the ileum-liver axis in nonalcoholic steatohepatitis (2012)
  • Author(s): Tsujimoto T, Kawaratani H, Kitazawa T, Uemura M, Fukui H.
  • Journal Title: Dig Dis Sci. Volume: 57 Pages: 1144-51
  • Peer Reviewed
• [Journal Article] How leaky gut and endotoxemia induce bacterial infection in cirrhosis and gastrointestinal hemorrhage? (2011)
  • Author(s): Fukui H.
  • Journal Title: J Gastroenterol Hepatol Volume: 26 Pages: 423-5
  • Peer Reviewed
• [Journal Article] 消化器内科領域におけるEndotoxin Activity Assay(EAA)の有用性についての検討 (2011)
  • Author(s): 藤本正男,武山真也,北澤利幸,辻本達寛,瓦谷英人,植村正人,福井博
  • Journal Title: エンドトキシン血症救命治療研究会誌 Volume: 15 Pages: 69-73
• [Presentation] 自然免疫制御による肝線維化の抑制:小腸Tight Junction Proteinの役割 (2014)
  • Author(s): 堂原彰敏,吉治仁志,福井博
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20140528-30
• [Presentation] 肝障害をめぐる腸肝相関DSS腸炎モデルとNASHモデルの対比 (2013)
  • Author(s): 瓦谷英人,守屋圭,高谷広章,堂原彰敏,辻本達寛,吉治仁志,藤本正男,植村正人,福井博
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 20131009-10
• [Presentation] NASH肝線維化進展における腸管透過性亢進の役割 (2013)
  • Author(s): 堂原彰敏,吉治仁志,守屋圭,野口隆一,浪崎正,相原洋祐,瓦谷英人,北出光輝,福井博
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 20131009-10
• [Presentation] ウルソデオキシコール酸とアンジオテンシンII受容体阻害薬併用によるNASH肝線維化進展抑制の試み (2013)
  • Author(s): 浪崎正,吉治仁志,福井博
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20130606-07
• [Presentation] 内因性エンドトキシン制御による肝線維化抑制作用機序の検討 (2013)
  • Author(s): 堂原彰敏,吉治仁志,守屋圭,野口隆一,浪崎正,相原洋祐,瓦谷英人,福井博
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20130606-07
• [Presentation] Beneficial effects of combined treatment with ursodoxycholic acid (UDCA) and Angiotensin-IItype1 receptor blocker(ARB) on liver fibrosis development in the rat model of nonalcoholic steatohepatitis (2013)
  • Author(s): Namisaki T, Yoshiji H, Noguchi R, Moriya K, Kitade M, Aihara Y, Douhara A, Kawaratani H, Nishimura N, Fukui H.
  • Organizer: Annual Meeting of the Japanese Society for the Research of Hepatic Cells
  • Place of Presentation: 大阪
  • Year and Date: 2013-09-26
• [Presentation] Inhibition of endotoxin cascade with antibiotics attenuates the liver fibrosis development in rat model of nonalcoholic steatohepatitis (2013)
  • Author(s): Douhara A, Moriya K, Yoshiji H, Noguchi R, Namisaki T, Kitade M, Aihara Y, Kawaratani H, Nishimura N, Fukui H.
  • Organizer: International Society for Hepatic Sinusoidal Research
  • Place of Presentation: 大阪
  • Year and Date: 2013-09-24
• [Presentation] 内因性エンドトキシン制御による肝線維化抑制 (2013)
  • Author(s): 堂原彰敏,吉治仁志,福井博
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島
  • Year and Date: 2013-03-26
• [Presentation] Endotoxin activity as a novel marker reflecting decompensation in patients with liver cirrhosis (2012)
  • Author(s): Fujimoto M, Uemura M, Takaya H, Takeyama S, Fukui H.
  • Organizer: IEIIS2012
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] Potential role of endotoxemia on the decreased activity of plasma ADAMTS13 in patients with chronic and acute hepatic failure (2012)
  • Author(s): Takaya H, Uemura M, Fujimoto M, Matsuyama T, Morioka C, Ishikawa M, Kawaratani H, Matsumoto M, Fujimura Y, Fukui H.
  • Organizer: IEIIS2012
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] Endotoxin innate immunity and platelet aggregation in acute liver failure : new therapeutic approach by TLR4 regulation (2012)
  • Author(s): Takaya H, Kitazawa T, Kawaratani H, Tsujimoto T, Uemura M, Fukui H.
  • Organizer: IEIIS2012
  • Place of Presentation: 東京
  • Year and Date: 2012-10-24
• [Presentation] Therapeutic effect of cytokine modulator Y-40138 in the rat alcoholic liver disease model (2012)
  • Author(s): Kawaratani H, Tsujimoto T, Moriya K, Douhara A, Takaya H, Mitoro A, Yoshiji H, Uemura M, Fukui H.
  • Organizer: IEIIS2012
  • Place of Presentation: 東京
  • Year and Date: 2012-10-24
• [Presentation] Expression of TLR4 and TNF-a in the rat dextran sulfate sodium(DSS) induced colitis model (2012)
  • Author(s): K awaratani H, Moriya K, Takaya H, Douhara A, Yoshiji H, Fujimoto M, Uemura M, Fukui H.
  • Organizer: IEIIS2012
  • Place of Presentation: 東京
  • Year and Date: 2012-10-23
• [Book] アルコール性肝障害と炎症性サイトカイン (2013)
  • Author(s): 瓦谷英人,辻本達寛,守屋圭,高谷広章,堂原彰敏,美登路昭,吉治仁志,藤本正男,福井博
  • Total Pages: 16:12-15
  • Publisher: エンドトキシン・自然免疫研究
• [Book] 急性肝不全における血漿エンドトキシン濃度とADAMTS13活性の動態新規治療法の可能性を含めて (2013)
  • Author(s): 高谷広章,植村正人,藤本正男,松山友美,森岡千恵,石川昌利,辻本達寛,瓦谷英人,北澤利幸,早川正樹,松本雅則,藤村吉博,福井博
  • Total Pages: 16:16-20
  • Publisher: エンドトキシン・自然免疫研究
• [Book] 消化器内科領域におけるEndotoxin Activity Assay(EAA)の有用性についての検討 (2011)
  • Author(s): 藤本正男,武山真也,北澤利幸,辻本達寛,瓦谷英人,植村正人,福井博
  • Total Pages: 15:69-73
  • Publisher: エンドトキシン血症救命治療研究会誌
• [Book] アルコール性肝障害の病態と自然免疫機構 (2011)
  • Author(s): 瓦谷英人,辻本達寛,北澤利幸,藤本正男,植村正人,福井博
  • Total Pages: 14:66-69
  • Publisher: エンドトキシン・自然免疫研究
• [Book] 肝不全における血漿エンドトキシン濃度とADAMTS13活性の動態 (2011)
  • Author(s): 高谷広章,植村正人,藤本正男,松山友美,森岡千恵,石川昌利,辻本達寛,瓦谷英人,松本雅則,藤村吉博,福井博
  • Total Pages: 14;61-65
  • Publisher: エンドトキシン・自然免疫研究
• [Book] 血中エンドトキシン測定の展望Endotoxin Activity Assay(EAA) (2011)
  • Author(s): 藤本正男,福井博
  • Total Pages: 14:27-30
  • Publisher: エンドトキシン・自然免疫研究