To identify the mechanism of inflammatory bowel disease by using human microbe mono-associated mouse

• Project/Area Number: 15H02534
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: KANAI TAKANORI 慶應義塾大学, 医学部(信濃町), 教授 (40245478)
• Co-Investigator(Kenkyū-buntansha): 長沼 誠 慶應義塾大学, 医学部, 講師 (00265810) ; 久松 理一 杏林大学, 医学部, 教授 (60255437)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥42,120,000 (Direct Cost: ¥32,400,000、Indirect Cost: ¥9,720,000); Fiscal Year 2017: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2016: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000); Fiscal Year 2015: ¥22,230,000 (Direct Cost: ¥17,100,000、Indirect Cost: ¥5,130,000)
• Keywords: 腸内細菌 / 炎症性腸疾患 / 潰瘍性大腸炎 / 原発性硬化性胆管炎 / 腸管外合併症 / Th17細胞 / 下部消化管学 / 下部消化管 / 免疫学

Outline of Final Research Achievements

We transplanted feces of ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) patients to germ-free (GF) mice (UC mice or PSC/UC mice). The ratio of Th17 cells was significantly increased in the liver of the PSC/UC mice compared to the UC mice. Klebsiella pneumonia (Kp), Proteus mirabillus, Enterococcus gallineum were frequently detected in feces of PSC+UC patient. We inoculated these three bacteria to GF mice (3 microbe mix mice; 3 mix mice). Th17 cells were accumulated in the liver. We also confirmed 3mix mice induce severe liver damage after DDC treatment compare to UC mice. Kp is found in the lamina propria of Kp mono associated mice. Kp induced epithelial cell apoptosis by using co-culture of Kp and human colon epithelial cells. As above, we revealed Kp destroys intestinal epithelial cells and induces "leaky gut" in the pathological condition of PSC.

Research Products

• [Journal Article] Reconstruction of the Human Colon Epithelium In Vivo. (2018)
  • Author(s): Sugimoto S, Ohta Y, Fujii M, Matano M, Shimokawa M, Nanki K, Date S, Nishikori S, Nakazato Y, Nakamura T, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 2 Pages: 171-176
  • DOI: 10.1016/j.stem.2017.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling (2017)
  • Author(s): Teratani Toshiaki、Tomita Kengo、Suzuki Takahiro、Furuhashi Hirotaka、Irie Rie、Hida Shigeaki、Okada Yoshikiyo、Kurihara Chie、Ebinuma Hirotoshi、Nakamoto Nobuhiro、Saito Hidetsugu、Hibi Toshifumi、Miura Soichiro、Hokari Ryota、Kanai Takanori
  • Journal Title: Journal of Hepatology Volume: 67 Issue: 4 Pages: 780-790
  • DOI: 10.1016/j.jhep.2017.05.020
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice (2017)
  • Author(s): Hayashi Atsushi、Mikami Yohei、Miyamoto Kentaro、Kamada Nobuhiko、Sato Toshiro、Mizuno Shinta、Naganuma Makoto、Teratani Toshiaki、Aoki Ryo、Fukuda Shinji、Suda Wataru、Hattori Masahira、Amagai Masayuki、Ohyama Manabu、Kanai Takanori
  • Journal Title: Cell Reports Volume: 20 Issue: 7 Pages: 1513-1524
  • DOI: 10.1016/j.celrep.2017.07.057
  • Peer Reviewed / Open Access
• [Journal Article] Commensal Lactobacillus controls immune tolerance during acute liver injury in mice (2017)
  • Author(s): Nakamoto N, Amiya T, Aoki R, Taniki N, Koda Y, Miyamoto K, Teratani T, Suzuki T, Chiba S, Chu PS, Hayashi A, Yamaguchi A, Shiba S, Miyake R, Katayama T, Suda W, Mikami Y, Kamada N, Ebinuma H, Saito H, Hattori M, Kanai T
  • Journal Title: Cell Reports Volume: 5 Issue: 5 Pages: 1215-1226
  • DOI: 10.1016/j.celrep.2017.10.022
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of Indigo naturalis in a Multicenter Randomized Controlled Trial of Patients with Ulcerative Colitis (2017)
  • Author(s): .Naganuma M, Sugimoto S, Mitsuyama K, Kobayashi T, Yoshimura N, Ohi H, Tanaka S, Andoh A, Ohmiya N, Saigusa K, Yamamoto T, Morohoshi Y, Ichikawa H, Matsuoka K, Hisamatsu T, Watanabe K, Mizuno S, Suda W, Hattori M, Fukuda S, Hirayama A, Abe T, Watanabe M, Hibi T, Suzuki Y, Kanai T
  • Journal Title: Gastroenterology Volume: 4 Issue: 4 Pages: 935-947
  • DOI: 10.1053/j.gastro.2017.11.024
  • Peer Reviewed / Open Access
• [Journal Article] Visualization and Targeting of LGR5+ Human Colon Cancer Stem Cells (2017)
  • Author(s): Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T
  • Journal Title: Nature Volume: 印刷中 Issue: 7653 Pages: 13-14
  • DOI: 10.1038/nature22081
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Single fecal microbiota transplantation failed to change intestinal microbiota and had limited effectiveness against ulcerative colitis in Japanese patients (2017)
  • Author(s): Mizuno S, Nanki K, Matsuoka K, Saigusa K, Ono K, Arai M, Sugimoto S, Kiyohara H, Nakashima M, Takeshita K, Naganuma M, Suda W, Hattori M, Kanai T.
  • Journal Title: Intest Res Volume: 15(1) Issue: 1 Pages: 68-74
  • DOI: 10.5217/ir.2017.15.1.68
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic morphologic features of ulcerative colitis-associated dysplasia classified according to the SCENIC consensus statement (2016)
  • Author(s): Sugimoto S, Naganuma M, Iwao Y, Matsuoka K, Shimoda M, Mikami S, Mizuno S, Nakazato Y, Nanki K, Inoue N, Ogata H, Kanai T.
  • Journal Title: Gastrointest Endosc. Volume: 85(3) Issue: 3 Pages: 639-646
  • DOI: 10.1016/j.gie.2016.11.013
  • Peer Reviewed
• [Journal Article] Adalimumab Monotherapy and a Combination with Azathioprine for Crohn's Disease: A Prospective, Randomized Trial. (2016)
  • Author(s): Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, Ishida T, Kato S, Nakagawa T, Esaki M, Nagahori M, Matsui T, Naito Y, Kanai T, Suzuki Y, Nojima M, Watanabe M, Hibi T
  • Journal Title: J Crohns Colitis. Volume: 10(11) Pages: 1259-1266
• [Journal Article] Findings of ulceration and severe stricture on MRE can predict prognosis of Crohn's disease in patients treated with anti-TNF treatment. (2016)
  • Author(s): Naganuma M, Okuda S, Hisamatsu T, Matsuoka K, Mori K, Hosoe N, Nakazato Y, Ogata H, Kanai T.
  • Journal Title: Abdom Radiol (NY). Volume: 42(1) Issue: 1 Pages: 141-151
  • DOI: 10.1007/s00261-016-0878-5
  • Peer Reviewed
• [Journal Article] Clinical Efficacy and Safety of Oral Qing-Dai in Patients with Ulcerative Colitis: A Single-Center Open-Label Prospective Study. (2016)
  • Author(s): Sugimoto S, Naganuma M, Kiyohara H, Arai M, Ono K, Mori K, Saigusa K, Nanki K, Takeshita K, Takeshita T, Mutaguchi M, Mizuno S, Ogata H, Iwao Y, Kanai T
  • Journal Title: Digestion Volume: 93 Issue: 3 Pages: 193-201
  • DOI: 10.1159/000444217
  • Peer Reviewed / Open Access
• [Journal Article] Indole compounds may be promising medicines for ulcerative colitis. (2016)
  • Author(s): Sugimoto S, Naganuma M, Kanai T.
  • Journal Title: J Gastroenterol. Volume: 51(9) Issue: 9 Pages: 853-61
  • DOI: 10.1007/s00535-016-1220-2
  • Peer Reviewed
• [Journal Article] The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is useful to predict medium to long-term prognosis in ulcerative colitis patients with clinical remission. (2016)
  • Author(s): Arai M, Naganuma M, Sugimoto S, Kiyohara H, Ono K, Mori K, Saigusa K, Nanki K, Mutaguchi M, Mizuno S, Bessho R, Nakazato Y, Hosoe N, Matsuoka K, Inoue N, Ogata H, Iwao Y, Kanai T.
  • Journal Title: J Crohns Colitis Volume: 10(11) Issue: 11 Pages: 1303-1309
  • DOI: 10.1093/ecco-jcc/jjw104
  • Peer Reviewed
• [Journal Article] A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements. (2016)
  • Author(s): Fujii M, Shimokawa M, Date S, Takano A, Matano M, Ohta Y, Nanki K, Kawasaki K, Nakazato Y, Uraoka T, Watanabe T, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell Volume: 18 Issue: 6 Pages: 827-838
  • DOI: 10.1016/j.stem.2016.04.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Up-to-date medical treatment for ulcerative colitis (2016)
  • Author(s): Kiyohara H, Mizuno S, Naganuma M, Kanai T
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 113 Issue: 3 Pages: 413-423
  • DOI: 10.11405/nisshoshi.113.413
  • NAID: 130005131305
  • ISSN: 0446-6586, 1349-7693
  • Peer Reviewed
• [Journal Article] Inflammatory bowel disease and the intestinal microbiota (2015)
  • Author(s): 3.Nanki K, Mizuno S, Naganuma M, Kanai T
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 112 Issue: 11 Pages: 1947-1955
  • DOI: 10.11405/nisshoshi.112.1947
  • NAID: 130005107575
  • ISSN: 0446-6586, 1349-7693
  • Peer Reviewed
• [Journal Article] Inflammatory bowel disease and bone decreased bone mineral density (2015)
  • Author(s): Hisamatsu T, Wada Y, Kanai T
  • Journal Title: Clin Calcium Volume: 25(11) Pages: 1639-44
  • Peer Reviewed
• [Journal Article] Decreased Plasma Histidine Level Predicts Risk of Relapse in Patients with Ulcerative Colitis in Remission. (2015)
  • Author(s): Hisamatsu T, Ono N, Imaizumi A, Mori M, Suzuki H, Uo M, Hashimoto M, Naganuma M, Matsuoka K, Mizuno S, Kitazume MT, Yajima T, Ogata H, Iwao Y, Hibi T, Kanai T
  • Journal Title: PLoS One. Volume: 10 Issue: 10 Pages: 1-10
  • DOI: 10.1371/journal.pone.0140716
  • Peer Reviewed / Open Access
• [Journal Article] Crohn's Disease in which the Patient Developed Aortitis during Treatment with Adalimumab (2015)
  • Author(s): 6.Kiyohara H, Hisamatsu T, Matsuoka K, Naganuma M, Kameda H, Seta N, Takeuchi T, Kanai T
  • Journal Title: Internal Medicine Volume: 54 Issue: 14 Pages: 1725-1732
  • DOI: 10.2169/internalmedicine.54.3853
  • NAID: 130005088259
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Computer-Aided Prediction of Long-Term Prognosis of Patients with Ulcerative Colitis after Cytoapheresis Therapy (2015)
  • Author(s): 7.Takayama T, Okamoto S, Hisamatsu T, Naganuma M, Matsuoka K, Mizuno S, Bessho R, Hibi T, Kanai T
  • Journal Title: PLoS One Volume: 10(6) Issue: 6 Pages: e0131197-e0131197
  • DOI: 10.1371/journal.pone.0131197
  • Peer Reviewed
• [Journal Article] Recent trends in diagnostic techniques for inflammatory bowel disease (2015)
  • Author(s): Naganuma M, Hosoe N, Kanai T, Ogata H
  • Journal Title: Korean J Intern Med Volume: 30(3) Issue: 3 Pages: 271-8
  • DOI: 10.3904/kjim.2015.30.3.271
  • Peer Reviewed
• [Journal Article] A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease (2015)
  • Author(s): Kanai T, Mikami Y, Hayashi A
  • Journal Title: Journal of Gastroenterology Volume: 50(9) Issue: 9 Pages: 928-39
  • DOI: 10.1007/s00535-015-1084-x
  • Peer Reviewed
• [Presentation] 腸内細菌，腸管粘膜バリアの修飾を介した肝臓内免疫応答・免疫寛容誘導機序 (2017)
  • Author(s): 中本 伸宏，谷木 信仁，金井 隆典
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] 原発性硬化性胆管炎の病態における腸内細菌の関与 (2017)
  • Author(s): 中本伸宏，谷木信仁，金井隆典
  • Organizer: 第59回日本消化器病学会大会
• [Presentation] 腸疾患における糞便微生物移植法の現状と将来 (2016)
  • Author(s): 金井隆典
  • Organizer: 日本大腸肛門病学会
  • Place of Presentation: 三重県営サンアリーナ 三重県津市
  • Invited
• [Presentation] 治療抵抗性・難治性潰瘍性大腸炎に対する青黛の有用性 (2016)
  • Author(s): 福田知広，長沼 誠，金井隆典
  • Organizer: 第58回日本消化器病学会
  • Place of Presentation: 神戸コンベンションセンター 兵庫県神戸市
• [Presentation] 内視鏡的活動期の潰瘍性大腸炎に対する治療介入が臨床経過と粘膜治癒に与える影響 (2016)
  • Author(s): 大野恵子，長沼 誠，金井隆典
  • Organizer: 第58回日本消化器病学会
  • Place of Presentation: 神戸コンベンションセンター 兵庫県神戸市
• [Presentation] 腸管上皮オルガノイドを用いた幹細胞移植技術の確立 (2016)
  • Author(s): 杉本真也，金井隆典，佐藤俊朗
  • Organizer: 第58回日本消化器病学会
  • Place of Presentation: 神戸コンベンションセンター 兵庫県神戸市
• [Presentation] 腸内細菌を標的にした疾患治療 (2016)
  • Author(s): 金井 隆典
  • Organizer: 第44回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル 東京都新宿区
  • Invited
• [Presentation] gut-liver-brain axis によるマウス大腸炎抑制制御メカニズム (2016)
  • Author(s): 寺谷 俊昭, 中本 伸宏, 千葉 明子, 鈴木 貴博, 水野 慎大, 長沼 誠, 金井 隆典
  • Organizer: 第 53 回日本消化器免疫学会総会
  • Place of Presentation: ホテルニューオータニ大阪 大阪府大阪市
• [Presentation] 難治性消化管疾患に対する糞便微生物移植法の経過報告 (2016)
  • Author(s): 水野 慎大，正岡 建洋，金井 隆典
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル 東京都新宿区
• [Presentation] エンドサイトを用いた潰瘍性大腸炎内視鏡的寛解例における組織学的活動度評価の意義 (2016)
  • Author(s): 中里 圭宏，長沼 誠，金井 隆典
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル 東京都新宿区
• [Presentation] 炎症性腸疾患に対する外来ステロイド療法の有用性 (2016)
  • Author(s): 牟田口 真，長沼 誠，金井 隆
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル 東京都新宿区
• [Presentation] カプセル化した青黛の潰瘍性大腸炎の寛解導入における有用性 (2016)
  • Author(s): 杉本 真也，長沼 誠，金井 隆典
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル 東京都新宿区
• [Presentation] 炎症性腸疾患における腸内細菌の関与 (2015)
  • Author(s): 水野慎大、南木康作、長沼誠、金井隆典
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸国際会議場 兵庫県神戸市
  • Year and Date: 2015-10-23
• [Presentation] 非特異性多発性小腸潰瘍症の診断における内視鏡下生検の意味 (2015)
  • Author(s): 久松理一、細江直樹、金井隆典
  • Organizer: 第89回日本消化器内視鏡学会
  • Place of Presentation: 名古屋国際会議場 愛知県名古屋市
  • Year and Date: 2015-05-31
• [Presentation] New drug development for inflammatory bowel disease in Japan: an example of collaboration among academia, industry, and government. (2015)
  • Author(s): Katsuyoshi Matsuoka, Makoto Naganuma, Takanori Kanai
  • Organizer: 第101回日本消化器病学会
  • Place of Presentation: 仙台 国際センター 宮城県仙台市
  • Year and Date: 2015-04-25
• [Presentation] 潰瘍性大腸炎患者におけるサイトメガロウイルス活性化に対しての抗ウイルス療法の必要性の検討 (2015)
  • Author(s): 南木康作、武内悠里子、金井隆典
  • Organizer: 第101回日本消化器病学会
  • Place of Presentation: 仙台 国際センター 宮城県仙台市
  • Year and Date: 2015-04-25
• [Presentation] 潰瘍性大腸炎合併大腸癌・dysplasiaの内視鏡的危険因子の検討 (2015)
  • Author(s): 金井隆典、長沼誠、岩男泰
  • Organizer: 第101回日本消化器病学会
  • Place of Presentation: 仙台 国際センター 宮城県仙台市
  • Year and Date: 2015-04-25
• [Presentation] ワークショップ4「小腸疾患：病態解明への新たな知見」 (2015)
  • Author(s): 久松理一、細江直樹、金井隆典
  • Organizer: 第101回日本消化器病学会
  • Place of Presentation: 仙台 国際センター 宮城県仙台市
  • Year and Date: 2015-04-23
• [Presentation] クローン病生物学的製剤2次無効例に対する画像評価の有用性 (2015)
  • Author(s): 中里圭宏、長沼誠、金井隆典
  • Organizer: 第101回日本消化器病学会
  • Place of Presentation: 仙台 国際センター 宮城県仙台市
  • Year and Date: 2015-04-23