Elucidation of pathogenic mechanism of chronic inflammation

• Project/Area Number: 17KT0055
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Keio University
• Principal Investigator: Hase Koji 慶應義塾大学, 薬学部(芝共立), 教授 (20359714)
• Project Period (FY): 2017-07-18 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 炎症性腸疾患 / ディスバイオーシス / 酪酸 / リーキーガット / 自己抗体 / 腸内細菌 / 慢性炎症 / 微生物 / 病理学

Outline of Final Research Achievements

The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases; however, the underlying mechanisms have not yet been elucidated. Levels of n-butyrate were significantly lower in stools of both CD and UC patients than in stools of healthy subjects. The major n-butyrate producer was particularly underrepresented in CD patients, but not in UC patients. The decrease in butyrate production in UC patients was attributed to abnormal mucin utilisation that is one of the pathways for n-butyrate production.

Academic Significance and Societal Importance of the Research Achievements

腸内細菌のバランス失調はディバイオーシスと呼ばれる。近年確立された分子生物学的手法を用いた腸内細菌叢の解析によって、各種疾患におけるディスバーシスの特徴が報告している。興味深いことに、炎症性腸疾患、関節リウマチ、肝硬変、メタボリックシンドロームなど何らかの炎症反応を伴う疾患で共通して見られる異常の一つは、酪酸産生に関わる菌種の減少である。本研究において、潰瘍性大腸炎に特有な酪酸産生低下の原因が明らかとなったことから、今後は本疾患の病態メカニズムの理解が進むと期待される。

Research Products

• [Journal Article] Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice (2020)
  • Author(s): Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K.
  • Journal Title: Science Volume: 367 Issue: 6481 Pages: 8429-8429
  • DOI: 10.1126/science.aaw8429
  • Peer Reviewed / Open Access
• [Journal Article] Osteoprotegerin-dependent Mcell self-regulation balances gut infection and immunity. (2020)
  • Author(s): Kimura S, Nakamura Y, Kobayashi N, Shiroguchi K, KawakamiE, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, KaishoT, Iwanaga T, Hase K.
  • Journal Title: Nat Commun Volume: 11 Issue: 1 Pages: 234-234
  • DOI: 10.1038/s41467-019-13883-y
  • Peer Reviewed / Open Access
• [Journal Article] Microfold cell-dependent antigen transport alleviates infectious colitis by inducing antigen-specific cellular immunity (2020)
  • Author(s): Nakamura Yutaka、Mimuro Hitomi、Kunisawa Jun、Furusawa Yukihiro、Takahashi Daisuke、Fujimura Yumiko、Kaisho Tsuneyasu、Kiyono Hiroshi、Hase Koji
  • Journal Title: Mucosal Immunology Volume: in press Issue: 4 Pages: 679-690
  • DOI: 10.1038/s41385-020-0263-0
  • Peer Reviewed / Open Access
• [Journal Article] Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon. (2020)
  • Author(s): Junya Isobe, Shintarou Maeda, Yuuki Obata, Keito Iizuka, Yutaka Nakamura, Yumiko Fujimura, Tatsuki Kimizuka, Kouya Hattori, Yun-Gi Kim, Tatsuya Morita, Ikuo Kimura, Stefan Offermanns, Takahiro Adachi, Atsuhito Nakao, Hiroshi Kiyono, Daisuke Takahashi, Koji Hase
  • Journal Title: International Immunology Volume: 32 Issue: 4 Pages: 243-258
  • DOI: 10.1093/intimm/dxz078
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces (2019)
  • Author(s): Mabbott Neil A.、Hase Koji
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 2773-2773
  • DOI: 10.3389/fimmu.2019.02773
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases (2019)
  • Author(s): Kobayashi Nobuhide、Takahashi Daisuke、Takano Shunsuke、Kimura Shunsuke、Hase Koji
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 2345-2345
  • DOI: 10.3389/fimmu.2019.02345
  • Peer Reviewed / Open Access
• [Journal Article] Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses (2019)
  • Author(s): Nagai M、Noguchi R、Takahashi D、Morikawa T、Koshida K、Komiyama S、Ishihara N、Yamada T、Kawamura YI.、Muroi K、Hattori K、Kobayashi N、Fujimura Y、Hirota M、Matsumoto R、Aoki R、Tamura-Nakano M、Sugiyama M、Katakai T、Sato S、Takubo K、Dohi T、Hase K
  • Journal Title: Cell Volume: 178 Issue: 5 Pages: 1072-1087
  • DOI: 10.1016/j.cell.2019.07.047
  • Peer Reviewed
• [Journal Article] Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis (2019)
  • Author(s): Yamada Takahiro、Hino Shingo、Iijima Hideki、Genda Tomomi、Aoki Ryo、Nagata Ryuji、Han Kyu-Ho、Hirota Masato、Kinashi Yusuke、Oguchi Hiroyuki、Suda Wataru、Furusawa Yukihiro、Fujimura Yumiko、Kunisawa Jun、Hattori Masahira、Fukushima Michihiro、Morita Tatsuya、Hase Koji
  • Journal Title: EBioMedicine Volume: 48 Pages: 513-525
  • DOI: 10.1016/j.ebiom.2019.09.008
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of inflammatory response of macrophages and induction of regulatory T cells by using retinoic acid-loaded nanostructured lipid carrier (2019)
  • Author(s): Zai Khadijah、Ishihara Narumi、Oguchi Hiroyuki、Hirota Masato、Kishimura Akihiro、Mori Takeshi、Hase Koji、Katayama Yoshiki
  • Journal Title: Journal of Biomaterials Science, Polymer Edition Volume: 30 Issue: 1 Pages: 1-11
  • DOI: 10.1080/09205063.2018.1493671
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A partial agonist for retinoid X receptor mitigates experimental colitis (2018)
  • Author(s): Onuki Masayoshi、Watanabe Masaki、Ishihara Narumi、Suzuki Koichiro、Takizawa Kei、Hirota Masato、Yamada Takahiro、Egawa Aiko、Shibahara Osamu、Nishii Midori、Fujihara Michiko、Makishima Makoto、Takahashi Daisuke、Furusawa Yukihiro、Kakuta Hiroki、Hase Koji
  • Journal Title: International Immunology Volume: 31 Issue: 4 Pages: 251-262
  • DOI: 10.1093/intimm/dxy089
  • Peer Reviewed / Open Access
• [Journal Article] Oral Administration of Porphyromonas gingivalis Alters the Gut Microbiome and Serum Metabolome (2018)
  • Author(s): Kato Tamotsu、Yamazaki Kyoko、Nakajima Mayuka、Date Yasuhiro、Kikuchi Jun、Hase Koji、Ohno Hiroshi、Yamazaki Kazuhisa
  • Journal Title: mSphere Volume: 3 Issue: 5 Pages: 1-11
  • DOI: 10.1128/msphere.00460-18
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic effect of vitamin D3-containing nanostructured lipid carriers on inflammatory bowel disease (2018)
  • Author(s): Zai Khadijah、Hirota Masato、Yamada Takahiro、Ishihara Narumi、Mori Takeshi、Kishimura Akihiro、Suzuki Koichiro、Hase Koji、Katayama Yoshiki
  • Journal Title: Journal of Controlled Release Volume: 286 Pages: 94-102
  • DOI: 10.1016/j.jconrel.2018.07.019
  • Int'l Joint Research
• [Journal Article] Intestinal Epithelial Cell-specific Deletion of α-Mannosidase II Ameliorates Experimental Colitis (2018)
  • Author(s): Suzuki K., Yamada T, Yamazaki K, Hirota M, Ishihara N, Sakamoto M, Takahashi D, Iijima H, Hase K.
  • Journal Title: Cell Structure and Function Volume: 43 Issue: 1 Pages: 25-39
  • DOI: 10.1247/csf.17022
  • NAID: 130006513071
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] Macrophage extracellular chromatin release induced by Mac-1 mediated platelet-macrophage interactions triggers acute kidney injury in rhabdomyolysis. (2018)
  • Author(s): Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A, Yamamoto K, Hase K, Homma K, Sasaki J, Miyauchi H, Hoshino T, Hayashi M, Mayadas TN, Hirahashi J.
  • Journal Title: Nat. Med. Volume: 24 Issue: 2 Pages: 232-238
  • DOI: 10.1038/nm.4462
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NALT M cells are important for immune induction for the common mucosal immune system. (2017)
  • Author(s): Date Y, Ebisawa M, Fukuda S, Shima H, Obata Y, Takahashi D, Kato T, Hanazato M, Nakato G, Williams IR, Hase K, Ohno H.
  • Journal Title: Int. Immunol. Volume: 29 Issue: 10 Pages: 471-478
  • DOI: 10.1093/intimm/dxx064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Attenuation of CD4+CD25+regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug (2017)
  • Author(s): Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, Furusawa Y, Hase K, Sasaki A, Udono H.
  • Journal Title: EBioMedicine Volume: 25 Pages: 154-164
  • DOI: 10.1016/j.ebiom.2017.10.009
  • NAID: 120006767320
  • Peer Reviewed / Open Access
• [Journal Article] IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake. (2017)
  • Author(s): Jinnohara T, Kanaya T, Hase K, Sakakibara S, Kato T, Tachibana N, Sasaki T, Hashimoto Y, Sato T, Watarai H, Kunisawa J, Shibata N, Williams I, Kiyono H, and Ohno H.
  • Journal Title: J. Exp. Med. Volume: 214 Issue: 6 Pages: 1607-1618
  • DOI: 10.1084/jem.20160770
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 栄養シグナルによる免疫バリアの制御 (2020)
  • Author(s): 長谷耕二
  • Organizer: 東邦大学研究ブランディング事業最終シンポジウム
  • Invited
• [Presentation] Nutritional signals regulate lymphocyte homing to gut-associated lymphoid tissue (2019)
  • Author(s): Koji Hase
  • Organizer: The 7th International Conference on Food Factors (ICoFF2019)
  • Int'l Joint Research / Invited
• [Presentation] 栄養シグナルによるパイエル板リンパ球動態制御 (2019)
  • Author(s): 長谷耕二
  • Organizer: Science Pioneers Consortium (SPC) 2019
  • Invited
• [Presentation] 腸内細菌を標的とした創薬イノベーション (2019)
  • Author(s): 長谷耕二
  • Organizer: JASIS2019ライフサイエンスイノベーション
  • Invited
• [Presentation] Nutritional Signals regulate lymphocyte homing to gut-associated lymphoid tissue (2019)
  • Author(s): Koji Hase
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
  • Int'l Joint Research / Invited
• [Presentation] 食物アレルギーの発症に及ぼす腸内代謝物の影響 (2019)
  • Author(s): 長谷耕二
  • Organizer: 第68回日本アレルギー学会
  • Invited
• [Presentation] 栄養シグナルによるパイエル板リンパ球動態制御 (2019)
  • Author(s): 長谷耕二
  • Organizer: 日本食品免疫学会設立15周年記念学術集会
  • Invited
• [Presentation] 腸管における免疫監視機構 (2019)
  • Author(s): 長谷耕二
  • Organizer: 第22回 日本臨床腸内微生物学会総会・学術集会
  • Invited
• [Presentation] Microbiota-derived metabolites shape mucosal barrier and immunity (2017)
  • Author(s): Koji Hase
  • Organizer: 2017 International Congress on Obesity and Metabolic Syndromes (ICOMES)
  • Int'l Joint Research / Invited