Hase, Koji



Faculty of Pharmacy, Department of Pharmaceutical Sciences 生化学講座 (Shiba-Kyoritsu)



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Research Areas 【 Display / hide

  • Immunology

  • Gastroenterology

Research Keywords 【 Display / hide

  • Mucosal Immunology

  • Intestinal Micorobiology

  • Microfold cells

  • Inflammatory bowel disease


Books 【 Display / hide

  • 腸内細菌−宿主のクロストークと食事因子(日本栄養・食糧学会監修)

    山田恭央, 長谷耕二., 建帛社, 2019.05

    Scope: 炎症性腸疾患における腸内代謝物の異常とそのメカニズム. 腸内細菌−宿主のクロストークとこれを修飾する食事要因,  Contact page: 120-144

  • 腸内細菌−宿主のクロストークと食事因子(日本栄養・食糧学会監修)

    長谷耕二, 高橋大輔, 建帛社, 2019.05

    Scope: 自己免疫疾患の発症を制御する短鎖脂肪酸,  Contact page: 191-201

  • The Frontier in Life Science: 免疫・炎症病態×治療 Update

    松本龍太郎, 高橋大輔, 長谷耕二, 2019.04

    Scope: 腸管免疫学研究のフロントライン

  • ヒトマイクロバイオーム研究最前線

    長谷 耕二, (株)エヌ・ティー・エス , 2016.03

    Scope: 腸内細菌定着と宿主エピゲノム変化

  • エピジェネティクスキーワード事典

    長谷 耕二, 古澤之裕, 尾畑佑樹, 羊土社, 2013.12

    Scope: 自己免疫・アレルギー疾患とエピジェネティクス

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Papers 【 Display / hide

  • Maternal gut microbiota in pregnancy influences offspring metabolic phenotype

    *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, and *Hase K

    Science (Science)  367 ( 6481 ) eaaw8429 2020.02

    Research paper (scientific journal), Accepted,  ISSN  00368075

     View Summary

    Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.

  • Osteoprotegerin-dependent M-cell self-regulation balances gut infection and immunity.

    1 Kimura S*, Nakamura Y, Kobayashi N, Shiroguchi N, Kawakami E, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, Kaisho T, Iwanaga T, and Hase K

    Nature Commun. (Nature Communications)  in press ( 1 )  2020.01

    Research paper (scientific journal), Joint Work, Accepted

     View Summary

    © 2020, The Author(s). Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.

  • Microfold cell-dependent antigen transport alleviates infectious colitis by inducing antigen-specific cellular immunity

    Nakamura Y., Mimuro H., Kunisawa J., Furusawa Y., Takahashi D., Fujimura Y., Kaisho T., Kiyono H., Hase K.

    Mucosal Immunology (Mucosal Immunology)  13 ( 4 ) 679 - 690 2020.01

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  19330219

     View Summary

    Infectious colitis is one of the most common health issues worldwide. Microfold (M) cells actively transport luminal antigens to gut-associated lymphoid tissue to induce IgA responses; however, it remains unknown whether M cells contribute to the induction of cellular immune responses. Here we report that M cell-dependent antigen transport plays a critical role in the induction of Th1, Th17, and Th22 responses against gut commensals in the steady state. The establishment of commensal-specific cellular immunity was a prerequisite for preventing bacterial dissemination during enteropathogenic Citrobacter rodentium infection. Therefore, M cell-null mice developed severe colitis with increased bacterial dissemination. This abnormality was associated with mucosal barrier dysfunction. These observations suggest that antigen transport by M cells may help maintain gut immune homeostasis by eliciting antigen-specific cellular immune responses.

  • Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

    Takahashi D, Hoshina N, Kabumoto Y, Maeda Y, Suzuki A, Tanabe H, Isobe J, Yamada T, Muroi K, Yanagisawa Y, Nakamura A, Fujimura Y, Saeki A, Ueda M, Matsumoto R, Asaoka H, Clarke JM, Harada Y, Umemoto E, Komatsu N, Okada T, Takayanagi H, Takeda K, Tomura M, Hase K.

    EBioMedicine in press 2020

    Research paper (scientific journal), Joint Work, Accepted

  • Commensal-bacteria-derived butyrate promotes the T cell-independent IgA response in the colon.

    4 Isobe J, Maeda S, Obata Y, Iizuka K, Nakamura Y, Fujimura Y, Kimizuka T, Hattori K, Kim YG, Morita T, Kimura I, Offermanns S, Adachi T, Nakao A, Kiyono H, *Takahashi D, *Hase K.

    Int. Immunol (International Immunology)  32 ( 4 ) 243 - 258 2019.12

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  09538178

     View Summary

    © 2020 Oxford University Press. All rights reserved. Secretory immunoglobulin A (SIgA), the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensalbacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon. Notably, the butyrate concentration in human stools correlated positively with the amount of IgA. Butyrate up-regulated the production of transforming growth factor β1 and all-trans retinoic acid by CD103+CD11b+ dendritic cells, both of which are critical for T-cell-independent IgA CSR. This effect was mediated by G-protein-coupled receptor 41 (GPR41/FFA3) and GPR109a/HCA2, and the inhibition of histone deacetylase. The butyrate-induced IgA response reinforced the colonic barrier function, preventing systemic bacterial dissemination under inflammatory conditions. These observations demonstrate that commensal-bacteria-derived butyrate contributes to the maintenance of the gut immune homeostasis by facilitating the T-cell-independent IgA response in the colon.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • 絶食―再摂食は免疫系細胞の動態と粘膜免疫応答に影響を及ぼす.

    永井基慈, 土肥多惠子, 長谷耕二.

    消化器病サイエンス 4 ( 1 ) 50 - 54 2020.03

    Introduction and explanation (commerce magazine), Joint Work

  • 絶食-再摂食によるパイエル板リンパ球動態と粘膜免疫応答の制御.

    永井基慈, 長谷耕二.

    実験医学 38   457 - 460 2020.01

    Introduction and explanation (commerce magazine), Joint Work

  • Sox8はM細胞取り込み能獲得を促進し,離乳期の抗原特異的IgA産生に必須である.

    木村俊介, 長谷耕二.

    臨床免疫・アレルギー科  73 ( 1 ) 89 - 95 2020.01

    Introduction and explanation (commerce magazine), Joint Work

  • 炎症性腸疾患とエピゲノム


    遺伝子医学 10 ( 1 ) 37 - 41 2020.01

    Introduction and explanation (commerce magazine), Joint Work

  • Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces

    Mabbott N., Hase K.

    Frontiers in Immunology (Frontiers in Immunology)  10 2019.11

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Presentations 【 Display / hide

  • 飢餓ストレスによるリンパ球の動態制御

    HASE Koji

    2017年度生命科学系学会合同年次大会 (ConBio2017), 2017.12, Oral Presentation(guest/special)

  • 腸内細菌由来の酪酸による全身性自己免応答の制御

    HASE Koji

    第22回日本食物繊維学会, 2017.11, Oral Presentation(guest/special)

  • マイクロバイオータとアレルギー

    HASE Koji

    第54回小児アレルギー学会, 2017.11, Oral Presentation(guest/special)

  • Intestinal microbiota-derived metabolites regulate autoimmunity through epigenetic modifications

    HASE Koji

    Fujihara Seminar (Tomakomai, Japan) , 2017.09, Oral Presentation(guest/special)

  • Microbiota-derived metabolites shape host immunity

    HASE Koji

    第59回歯科基礎医学会学術大会, 2017.09, Oral Presentation(guest/special)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 多変量解析による慢性炎症スパイラル形成機構の解明


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 長谷 耕二, Grant-in-Aid for Scientific Research (B), Principal Investigator

  • Elucidation of T-independent IgA class switch machinery


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 長谷 耕二, Grant-in-Aid for Scientific Research (B), Principal Investigator

  • 生物間代謝経路によって制御される脂質クオリティの解析


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 長谷 耕二, Grant-in-Aid for Scientific Research on Innovative Areas, Principal Investigator

  • Single cell analysis of T lymphocytes in the intestinal immune system


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 長谷 耕二, Grant-in-Aid for Challenging Exploratory Research, Principal Investigator

Awards 【 Display / hide

  • 第36回 井上学術賞

    2020.02, 公益財団法人井上科学振興財団, 腸管免疫系の制御機構の解明

    Type of Award: Other Awards

  • 2019年度日本食品免疫学会賞

    2019.10, 日本食品免疫学会, 食品が最初に接する上皮バリアと粘膜免疫系の連携に着目した粘膜バリアシステムの研究

    Type of Award: Awards of National Conference, Council and Symposium

  • 第53回ベルツ賞(2等賞)

    2016.11, べーリンガーインゲルハイム, 宿主-腸内細菌叢相互作用

    Type of Award: Other Awards

  • 第12回日本学術振興会賞

    2016.02, 粘膜面における免疫制御機構の解明

    Type of Award: Other Awards


Courses Taught 【 Display / hide











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