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

  • Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity

    Kinashi Y., Hase K.

    Frontiers in Immunology (Frontiers in Immunology)  12 2021.04

     View Summary

    The intestinal surface is constitutively exposed to diverse antigens, such as food antigens, food-borne pathogens, and commensal microbes. Intestinal epithelial cells have developed unique barrier functions that prevent the translocation of potentially hostile antigens into the body. Disruption of the epithelial barrier increases intestinal permeability, resulting in leaky gut syndrome (LGS). Clinical reports have suggested that LGS contributes to autoimmune diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and celiac disease. Furthermore, the gut commensal microbiota plays a critical role in regulating host immunity; abnormalities of the microbial community, known as dysbiosis, are observed in patients with autoimmune diseases. However, the pathological links among intestinal dysbiosis, LGS, and autoimmune diseases have not been fully elucidated. This review discusses the current understanding of how commensal microbiota contributes to the pathogenesis of autoimmune diseases by modifying the epithelial barrier.

  • Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon

    Nakamura A., Kurihara S., Takahashi D., Ohashi W., Nakamura Y., Kimura S., Onuki M., Kume A., Sasazawa Y., Furusawa Y., Obata Y., Fukuda S., Saiki S., Matsumoto M., Hase K.

    Nature Communications (Nature Communications)  12   2105 2021.04

    Research paper (scientific journal), Joint Work, Accepted

     View Summary

    Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.

  • Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation

    Kurashima Y., Kigoshi T., Murasaki S., Arai F., Shimada K., Seki N., Kim Y.G., Hase K., Ohno H., Kawano K., Ashida H., Suzuki T., Morimoto M., Saito Y., Sasou A., Goda Y., Yuki Y., Inagaki Y., Iijima H., Suda W., Hattori M., Kiyono H.

    Nature Communications (Nature Communications)  12 ( 1 )  2021.02

    Research paper (scientific journal), Accepted

     View Summary

    Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF–dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn’s diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas–intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

  • Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

    Okawa T., Nagai M., Hase K.

    Frontiers in Immunology (Frontiers in Immunology)  11 2021.02

     View Summary

    Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.

  • Polyvinyl Butyrate Nanoparticles as Butyrate Donors for Colitis Treatment

    Mu Y., Kinashi Y., Li J., Yoshikawa T., Kishimura A., Tanaka M., Matsui T., Mori T., Hase K., Katayama Y.

    ACS Applied Bio Materials (ACS Applied Bio Materials)   2021

     View Summary

    © 2021 American Chemical Society. Butyrate has been attracting attention for the suppression of inflammatory bowel disease (IBD). However, clinical trials of butyrate for IBD treatment have resulted in controversial outcomes, likely owing to the adverse effect of butyrate on the intestinal epithelium that was observed at high butyrate concentrations. Herein, we propose polyvinyl butyrate (PVBu) nanoparticles (NPs) as butyrate donors for delivery to the lower part of the intestine for the treatment of colitis. The PVBu NPs suppressed the inflammatory activation of macrophages in vitro, although sodium butyrate inversely further activated macrophages. Oral administration of NPs did not change the luminal concentration of free butyrate; however, NPs showed a therapeutic effect on a colitis mouse model. In addition, incorporation of vitamin D3 into the NPs enhanced the therapeutic effect on colitis. Hence, PVBu NPs are a promising therapeutic for IBD treatment, not only as a butyrate donor but also as a carrier for hydrophobic drugs like vitamin D3.

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

Reviews, Commentaries, etc. 【 Display / hide

  • Psychiatric disorder and intestinal microibota

    長谷 耕二

    実験医学 39 ( 9 ) 1349 - 1355 2021.06

    Introduction and explanation (commerce magazine), Single Work

  • OsteoprotegrinによるM細胞の自己調節は粘膜免疫応答と上皮バリア機構のバランスを制御する

    木村俊介, 長谷耕二.

    臨床免疫・アレルギー科 75 ( 2 ) 194 - 200 2021.02

    Introduction and explanation (commerce magazine), Joint Work

  • 自己免疫疾患における粘膜免疫系の関与:M細胞の潜在的役割

    大谷佑貴, 木村俊介, 長谷耕二

    臨床免疫・アレルギー科 75 ( 1 ) 1 - 8 2021.01

    Introduction and explanation (commerce magazine), Joint Work

  • 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

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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

  • Starvation response of the immune system along the gut-bone marrow axis


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

  • 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

  • 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

  • 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

Awards 【 Display / hide

  • 第23回日本免疫学会賞


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

  • 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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