Hase, Koji

写真a

Affiliation

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

Position

Professor

E-mail Address

E-mail address

Related Websites

External Links

 

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

  • Characterization of M Cells in Tear Duct-Associated Lymphoid Tissue of Mice: A Potential Role in Immunosurveillance on the Ocular Surface

    Oya Y., Kimura S., Nakamura Y., Ishihara N., Takano S., Morita R., Endo M., Hase K.

    Frontiers in Immunology (Frontiers in Immunology)  12   779709 2021.11

    Research paper (scientific journal), Accepted

     View Summary

    The ocular mucosal tissues are exposed to potentially harmful foreign antigens in the air and tear fluid. The tear duct-associated lymphoid tissue (TALT) may contribute to immune surveillance in the eye region. Follicle-associated epithelium (FAE) of TALTs is classified as stratified squamous epithelium and consists of squamous epithelial cells arranged in layers on the basement membrane. In contrast, most mucosa-associated lymphoid tissue is covered by a monolayer of epithelium containing microfold (M) cells. Therefore, antigen uptake and the presence of M cells in TALT are not fully understood. The present study found that a small population of FAE cells in the TALT expressed intestinal M-cell markers, namely Sox8, Tnfaip2, GP2, and OPG. This cell population was identified as functional M cells because of their uptake capacity of luminal nanoparticles. In addition, RANKL, which is essential for M-cell differentiation, was expressed by stroma-like cells at the subepithelial region and its receptor RANK by the FAE in the TALT. The administration of RANKL markedly increased the number of Sox8+ M cells. In contrast, deficiency in OPG, an endogenous inhibitor of RANKL, increased the number of M cells in the TALT. These data demonstrate that the RANKL-RANK axis is essential for M-cell differentiation in the TALT. Furthermore, immunization via eye drops elicited the production of antigen-specific antibodies in tears, which was enhanced by RANKL administration. Thus, TALT M cells play an important role in the immunosurveillance of the eye region.

  • Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group

    Kurohara T., Tanaka K., Takahashi D., Ueda S., Yamashita Y., Takada Y., Takeshima H., Yu S., Itoh Y., Hase K., Suzuki T.

    ChemBioChem (ChemBioChem)  22 ( 22 ) 3158 - 3163 2021.11

    ISSN  14394227

     View Summary

    Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

  • Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice

    Aoki R., Onuki M., Hattori K., Ito M., Yamada T., Kamikado K., Kim Y.G., Nakamoto N., Kimura I., Clarke J.M., Kanai T., Hase K.

    Microbiome (Microbiome)  9 ( 1 )  2021.09

    Research paper (scientific journal), Joint Work

     View Summary

    Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. Results: We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. Conclusion: These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. [MediaObject not available: see fulltext.]

  • A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice

    Matsumoto R., Takahashi D., Watanabe M., Nakatani S., Takamura Y., Kurosaki Y., Kakuta H., Hase K.

    Frontiers in Pharmacology (Frontiers in Pharmacology)  12 2021.08

     View Summary

    Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

  • Gut microbiota prevents sugar alcohol-induced diarrhea

    Hattori K., Akiyama M., Seki N., Yakabe K., Hase K., Kim Y.G.

    Nutrients (Nutrients)  13 ( 6 )  2021.06

     View Summary

    While poorly-absorbed sugar alcohols such as sorbitol are widely used as sweeteners, they may induce diarrhea in some individuals. However, the factors which determine an individual’s susceptibility to sugar alcohol-induced diarrhea remain unknown. Here, we show that specific gut bacteria are involved in the suppression of sorbitol-induced diarrhea. Based on 16S rDNA analysis, the abundance of Enterobacteriaceae bacteria increased in response to sorbitol consumption. We found that Escherichia coli of the family Enterobacteriaceae degraded sorbitol and suppressed sorbitol-induced diarrhea. Finally, we showed that the metabolism of sorbitol by the E. coli sugar phosphotransferase system helped suppress sorbitol-induced diarrhea. Therefore, gut microbiota prevented sugar alcohol-induced diarrhea by degrading sorbitol in the gut. The identification of the gut bacteria which respond to and degrade sugar alcohols in the intestine has implications for microbiome science, processed food science, and public health.

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

Reviews, Commentaries, etc. 【 Display / hide

  • 空気中の異物を体内に取り込む呼吸器M細胞の発見

    河合真悟, 木村俊介, 長谷耕二

    呼吸器内科 40 ( 6 ) 590 - 595 2021.12

    Introduction and explanation (commerce magazine), Joint Work

  • 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

  • Adverse effects of methylmercury on gut bacteria and accelerated accumulation of mercury in organs due to disruption of gut microbiota

    Seki N., Akiyama M., Yamakawa H., Hase K., Kumagai Y., Kim Y.G.

    Journal of Toxicological Sciences (Journal of Toxicological Sciences)  46 ( 2 ) 91 - 97 2021

    ISSN  18803989

     View Summary

    Methylmercury (MeHg), an environmental electrophile, binds covalently to the cysteine residues of proteins in organs, altering protein function and causing cytotoxicity. MeHg has also been shown to alter the composition of gut microbes. The gut microbiota is a complex community, the distur-bance of which has been linked to the development of certain diseases. However, the relationship between MeHg and gut bacteria remains poorly understood. In this study, we showed that MeHg binds covalently to gut bacterial proteins via cysteine residues. We examined the effects of MeHg on the growth of select-ed Lactobacillus species, namely, L. reuteri, L. gasseri, L. casei, and L. acidophilus, that are frequent-ly either positively or negatively correlated with human diseases. The results revealed that MeHg inhibits the growth of Lactobacillus to varying degrees depending on the species. Furthermore, the growth of L. reuteri, which was inhibited by MeHg exposure, was restored by Na2 S2 treatment. By comparing mice with and without gut microbiota colonization, we found that gut bacteria contribute to the production of reactive sulfur species such as hydrogen sulfide and hydrogen persulfide in the gut. We also discovered that the removal of gut bacteria accelerated accumulation of mercury in the cerebellum, liver, and lungs of mice subsequent to MeHg exposure. These results accordingly indicate that MeHg is captured and inacti-vated by the hydrogen sulfide and hydrogen persulfide produced by intestinal microbes, thereby providing evidence for the role played by gut microbiota in reducing MeHg toxicity.

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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

    2020.04
    -
    2023.03

    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

    2017.07
    -
    2020.03

    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

    2017.04
    -
    2020.03

    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

    2016.04
    -
    2018.03

    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

    2016.04
    -
    2018.03

    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

    2020.12

    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

  • STUDY OF MAJOR FIELD: (BIOCHEMISTRY)

    2021

  • SEMINAR: (BIOCHEMISTRY)

    2021

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2021

  • RESEARCH FOR BACHELOR'S THESIS 1

    2021

  • PHARMACEUTICAL-ENGLISH SEMINAR

    2021

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