KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2008.04

  -

  2012.03

  RIKEN RCAI

• 2012.04

  -

  2015.03

  La Jolla Institute for Allergy & Immunology

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• Ph.D., Yokohama City University, Coursework, 2011.11

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

• Life Science / Cell biology (Intestinal epithelial cell)

• Life Science / Immunology (T lymphocyte)

Research Keywords 【 Display / hide 】

Research Keywords 【 Display / hide 】

• Treg

• Mucosal Immunology

• IEC

• IEL

• Butyric acid

Research Themes 【 Display / hide 】

Research Themes 【 Display / hide 】

• Analysis of the Interaction between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs), 

  2015.04

  -

  Present

• Examination of the mechanism that communal bacteria derived SCFAs ameliorate rheumatoid arthritis., 

  2015.04

  -

  Present

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• AP-1B regulates interactions of epithelial cells and intraepithelial lymphocytes in the intestine

  Ryohtaroh Matsumoto, Kosuke Ogata, Daisuke Takahashi, Yusuke Kinashi, Takahiro Yamada, Ryo Morita, Keisuke Tanaka, Kouya Hattori, Mayumi Endo, Yumiko Fujimura, Nobuo Sasaki, Hiroshi Ohno, Yasushi Ishihama, Shunsuke Kimura, Koji Hase

  Cellular and Molecular Life Sciences (Springer Science and Business Media LLC)  81 ( 1 ) 425 2024.10

  Accepted,  ISSN  1420-682X

  • Access to Document (DOI)

• Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice.

  Yusuke Kinashi, Keisuke Tanaka, Shunsuke Kimura, Masato Hirota, Seiga Komiyama, Tomoko Shindo, Akinori Hashiguchi, Daisuke Takahashi, Shinsuke Shibata, Shin-Ichiro Karaki, Hiroshi Ohno, Koji Hase

  EBioMedicine 106   105256 - 105256 2024.07

  Accepted,  ISSN  2352-3964

  　View Summary

  BACKGROUND: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. METHODS: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. FINDINGS: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. INTERPRETATION: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. FUNDING: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

  • Access to Document (DOI)

• Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine.

  Motoyoshi Nagai, Takuma Okawa, Kazuaki Nakata, Daisuke Takahashi, Reina Miyajima, Hiroaki Shiratori, Daisuke Yamanaka, Atsuo Nakamura, Chinatsu Oyama, Shin-Ichiro Takahashi, Noriko Toyama-Sorimachi, Koichiro Suzuki, Wakana Ohashi, Taeko Dohi, Yuki I Kawamura, Koji Hase

  Cell reports (Elsevier BV)  43 ( 7 ) 114490 - 114490 2024.07

  Accepted,  ISSN  2211-1247

  　View Summary

  Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

  • Access to Document (DOI)

• Purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations.

  Hiroaki Shiratori, Kisara M Hattori, Kazuaki Nakata, Takuma Okawa, Seiga Komiyama, Yusuke Kinashi, Yuma Kabumoto, Yuria Kaneko, Motoyoshi Nagai, Tomoko Shindo, Nobuko Moritoki, Yuki I Kawamura, Taeko Dohi, Daisuke Takahashi, Shunsuke Kimura, Koji Hase

  International immunology (Oxford University Press (OUP))  36 ( 5 ) 223 - 240 2024.01

  Accepted,  ISSN  0953-8178

  　View Summary

  The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including islet-derived protein 3γ (REG3γ), were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

  • Access to Document (DOI)

• Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles

  Shunyi Li, Hiroki Toriumi, Daisuke Takahashi, Tomoko Kamasaki, Yoichiro Fujioka, Satoru Nagatoishi, Jinting Li, Yiwei Liu, Takanatsu Hosokawa, Kouhei Tsumoto, Yusuke Ohba, Yoshiki Katayama, Daisuke Murakami, Koji Hase, Takeshi Mori

  Biomaterials (Elsevier BV)  303   122381 - 122381 2023.12

  Research paper (scientific journal), Joint Work, Accepted,  ISSN  0142-9612

  　View Summary

  Allergen immunotherapy (AIT) is the only curative treatment for allergic diseases. However, AIT has many disadvantages related to efficiency, safety, long-term duration, and patient compliance. Dendritic cells (DCs) have an important role in antigen-specific tolerance induction; thus, DC-targeting strategies to treat allergies such as glutaraldehyde crosslinked antigen to mannoprotein (MAN) have been established. However, glutaraldehyde crosslinking may reduce the antigen presentation efficiency of DCs. To overcome this, we developed a MAN-coated ovalbumin (OVA) nanoparticle (MDO), which uses intermolecular disulfide bond to crosslink OVA and MAN. MDO effectively targeted DCs resulting in tolerogenic DCs, and promoted higher antigen presentation efficiency by DCs compared with OVA or glutaraldehyde crosslinked nanoparticles. In vitro and in vivo experiments showed that DCs exposed to MDO induced Treg cells. Moreover, MDO had low reactivity with anti-OVA antibodies and did not induce anaphylaxis in allergic mice, demonstrating its high safety profile. In a mouse model of allergic asthma, MDO had significant preventative and therapeutic effects when administered orally or subcutaneously. Therefore, MDO represents a promising new approach for the efficient and safe treatment of allergies.

  • Access to Document (DOI)

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

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

• Dietary factor-mediated enhancement of neutralizing antibody production against enterovirus in the intestinal tract

  Takahashi, Daisuke

  学事振興資金研究成果実績報告書 (慶應義塾大学)  2021

• Elucidation of follicular regulatory T cell differentiation mechanism using chemical biology

  Takahashi, Daisuke

  福澤諭吉記念慶應義塾学事振興基金事業報告集 (福澤基金運営委員会)  2021

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

  Takahashi, Daisuke

  科学研究費補助金研究成果報告書 2020

• Study of IEC-IEL interaction in the development of gut epithelial immune system.

  Takahashi, Daisuke

  科学研究費補助金研究成果報告書 2016

Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases

  Nobuhide Kobayashi*, Daisuke Takahashi* (*equal contribution), Shunsuke Takano, Shunsuke Kimura and Koji Hase

  frontiers in Immunology (Frontiers Media S.A.)   2019.12

  Article, review, commentary, editorial, etc. (scientific journal)

  • Access to Document (DOI)

• 自己免疫疾患の発症を制御する短鎖脂肪酸

  長谷 耕二、髙橋 大輔

  腸内細菌-宿主のクロストークと食事要因 (建帛社)     191 - 200 2019.05

  Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work

• 腸管免疫学研究のフロントライン

  松本 龍太郎, 髙橋 大輔, 長谷 耕二

  免疫・炎症病態×治療 Update (南山堂)     192 - 199 2019.05

  Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)

• 腸内細菌と自己免疫疾患

  髙橋 大輔、長谷 耕二

  実験医学増刊 腸内細菌叢 健康と疾患を制御するエコシステム 137   91 - 96 2019.02

  Joint Work

• 短鎖脂肪酸による免疫・代謝制御

  髙橋 大輔長谷 耕二

  血管医学 17 2016.10

  Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work

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Presentations 【 Display / hide 】

Presentations 【 Display / hide 】

• Microbial fermentation product butyrate Ameliorates Autoimmune Arthritis.

  Daisuke Takahashi, Trevor Lockett, Julie M Clarke, David L Topping, Koji Hase

  The 46th Annual Meeting of The Japanese Society for Immunology, 

  2017.12

  , 

  Oral presentation (general)

• 腸内細菌代謝物の酪酸によるIgA産生細胞誘導機構の解明

  髙橋 大輔長谷 耕二

  第46回日本腎臓学会西部学術大会, 

  2016.10

  , 

  Oral presentation (invited, special)

• The microbial metabolite butyrate attenuates autoimmune arthritis in mice.

  Takahashi DaisukeHase Koji

  フォーラム2016 衛生薬学・環境トキシコロジー, 

  2016.09

  , 

  Oral presentation (invited, special)

• Microbial fermentation product butyrate Ameliorates Autoimmune Arthritis.

  Takahashi Daisuke

  International Congress of Immunology 2016 (ICI2016) (Australia Melbourne) , 

  2016.08

  , 

  Poster presentation

• 「腸内細菌由来の酪酸を介した免疫システムの制御」 第89回 日本細菌学会総会 2016.3.23

  Takahashi Daisuke

  第89回 日本細菌学会総会, 

  2016.03

  , 

  Oral presentation (invited, special)

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

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

• 腸内細菌を自己として認識するγδT17細胞による宿主-腸内細菌共生関係構築

  2023.04

  -

  2025.03

  2023年度 学術変革領域研究(A) (公募研究), Research grant, Principal investigator

• ケミカルバイオロジーを利用した濾胞制御性T細胞分化機序の解明

  2020.04

  -

  2025.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

• 腸内細菌が産生する酪酸による関節リウマチ抑制メカニズムの解明

  2017.04

  -

  2020.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Young Scientists (B), Principal investigator

• 腸上皮と上皮間リンパ球の相互作用に基づく粘膜上皮層免疫システムの成立機構の解析

  2015.11

  -

  2017.03

  Grant-in-Aid for Scientific Research, Principal investigator

Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• STUDY OF MAJOR FIELD: (BIOCHEMISTRY)

  2024

• SPECIAL PRACTICE IN TISSUE CULTURE AND GENE TECHNOLOGY

  2024

• SEMINAR: (BIOCHEMISTRY)

  2024

• RESEARCH FOR BACHELOR'S THESIS 1

  2024

• RESEARCH APPARATUS LABORATORY COURSE

  2024

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