NKT cells control obesity by regulating the microbiota

• Project/Area Number: 19K09011
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kitasato University
• Principal Investigator: Satoh Masashi 北里大学, 医学部, 講師 (40611843)
• Co-Investigator(Kenkyū-buntansha): 岩渕 和也 北里大学, 医学部, 名誉教授 (20184898)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: NKT細胞 / 腸内細菌叢 / 脂肪組織 / マクロファージ / 肥満 / 組織炎症 / 脂肪細胞 / 脂肪組織炎症 / インスリン抵抗性 / NKT cell / microbiota / obesity / inflammation / intestine

Outline of Research at the Start

本研究は、NKT細胞・肥満・腸内細菌叢の関係性を肥満マウスモデルを用いて明らかにすることを目的とする。高脂肪食を給餌した野生型マウスまたはNKT細胞欠損マウスにおけるメタゲノム解析により、腸内細菌叢の変化を比較する。さらに、腸管や肝臓NKT細胞の活性化を測定し、抗生物質の投与実験からその活性化が腸内細菌叢依存的かを検討する。NKT細胞が高脂肪食によって機能修飾を受けるのか、またその影響が腸内細菌叢のバランスを変化させ、肥満にどのように作用するのかについて、腸内細菌叢の組成バランスの解析やメタボローム解析、腸管における遺伝子発現変化などを調べ、肥満メカニズムの解明に貢献する。

Outline of Final Research Achievements

We examined the relationship among NKT cell, microbiota and obesity using diet-induced obesity model. As a results, Allobaculum that related to body fat was more observed in WT mice than CD1d-/- mice. In contrast, Bacteroides that improve diet-induced obesity was decreased in WT mice compared with CD1d-/- mice. These data suggested that NKT cells control microbiota composituion and development of obesity.

Academic Significance and Societal Importance of the Research Achievements

腸内細菌叢は肥満をはじめ、さまざまな疾患と関連があることが最近の研究で明らかとなっている。本研究から、NKT細胞が腸内細菌叢の形成に関与していることが示唆され、NKT細胞を介して腸内細菌叢をコントロールできる可能性が見出された。NKT細胞による腸内細菌叢の制御メカニズムが明らかとなれば、NKT細胞を介した新たな肥満等に対する治療アプローチの確立が期待できる。今後は、腸管NKT細胞がどのように活性化されるのか、どのような機能を有するのかなど詳細な解析が必要である。

Research Products

• [Int'l Joint Research] Vanderbilt University(米国)
• [Journal Article] Deletion of miR-150 Prevents Spontaneous T Cell Proliferation and the Development of Colitis (2023)
  • Author(s): Ishihara S*, Sato M*, Miyazaki H, Saito H, Sato T, Fujikado N, Sawai S, Kotani A, Katagiri K.
  • Journal Title: Gastro Hep Advances Volume: 2 Issue: 4 Pages: 487-496
  • DOI: 10.1016/j.gastha.2023.01.021
  • Peer Reviewed / Open Access
• [Journal Article] Immunomodulatory Functions of α-GalCer and a Derivative, α-Carba-GalCer (2023)
  • Author(s): Satoh M., Iwabuchi K
  • Journal Title: Methods in Molecular Biology Volume: 2613 Pages: 1-12
  • DOI: 10.1007/978-1-0716-2910-9_1
  • ISBN: 9781071629093, 9781071629109
  • Peer Reviewed
• [Journal Article] Strongyloides venezuelensis-derived venestatin ameliorates asthma pathogenesis by suppressing receptor for advanced glycation end-products-mediated signaling (2022)
  • Author(s): Tsubokawa Daigo、Satoh Masashi
  • Journal Title: Pulmonary Pharmacology & Therapeutics Volume: 75 Pages: 102148-102148
  • DOI: 10.1016/j.pupt.2022.102148
  • Peer Reviewed
• [Journal Article] Origin of M2 Mf and its macrophage polarization by TGF-β in a mice intervertebral injury model. (2022)
  • Author(s): Kawakubo A, Miyagi M, Yokozeki Y, Nakawaki M, Takano S, Satoh M, Itakura M, Inoue G, Takaso M, Uchida K
  • Journal Title: Int J Immunopathol Pharmacol Volume: - Pages: 1-11
  • DOI: 10.1177/03946320221103792
  • Peer Reviewed / Open Access
• [Journal Article] Mild inflammation persists in the glenohumeral joint of patients with shoulder instability: Cross-sectional study (2022)
  • Author(s): Muneshige K, Kenmoku T, Uchida K, Aredt-Nielsen L, Tazawa R, Nakawaki M, Satoh M, Inoue G, Takaso M.
  • Journal Title: Osteoarthr Cartil Open Volume: 4 Issue: 2 Pages: 100241-100241
  • DOI: 10.1016/j.ocarto.2022.100241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nerve decompression surgery suppresses TNF-a; expression and T cell infiltration in a rat sciatic nerve chronic constriction injury model (2022)
  • Author(s): Mukai M, Uchida K, Inoue G, Satoh M, Miyagi M, Yokozeki Y, Hirosawa N, Matsuura Y, Ohtori S, Takaso M
  • Journal Title: J Orthop Res Volume: in press Issue: 11 Pages: 0-0
  • DOI: 10.1002/jor.25280
  • Peer Reviewed / Open Access
• [Journal Article] Adipose invariant NKT cells interact with CD1d‐expressing macrophages to regulate obesity‐related inflammation (2022)
  • Author(s): Satoh Masashi、Iizuka Misao、Majima Masataka、Ohwa Chizuru、Hattori Akito、Van Kaer Luc、Iwabuchi Kazuya
  • Journal Title: Immunology Volume: 165 Issue: 4 Pages: 414-427
  • DOI: 10.1111/imm.13447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlation between CD163 expression and resting pain in patients with hip osteoarthritis: Possible contribution of CD163+ monocytes/macrophages to pain pathogenesis (2022)
  • Author(s): Ohashi Yoshihisa、Uchida Kentaro、Fukushima Kensuke、Satoh Masashi、Koyama Tomohisa、Tsuchiya Maho、Saito Hiroki、Uchiyama Katsufumi、Takahira Naonobu、Inoue Gen、Takaso Masashi
  • Journal Title: Journal of Orthopaedic Research Volume: ー Issue: 6 Pages: 1365-1374
  • DOI: 10.1002/jor.25157
  • Peer Reviewed
• [Journal Article] NGF expression and elevation in hip osteoarthritis patients with pain and central sensitization. (2021)
  • Author(s): Ohashi Y, Uchida K, Fukushima K, Satoh M, Koyama T, Tsuchiya M, Saito H, Takahira N, Inoue G, Takaso M
  • Journal Title: BioMed Research International Volume: - Pages: 9212585-9212585
  • DOI: 10.1155/2021/9212585
  • Peer Reviewed / Open Access
• [Journal Article] Activation of iNKT Cells Facilitates Liver Repair After Hepatic Ischemia Reperfusion Injury Through Acceleration of Macrophage Polarization. (2021)
  • Author(s): Goto T, Ito Y, Satoh M, Nakamoto S, Nishizawa N, Hosono K, Naitoh T, Eshima K, Iwabuchi K, Hiki N, Amano H.
  • Journal Title: Front Immunol. Volume: 12 Pages: 754106-754106
  • DOI: 10.3389/fimmu.2021.754106
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of tumor necrosis factor-alpha by peptide Lv in bone marrow macrophage and synovium (2021)
  • Author(s): 3.Mukai M, Uchida K. Okubo T, Takano S, Matsumoto T, Satoh M, Inoue G, Takaso M
  • Journal Title: Frontiers in Medicine Rheumatology Volume: 8 Pages: 701216-701216
  • DOI: 10.3389/fmed.2021.702126
  • Peer Reviewed / Open Access
• [Journal Article] 実験的自己免疫性ぶどう膜炎モデルの炎症制御 (2021)
  • Author(s): 岩渕 和也, 田尻 夏海, 加藤 太喜, 佐藤 雅
  • Journal Title: 日本臨牀 Volume: 79
• [Journal Article] The protective function of invariant natural killer T cells in the relapse of experimental autoimmune uveoretinitis. (2021)
  • Author(s): Tajiri N, Kato T, Satoh M, Iizuka M, Taniguchi M, Kitaichi N, Iwabuchi K.
  • Journal Title: Exp Eye Res Volume: 203 Pages: 108406-108406
  • DOI: 10.1016/j.exer.2020.108406
  • Peer Reviewed
• [Journal Article] Investigation of resident and recruited macrophages following disc injury in mice. (2020)
  • Author(s): Kawakubo A, Uchida K, Miyagi M, Nakawaki M, Satoh M, Sekiguchi H, Yokozeki Y, Inoue G, Takaso M.
  • Journal Title: J Orthop Res Volume: - Issue: 8 Pages: 1703-1709
  • DOI: 10.1002/jor.24590
  • Peer Reviewed
• [Journal Article] Inactivation of REV7 enhances chemosensitivity and overcomes acquired chemoresistance in testicular germ cell tumors. (2020)
  • Author(s): Sakurai Y, Ichinoe M, Yoshida K, Nakazato Y, Saito S, Satoh M, Nakada N, Sanoyama I, Umezawa A, Numata Y, Shi-Xu J, Ichihara M, Takahashi M, Murakumo Y
  • Journal Title: Cancer Lett. Volume: 489 Pages: 100-110
  • DOI: 10.1016/j.canlet.2020.06.001
  • Peer Reviewed
• [Journal Article] Sequential CCL2 Expression Profile After Disc Injury in Mice. (2020)
  • Author(s): Nakawaki M, Uchida K, Miyagi M, Inoue G, Kawakubo A, Kuroda A, Satoh M, Takaso M
  • Journal Title: J Orthop Res Volume: 38 Issue: 4 Pages: 895-901
  • DOI: 10.1002/jor.24522
  • Peer Reviewed
• [Journal Article] De novo generation of CD1d1-deficient NKT-cell hybridomas from CD1d-/- mice or by gene editing of CD1d+ hybridomas (2020)
  • Author(s): Satoh M, Saeki M, Yoshino K, Mita K, Iizuka M, Hattori A, Takeuchi E, Eshima K, Iwabuchi K
  • Journal Title: Kitasato Med J Volume: 50 Pages: 34-43
  • Peer Reviewed
• [Journal Article] Amelioration of experimental autoimmune myocarditis through activation of invariant natural killer T cells by administration of a-galactosylceramide. (2020)
  • Author(s): Yoshino K, Satoh M, Iwayama T, Kobayashi S, Okamoto H, Eshima K, Watarai H, Iwabuchi K
  • Journal Title: Kitasato Med J Volume: 50 Pages: 60-72
  • Peer Reviewed
• [Journal Article] Attenuation of experimental autoimmune uveoretinitis in mice by IKKβ inhibitor IMD-0354 (2020)
  • Author(s): Liu Y, Kitaichi N, Wu D, Hase K, Satoh M, Iwata D, Namba K, Kanda A, Noda K, Itai A, Iwabuchi K, Ishida S
  • Journal Title: Biochem Biophys Res Commun Volume: 525 Issue: 3 Pages: 589-594
  • DOI: 10.1016/j.bbrc.2020.02.117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NKT細胞と脂肪組織 (2019)
  • Author(s): 岩渕 和也，佐藤 雅
  • Journal Title: 生体の科学 Volume: 70 Pages: 130-134
• [Journal Article] Changes in NGF expression and macrophage phenotype following intervertebral disc injury in mice (2019)
  • Author(s): Nakawaki M, Uchida K, Miyagi M, Inoue G, Kawakubo A, Sato M, Takaso M
  • Journal Title: J Orthop Res Volume: 印刷中 Issue: 8 Pages: 1798-1804
  • DOI: 10.1002/jor.24308
  • Peer Reviewed
• [Presentation] Receptor for advanced glycation products (RAGE) contributes to negative regulation of type 2 mucosal immunity to the intestinal nematode Nippostrongylus brasiliensis infection. (2022)
  • Author(s): Tsubokawa D, Satoh M, Kawakami F, Kawashima R and Ichikawa T
  • Organizer: 15th International Congress of Parasitology
  • Int'l Joint Research
• [Presentation] MR1 deficiency enhances IL-17 immune responses in allergic contact dermatitis (2022)
  • Author(s): Satoh M, Oowa C, Iwabuchi K.
  • Organizer: The 51th Annual Meeting of The Japanese Society for Immunology
• [Presentation] The regulatory mechanism of NKT cell and macrophage in ConA-induced hepatitis (2022)
  • Author(s): Oowa C, Kagawa C, Satoh M, Iwabuchi K
  • Organizer: The 51th Annual Meeting of The Japanese Society for Immunology
• [Presentation] NKT細胞を介した自己免疫性肝炎発症メカニズムの解析 (2022)
  • Author(s): 大和 千鶴，香川 千咲都，佐藤 雅
  • Organizer: 第35回北里大学バイオサイエンスフォーラム
• [Presentation] Recurrence of experimental autoimmune uveoretinitis (EAU) induced by administration of Staphylococcal Enterotoxin B was ameliorated by NKT-cell activation. (2021)
  • Author(s): Oowa C, Satoh M, Iwabuchi K.
  • Organizer: The 50th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Adipose iNKT cell interacting with macrophage regulates obesity-associated inflammation. (2021)
  • Author(s): Satoh M, Iwabuchi K.
  • Organizer: The 50th Annual Meeting of The Japanese Society for Immunology
• [Presentation] NKT細胞ハイブリドーマにおけるIL-10産生機構の検討. (2021)
  • Author(s): 大和 千鶴，佐藤 雅，櫻井 靖高，岩渕 和也
  • Organizer: 第33回北里大学バイオサイエンスフォーラム
• [Presentation] The interaction of NKT cell and macrophage has regulatory function in obesity. (2019)
  • Author(s): Satoh M, Iwabuchi K.
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Experimental autoimmune uveoretinitis (EAU) in relapse model are ameliorated by NKT cells. (2019)
  • Author(s): Tajiri N, Satoh M, Iwabuchi K.
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] The alteration of NKT-cell function in mice fed on high fat diet. (2019)
  • Author(s): Hane K, Satoh M, Iwabuchi K.
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] MR1/MAIT cell alleviates allergic contact dermatitis through reduction of IL-17 production (2019)
  • Author(s): Imahashi N, Satoh M, Iwabuchi K
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Potential role of invariant NKT cells in experimental autoimmune myocarditis in mice. (2019)
  • Author(s): Yoshino K, Satoh M, Iwabuchi K.
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Remarks] 北里大学医学部免疫学
  • URL: https://www.kitasato-u.ac.jp/med/research/departments/medicine/immunol.html
• [Remarks] 北里大学医学部免疫学
  • URL: https://www.med.kitasato-u.ac.jp/lab/immunology/
• [Remarks] 北里大学医学部免疫学
  • URL: http://www.med.kitasato-u.ac.jp/immunology/
• [Remarks] 北里大学医学部免疫学ホームページ
  • URL: http://www.med.kitasato-u.ac.jp/immunology/