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The potential of targeting oral microflora and periodontopathogenic bacteria to prevent dementia.

Research Project

Project/Area Number 20H03904
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 57080:Social dentistry-related
Research InstitutionNational Center for Geriatrics and Gerontology

Principal Investigator

Matsushita Kenji  国立研究開発法人国立長寿医療研究センター, 研究所 口腔疾患研究部, 部長 (90253898)

Co-Investigator(Kenkyū-buntansha) 佐治 直樹  国立研究開発法人国立長寿医療研究センター, 病院 もの忘れセンター, 客員研究員 (30624910)
里 直行  国立研究開発法人国立長寿医療研究センター, 研究所 認知症先進医療開発センター, 副センター長 (70372612)
多田 浩之  東北大学, 歯学研究科, 講師 (70431632)
山田 匡恵 (古川匡恵)  国立研究開発法人国立長寿医療研究センター, 研究所 口腔疾患研究部, 外来研究員 (90439456)
道川 誠  名古屋市立大学, 医薬学総合研究院(医学), 教授 (40270912)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2020: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords認知症 / 歯周病 / 口腔機能 / 口腔細菌叢 / オーラルフレイル / オーラルディアドコキネシス / アルツハイマー病 / Porphyromonas gingivalis / 血管炎症 / 脳血管障害 / 16S rRNA菌叢解析
Outline of Research at the Start

本研究は、認知症対策に焦点を絞り、口腔からのアプローチによる新たな認知症対策の可能性を探ることを目的とする。具体的には、①腸内細菌叢、口腔細菌叢と認知症、特にアルツハイマー病との関連性の解析(ヒトおよびマウス解析)、②特定の口腔細菌、特にPorphyromonas gingivalisと脳アミロイド血管症との関連性の解析(マウスモデル)、③細菌叢、およびP. gingivalisをターゲットとした認知症対策の可能性の検討、以上の結果を総合して、口腔から始める新たな認知症対策を提案することを目指す。

Outline of Final Research Achievements

Cognitive function tests and periodontal disease tests were conducted on 183 people who visited the National Institute for Longevity Sciences, and the correlation between the two items was investigated. Dementia subjects did not have regular dental visits, owned fewer teeth and brushed their teeth less frequently. In addition, cognitive decline was significantly correlated with the severity of periodontal disease. The relationship between various oral functions and cognitive function was assessed, and lower values of oral diadochokinesis /ka/ sound and repeated saliva swallowing tests were associated with a higher risk tendency for mild cognitive impairment and dementia. Furthermore, some bacterial genera and species associated with cognitive decline were identified in the bacterial flora of the subjects' tongue and subgingival plaque. In addition, bacteria in the subgingival plaque were strongly associated with levels of cognitive function.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、認知機能の低下と歯周病病態や口腔機能と相関関係があることが明らかとなった。本結果からは因果関係を明らかにすることはできなかったが、認知症患者における口腔ケアの重要性および口腔機能低下に対する対策の重要性を明示することができた。さらに、特定の口腔細菌の変動を調べることで、認知症のリスクを予測できる可能性が示唆された。今後、介入研究や縦断研究を実施し、因果関係を明確にすることで、口腔検査による認知症予測、さらには口腔の健康の維持・向上による認知症の予防の可能性も拡がるであろう。

Report

(4 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (46 results)

All 2024 2023 2022 2021 2020 Other

All Journal Article (15 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 15 results,  Open Access: 14 results) Presentation (30 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Oral infection with Porphyromonas gingivalis augmented gingival epithelial barrier molecules alteration with aging.2024

    • Author(s)
      Giri S, Takada A, Paudel D, Uehara O, Kurashige Y, Kuramitsu Y, Furukawa M, Matsushita K, Arakawa T, Nagasawa T, Abiko Y, Furuichi Y.
    • Journal Title

      J Oral Biosci.

      Volume: 66 Issue: 1 Pages: 126-133

    • DOI

      10.1016/j.job.2024.01.012

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Neutrophil extracellular traps inhibit osteoclastogenesis2024

    • Author(s)
      Numazaki Kento、Tada Hiroyuki、Nishioka Takashi、Nemoto Eiji、Matsushita Kenji、Mizoguchi Itaru、Sugawara Shunji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 705 Pages: 149743-149743

    • DOI

      10.1016/j.bbrc.2024.149743

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-Term Soft-Food Rearing in Young Mice Alters Brain Function and Mood-Related Behavior2023

    • Author(s)
      Furukawa Masae、Tada Hirobumi、Raju Resmi、Wang Jingshu、Yokoi Haruna、Yamada Mitsuyoshi、Shikama Yosuke、Matsushita Kenji
    • Journal Title

      Nutrients

      Volume: 15 Issue: 10 Pages: 2397-2397

    • DOI

      10.3390/nu15102397

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-Term Capsaicin Administration Ameliorates the Dysfunction and Astrogliosis of the Brain in Aged Mice with Missing Maxillary Molars2023

    • Author(s)
      Furukawa Masae、Tada Hirobumi、Raju Resmi、Wang Jingshu、Yokoi Haruna、Ikuyo Yoriko、Yamada Mitsuyoshi、Shikama Yosuke、Matsushita Kenji
    • Journal Title

      Nutrients

      Volume: 15 Issue: 11 Pages: 2471-2471

    • DOI

      10.3390/nu15112471

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Erythritol Can Inhibit the Expression of Senescence Molecules in Mouse Gingival Tissues and Human Gingival Fibroblasts2023

    • Author(s)
      Yokoi Haruna、Furukawa Masae、Wang Jingshu、Aoki Yu、Raju Resmi、Ikuyo Yoriko、Yamada Mitsuyoshi、Shikama Yosuke、Matsushita Kenji
    • Journal Title

      Nutrients

      Volume: 15 Issue: 18 Pages: 4050-4050

    • DOI

      10.3390/nu15184050

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Macrophage migration inhibitory factor-mediated mast cell extracellular traps induce inflammatory responses upon Fusobacterium nucleatum infection2023

    • Author(s)
      Tada, H., Nishioka, T., Ishiyama, R., Song, LT., Onoue, S., Kawahara, K., Nemoto, E., Matsushita, K., Sugawara, S.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 674 Pages: 90-96

    • DOI

      10.1016/j.bbrc.2023.06.060

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cross-Sectional Analysis of Periodontal Disease and Cognitive Impairment Conducted in a Memory Clinic: The Pearl Study2023

    • Author(s)
      N. Saji, Y. Ishihara, K. Murotani, A. Uchiyama, A. Takeda, T. Sakurai, K. Matsushitaf
    • Journal Title

      J Alzheimers Dis .

      Volume: 96 Issue: 1 Pages: 369-380

    • DOI

      10.3233/jad-230742

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Priming Potential of Interferon Lambda-1 for Antiviral Defense in the Oral Mucosa2022

    • Author(s)
      Shikama Yosuke、Kurosawa Mie、Furukawa Masae、Kudo Yasusei、Ishimaru Naozumi、Matsushita Kenji
    • Journal Title

      Inflammation

      Volume: - Issue: 3 Pages: 1-14

    • DOI

      10.1007/s10753-022-01624-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An in vitro senescence model of gingival epithelial cell induced by hydrogen peroxide treatment2021

    • Author(s)
      Giri Sarita、Takada Ayuko、Paudel Durga、Yoshida Koki、Furukawa Masae、Kuramitsu Yasuhiro、Matsushita Kenji、Abiko Yoshihiro、Furuichi Yasushi
    • Journal Title

      Odontology

      Volume: 110 Issue: 1 Pages: 44-53

    • DOI

      10.1007/s10266-021-00630-3

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Porphyromonas gingivalis Gingipains-Mediated Degradation of Plasminogen Activator Inhibitor-1 Leads to Delayed Wound Healing Responses in Human Endothelial Cells.2021

    • Author(s)
      Song LT, Tada H, Nishioka T, Nemoto E, Imamura T, Potempa J, Li CY, Matsushita K, Sugawara S
    • Journal Title

      J Innate Immun

      Volume: Nov 25 Issue: 4 Pages: 1-14

    • DOI

      10.1159/000519737

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effect of green propolis extracts on experimental aged gingival irritation in vivo and in vitro2021

    • Author(s)
      Furukawa Masae、Wang Jingshu、Kurosawa Mie、Ogiso Noboru、Shikama Yosuke、Kanekura Takuro、Matsushita Kenji
    • Journal Title

      Journal of Oral Biosciences

      Volume: 63 Issue: 1 Pages: 58-65

    • DOI

      10.1016/j.job.2020.12.003

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulation in Salivary Glands of Aged and Sj?gren’s Syndrome Model Mice2021

    • Author(s)
      Kurosawa Mie、Shikama Yosuke、Furukawa Masae、Arakaki Rieko、Ishimaru Naozumi、Matsushita Kenji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 5 Pages: 2302-2302

    • DOI

      10.3390/ijms22052302

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High concentration of glucose induces filaggrin-1 expression through AP-1 in skin keratinocytes2020

    • Author(s)
      Masae Furukawa, Kiyoko Yamada, Mie Kurosawa, Yosuke Shikama, Takuro Kanekura and Kenji Matsushita
    • Journal Title

      Journal of Dermatological Science

      Volume: - Issue: 2 Pages: 137-140

    • DOI

      10.1016/j.jdermsci.2020.04.002

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synthetic cell-permeable caveolin-1 scaffolding domain peptide activates phagocytosis of Escherichia coli by regulating Rab5 activity.2020

    • Author(s)
      Hagiwara M, Matsushita K
    • Journal Title

      Naturforsch C J Biosci

      Volume: 75(9-10) Issue: 9-10 Pages: 333-337

    • DOI

      10.1515/znc-2020-0023

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oral hypo function and its association with frailty in community-dwelling older people2020

    • Author(s)
      Shimazaki Yoshihiro, Nonoyama Toshiya, Tsushita Kazuyo, Arai Hidenori, Matsushita Kenji, Uchibori Noriyasu
    • Journal Title

      Geriatrics and Gerontology International

      Volume: 20 Issue: 10 Pages: 917-926

    • DOI

      10.1111/ggi.14015

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] もの忘れ外来患者の認知機能は口腔清掃状態と相関する.2023

    • Author(s)
      湯之上志保、石原裕一、武儀山みさき、細久保和美、伊土美南海、野原佳織、新明 桃、内山 章、松下健二
    • Organizer
      第72回日本口腔衛生学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] エリスリトールはマウス歯周組織およびヒト歯肉線維芽細胞における老化分子の発現を抑制する.2023

    • Author(s)
      山田(古川)匡恵、横井春奈、青木 優、杉山大二朗、王 静舒、幾代以子、嶋田智紀、松下健二
    • Organizer
      第23回抗加齢医学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] カプサイシンはStreptocccus mutansの増殖を抑制する~in vitroでの解析~2023

    • Author(s)
      幾代以子、王 静舒、山田(古川)匡恵、横井春奈、松下健二
    • Organizer
      第23回抗加齢医学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Capsaicin intake suppresses the increase of GFAP in the hippocampus.2023

    • Author(s)
      Furukawa M, Yokoi H, Ikuyo Y, Matsushita K
    • Organizer
      IAGG Asia Oceania Regional Congress2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 口腔の健康と認知症の関連性. 公募シンポジウム『口腔疾患がアルツハイマー病分子病態に及ぼす影響の分子メカニズムの検討』.2023

    • Author(s)
      松下健二
    • Organizer
      第64回日本神経病理学会・第66回日本神経科学会合同大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] エリスリトールはマウス歯肉およびヒト歯肉線維芽細胞における老化分子の発現を抑制する.2023

    • Author(s)
      横井春奈、古川匡恵、青木優、王 静舒、幾代依子、四釜洋介、松下健二
    • Organizer
      第65回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 歯周病マウスモデルにおけるPorphyromonas gingivalisと好中球による脳機能障害の検討.2023

    • Author(s)
      リュウ ドウシン、多田浩之、西岡貴志、松下健二、菅原俊二
    • Organizer
      第65回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] メトホルミンによる唾液・唾液腺におけるACE2, TMPRSS2, IgA発現の制御.2023

    • Author(s)
      四釜洋介、古川匡恵、松下健二
    • Organizer
      第65回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 老化歯肉におけるカプサイシンのβ-defensin誘導能 ー老齢マウスと老化歯周細胞培養系における解析ー2023

    • Author(s)
      幾代以子、横井春奈、古川匡恵、王 静舒、四釜洋介、松下健二
    • Organizer
      第65回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] メトホルミンによる唾液腺機能変容を介した新型コロナウイルス感染制御の可能性.2023

    • Author(s)
      四釜洋介、松下健二
    • Organizer
      第28 回日本エンドトキシン・自然免疫研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 歯周病原細菌プロテアーゼとNETsのクロストークによる脳機能障害.2023

    • Author(s)
      多田浩之、西岡貴志、松下健二
    • Organizer
      第28回日本エンドトキシン・自然免疫研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 玄米中に含まれる成分の免疫力活性化機構の解析.2022

    • Author(s)
      萩原真、永野忠聖、松下健二
    • Organizer
      日本農芸化学会2022年度大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] シンポジウム21 老いの入り“口”から認知症を読み解く 歯周病・口腔細菌と認知症の関連性のupdate.2021

    • Author(s)
      松下健二
    • Organizer
      第21回日本抗加齢医学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 軟食飼育が若齢マウスの視床下部および海馬に及ぼす影響2021

    • Author(s)
      古川匡恵、四釜洋介、松下健二
    • Organizer
      第63回秋歯科基礎医学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] An in vitro senescence model of gingival epithelial cell induced by hydrogen peroxide treatment and reversal of senescence by fisetin.2021

    • Author(s)
      Giri S, Takada A, Nagano K, Paudel D, Yoshida K, Furukawa M, Kuramitsu Y, Matsushita K, Abiko Y, Furuichi Y
    • Organizer
      第63回秋歯科基礎医学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Proteolysis of PAI-1 by P. gingivalis gingipains leading to delayed wound healing responses in endothelial cells.2021

    • Author(s)
      Tada H, Song L, Imamura T, Potempa J, Matsushita K, Sugawara S
    • Organizer
      16th Meeting of the International Endotoxin and Innate Immunity Society
    • Related Report
      2021 Annual Research Report
  • [Presentation] III型interferon(IFN)であるinterleukin(IL)-29の口腔粘膜における抗ウイルス応答増強作用.2021

    • Author(s)
      四釜洋介、古川匡恵、松下健二
    • Organizer
      第64回秋季日本歯周病学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Porphyromonas gingivalisジンジパインによる血管内皮細胞のPAI-1分解と創傷治癒遅延.2021

    • Author(s)
      多田浩之、松下健二、根本英二
    • Organizer
      第64回秋季日本歯周病学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 歯周組織の細胞老化について ~若齢および老齢マウスと培養ヒト歯肉線維芽細胞における検討~2021

    • Author(s)
      古川匡恵、田淵拓也、山田三良、四釜洋介、松下健二
    • Organizer
      第64回秋季日本歯周病学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Establishment of an in vitro senescence model of gingival epithelial cell induced by hydrogen peroxide treatment and reversal of senescence by fisetin.2021

    • Author(s)
      Giri1 S, Takada A, Paudel D, Yoshida K, Furukawa M, Kuramitsu Y, Matsushita K, Abiko Y, Furuichi Y
    • Organizer
      第64回秋季日本歯周病学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Concentration dependent of hydrogen peroxide to induce cellular senescence in gingival epithelial cells and reversal of senescence by fisetin.2021

    • Author(s)
      Giri S, Takada A, Furukawa M, Matsushita K, Furuichi Y
    • Organizer
      第39回北海道医療大学歯学会学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Porphyromonas gingivalis ジンジパインによるヒト血管内皮細胞のPAI-1分解作用.2021

    • Author(s)
      ソン・リーティン、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] P. gingivalisならびにF. nucleatum LPSはE. coli LPSによるヒト単球のIL-6産生を増強する.2021

    • Author(s)
      坂本雄哉、尾之上さくら、川原一芳、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ヤマブシタケエタノール抽出物によるエンドトキシン中和作用.2021

    • Author(s)
      大沢啓、尾之上さくら、川原一芳、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Analysis of expression of tight junction molecules in young and senescence induced gingival epithelial cells in response to Porphyromonas gingivalis lipopolysachharide.2020

    • Author(s)
      Giri S,Takada A,Furukawa M,Matsushita K,Furuichi Y
    • Organizer
      第63回春季日本歯周病学会学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 老いの入り口からアルツハイマー病を読み解く.2020

    • Author(s)
      松下健二
    • Organizer
      第62回歯科基礎医学会学術大会メインシンポジウム2 アルツハイマー病研究の新展開
    • Related Report
      2020 Annual Research Report
  • [Presentation] 老化関連T細胞および唾液腺上皮の細胞老化が口腔乾燥症の病態形成に関与する可能性.2020

    • Author(s)
      黒澤実愛、古川匡恵、松下健二、四釜洋介
    • Organizer
      第62回歯科基礎医学会学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 加齢による口腔乾燥症の病態形成における老化関連T細胞の関与.2020

    • Author(s)
      黒澤実愛、古川匡恵、松下健二
    • Organizer
      第20回抗加齢医学総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] プロポリスは高齢者の口腔粘膜炎の治療に有望である ~in vitroおよびin vivoにおける解析~2020

    • Author(s)
      山田(古川)匡恵、黒澤実愛、松下健二
    • Organizer
      第20回抗加齢医学総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Effect of aging on junctional molecules of gingival epithelial cells.2020

    • Author(s)
      Giri S, Takada A, Matsushita K, Furukawa M, Furuichi Y
    • Organizer
      106TH Annual Meeting of Americam Academy of Peiodontology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 国立研究開発法人国立長寿医療研究センター 研究所 口腔疾患研究部

    • URL

      https://www.ncgg.go.jp/ri/lab/gero/department/oralscience/index.html

    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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