Relations of periodontal diseases to systemic diseases and involvement of degradation of bioactive peptides by oral bacterial peptidases

• Project/Area Number: 16K11481
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Nagasaki University
• Principal Investigator: OHARA-NEMOTO Yuko 長崎大学, 医歯薬学総合研究科(歯学系), 准教授 (10164667)
• Co-Investigator(Kenkyū-buntansha): 根本 孝幸 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (90164665) ; 下山 佑 岩手医科大学, 歯学部, 講師 (90453331) ; 馬場 友巳 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (60189727) ; 小早川 健 長崎大学, 医歯薬学総合研究科(歯学系), 技術職員 (10153587) ; 木村 重信 関西女子短期大学, その他部局等, 教授 (10177917)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: DPP4 / インクレチン / 歯周病 / 2型糖尿病 / インスリン / ペプチダーゼ / 全身疾患 / 口腔細菌 / 口腔細菌叢 / GLP-1 / 歯周病菌 / GIP / 血糖 / ジペプチジルペプチダーゼ / 生理活性ペプチド / 糖尿病

Outline of Final Research Achievements

Enzymatic parameters and substrate specificities of periodontopathic bacterial dipeptidyl peptidases (DPP)4, DPP5, and DPP7 were determined. Bacterial DPP4 degraded human and mouse incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide). Administration of bacterial DPP4 to mouse decreased in concentrations of active glucagon-like peptide-1 and insulin in the blood, accompanied by a substantial elevation of postprandial hyperglycemia and delayed reduction of blood glucose. Databases search revealed that anaerobic Bacteroidetes bacteria possess the dpp4 genes, suggesting that a molecular mechanism of degradation of bioactive peptides by periodontopathic bacterial peptidases, which is possibly involved in the association between periodontal and systemic diseases.

Academic Significance and Societal Importance of the Research Achievements

我々が発見した新規ペプチダーゼ含む口腔細菌ペプチダーゼの基質特異性が確定し，酵素学的パラメーターが決定された。口腔細菌由来DPP4がヒトDPP4と同様にインスリン分泌誘導作用のある生理活性ペプチド（インクレチン，GLP-1，GIP)分解能があること示し，口腔細菌ペプチダーゼと血糖値調節について新たな知見が得られた。
概要に記した成果は，歯周病原性細菌に関係する歯学・医学分野での疾病予防と治療の観点から重要であるばかりでなく，ヒトでの新規のペプチド分解による制御系の発見に繋がる可能性があり，極めて意義のある研究である。

Research Products

• [Int'l Joint Research] University of Vienna(Austria)
• [Int'l Joint Research] European Molecular Biology Laboratory(France)
• [Int'l Joint Research] ウィーン大学/Max F. Perutz研究所(オーストリア)
• [Int'l Joint Research] ヨーロッパ分子生物学研究所(フランス)
• [Journal Article] Periodontopathic bacterial DPP4 as a risk factor for type 2 diabetes mellitus (2018)
  • Author(s): 中里 茉那美，下山 佑，根本 優子，佐々木 大輔，根本 孝幸，佐々木 実，八重柏 隆
  • Journal Title: Dental Journal of Iwate Medical University Volume: 43 Issue: 1 Pages: 48-60
  • DOI: 10.20663/iwateshigakukaishi.43.1_48
  • NAID: 130007396589
  • ISSN: 0385-1311, 2424-1822
  • Year and Date: 2018-05-25
  • Peer Reviewed / Open Access
• [Journal Article] Distribution of dipeptidyl peptidase (DPP) 4, DPP5, DPP7, and DPP11 in human oral microbiota ? potent biomarkers indicating presence of periodontopathic bacteria (2018)
  • Author(s): Ohara-Nemoto Yuko、Shimoyama Yu、Nakasato Manami、Nishimata Haruka、Ishikawa Taichi、Sasaki Minoru、Kimura Shigenobu、Nemoto Takayuki K
  • Journal Title: FEMS Microbiology Letters Volume: 365 Pages: 1-7
  • DOI: 10.1093/femsle/fny221
  • NAID: 120006987966
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of potent and specific synthetic substrate for dipeptidyl-peptidase 7. (2018)
  • Author(s): Nemoto TK, Ono T, Ohara-Nemoto Y.
  • Journal Title: Anal Biochem Volume: 548 Pages: 78-81
  • DOI: 10.1016/j.ab.2018.02.008
  • NAID: 120006987355
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a new subtype of dipeptidyl peptidase 11 and a third group of the S46-family members specifically present in the genus Bacteroides. (2018)
  • Author(s): Nemoto TK, Bezerra GA, Ono T, Nishimata H, Fujiwara T, Ohara-Nemoto Y.
  • Journal Title: Biochimie Volume: 147 Pages: 25-35
  • DOI: 10.1016/j.biochi.2017.10.015
  • NAID: 120006987398
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4. (2017)
  • Author(s): Ohara-Nemoto, Y., Nakasato, M., Shimoyama, Y., Baba, T., Kobayakawa, T., Ono, T., Yaegashi, T., Kimura, S., Nemoto, T.K.
  • Journal Title: Infection and Immunity Volume: 85 Issue: 9
  • DOI: 10.1128/iai.00277-17
  • NAID: 120006987494
  • Peer Reviewed / Open Access
• [Journal Article] Bacterial protease uses distinct thermodynamic signatures for substrate recognition. (2017)
  • Author(s): Bezerra, G. A., Ohara-Nemoto, Y., Fedosyuk, S., Cornaciu, I., Hoffmann, G., Round, A., Marquez, J. A., Nemoto, T.K., Djinovic-Carugo, K.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 2848-2848
  • DOI: 10.1038/s41598-017-03220-y
  • NAID: 120006987515
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dominant prevalence of Porphyromonas gingivalis fimA types I and IV in healthy Japanese children. (2017)
  • Author(s): Shimoyama Y, Ohara-Nemoto Y, Kimura M, Tanaka M, Kimura S, and Nemoto TK.
  • Journal Title: J Dent Sci. Volume: 印刷中 Issue: 3 Pages: 213-219
  • DOI: 10.1016/j.jds.2017.03.006
  • NAID: 120006987517
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Bacteroides属菌が有するS46ファミリージペプチジルペプチダーゼ (2017)
  • Author(s): 根本優子，小野俊雄，根本孝幸
  • Organizer: 第90回日本細菌学会総会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2017-03-19
• [Presentation] S46 family dipeptidyl peptidases (DPPs) in the genus Bacteroides (2017)
  • Author(s): 根本優子，小野俊雄，根本孝幸
  • Organizer: 第90回日本細菌学会総会
• [Presentation] Porphyromonas gingivalis および Tannerella forsythia のジペプチジルペプチダーゼ4 活性とインクレチン分解能 (2017)
  • Author(s): 2.中里茉那美，根本優子，下山佑，木村重信，佐々木大輔，伊東俊太郎，佐々木実，八重柏隆
  • Organizer: 第60回春季日本歯周病学会学術大会
• [Presentation] 歯周病原性細菌アシルペプチジルオリゴペプチダーゼ(AOP)のアシルペプチド選択機構 (2017)
  • Author(s): 根本孝幸，小野俊雄，根本優子
  • Organizer: 第59回歯科基礎医学会学術大会・総会
• [Presentation] Porphyromonas gingivalisのアミノ酸及びオリゴペプチド輸送系の解析 (2016)
  • Author(s): 根本優子，小早川健，馬場友巳，根本孝幸
  • Organizer: 第58回歯科基礎医学会学術大会・総会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2016-08-24
  • Int'l Joint Research
• [Presentation] Degradation of incretin by the prokaryotic dipeptidyl-peptidase 4 from Porphyromonas gingivalis. (2016)
  • Author(s): Shimoyama, Y., Ohara-Nemoto, Y., Nemoto, T.K., Nakasato, M., Yaegashi, T., Ishikawa, T., Sasaki, M., Kimura, S.
  • Organizer: Microbe 2016
  • Place of Presentation: ホ゛ストン(米国)
  • Year and Date: 2016-06-16
  • Int'l Joint Research
• [Presentation] Characterization of dipeptidyl-peptidase 4 from Tannerella forsythia. (2016)
  • Author(s): Nakasato, M., Shimoyama, Y., Ohara-Nemoto, Y., Nemoto, T.K., Takahashi, S., Ito, S., Sasaki, D., Yaegashi, T., Kimura, S.
  • Organizer: Microbe 2016
  • Place of Presentation: ホ゛ストン(米国)
  • Year and Date: 2016-06-16
  • Int'l Joint Research
• [Presentation] Porphyromonas sp. dipeptidyl peptidases 11 distinguish substrates from end products via distinct thermodynamic signatures. (2016)
  • Author(s): Bezerra, G. A., Ohara-Nemoto, Y., Fedosyuk, S., Cornaciu, I., Hoffmann, G., Marquez, J. A., Nemoto, T.K., Djinovic-Carugo, K.
  • Organizer: EMBO Conference The biochemistry and chemistry of biocatalysis: From understanding to design
  • Place of Presentation: オウル（フィンランド）
  • Year and Date: 2016-06-12
  • Int'l Joint Research