Identification of factors inducing hepatic glucose and lipid metabolism abnormalities via intestine and portal vein by periodontal infection using omics analysis.

• Project/Area Number: 18K09573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57030:Conservative dentistry-related
• Research Institution: Osaka University
• Principal Investigator: Kashiwagi Yoichiro 大阪大学, 歯学研究科, 助教 (20598396)
• Co-Investigator(Kenkyū-buntansha): 石濱 泰 京都大学, 薬学研究科, 教授 (30439244) ; 岩山 智明 大阪大学, 歯学研究科, 助教 (80757865)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 歯周病 / 糖尿病 / 腸内細菌叢 / 口腔内細菌 / 腸内細菌 / ディスバイオシス / 高血糖 / 歯周病菌 / 糖新生

Outline of Final Research Achievements

We hypothesized that periodontal bacteria that reach the gastrointestinal tract through the oral cavity cause dysbiosis in the intestine, and that the specific metabolites produced modify the metabolic function of the liver via the portal vein, thereby affecting diabetes mellitus.
We injected a suspension of P. gingivalis (P.g) from the oral cavity every 3 days for 30 days into 7~11 week old db/db mice as a model of experimental periodontitis. The results showed a significant increase in blood glucose level in the P.g-treated group and a significant enhancement of the expression of PCK1, a glycogenesis-related factor, and its transcription factor FOXO1 in the liver. Furthermore, metaproteome analysis of feces showed that the amino acid sequence unique to P.g bacteria was detected only in the P.g-treated group.

Academic Significance and Societal Importance of the Research Achievements

歯周病の主原因は歯周ポケット局所において、歯周病菌で構成される細菌バイオフィルムの蓄積により歯周組織の破壊が進行する病気である。近年、歯周病菌が他の食物栄養素と共に消化管へ到達する事により、腸内細菌叢が変化し全身に影響を及ぼしているという考えが報告されてきたが、糖尿病に対する詳しいメカニズム詳細はわかっていない。本研究計画によりP.g菌が腸内まで到達していることを示唆する結果が得られ、その流路にあたる小腸においてポリアミン関連分子の優位な低下が検出されたことは肝臓における糖新生亢進に関与している可能性が示唆された。

Research Products

• [Journal Article] A MapReduce-like Deep Learning Model for the Depth Estimation of Periodontal Pockets (2019)
  • Author(s): Moriyama Yusuke、Lee Chonho、Date Susumu、Kashiwagi Yoichiro、Narukawa Yuki、Nozaki Kazunori、Murakami Shinya
  • Journal Title: The 12th International Joint Conference on Biomedical Engineering Systems and Technologies Volume: 5 Pages: 388-395
  • DOI: 10.5220/0007405703880395
  • Peer Reviewed / Open Access
• [Presentation] 糖尿病マウスにおいて歯周病菌が肝臓代謝機能に及ぼす影響 (2020)
  • Author(s): 柏木陽一郎、生川由貴、和泉自泰、杉山直幸、馬場健史、石濱泰、柏木厚典、村上伸也
  • Organizer: 第63回日本糖尿病学会年次学術集会
• [Presentation] 高血糖状態が歯肉上皮の細胞接着に及ぼす影響 (2020)
  • Author(s): 生川由貴、柏木陽一郎、竹立匡秀、村上伸也
  • Organizer: 日本歯科保存学会2020年度春季学術大会(第151回)
• [Presentation] 高血糖状態がヒト歯肉上皮細胞および糖尿病マウス歯肉組織における細胞間接着に及ぼす影響 (2020)
  • Author(s): 生川由貴、富永翔太郎、柏木陽一郎、村上伸也
  • Organizer: 第63回秋季日本歯周病学会学術大会
• [Presentation] Intercellular Adhesion of Gingival Epithelium in Hyperglycemia (2020)
  • Author(s): Yuki Narukawa, Yoichiro Kashiwagi, Chiaki Morimoto, Keigo Sawada, Masahide Takedachi, Shinya Murakami.
  • Organizer: 2020 IADR/ AADR/ CADR General Session & Exhibition
  • Int'l Joint Research
• [Presentation] Porphyromonas gingivalis exacerbates hyperglycemia in diabetic mice via gut dysbiosis (2019)
  • Author(s): Yoichiro Kashiwagi, Yuki Narukawa, Shiori Hasegawa, Masahide Takedachi, Yoshihiro Izumi, Takeshi Bamba, Yasushi Ishihama, and Shinya Murakami
  • Organizer: 4th Meeting of the International Association for Dental Research
  • Int'l Joint Research
• [Presentation] Intercellular Adhesion of Gingival Epithelial Cells in Hyperglycemic Condition (2019)
  • Author(s): Yuki Narukawa, Yoichiro Kashiwagi, Chiaki Morimoto, Keigo Sawada, Masahide Takedachi, Shinya Murakami.
  • Organizer: 4th Meeting of the International Association for Dental Research
  • Int'l Joint Research
• [Presentation] Intercellular Adhesion of Gingival Epithelium in Hyperglycemia (2019)
  • Author(s): Yuki Narukawa, Yoichiro Kashiwagi, Chiaki Morimoto, Keigo Sawada, Masahide Takedachi, Shinya Murakami.
  • Organizer: 98th General Session & Exhibition of the IADR
  • Int'l Joint Research
• [Presentation] 高血糖状態が歯肉上皮の細胞接着に及ぼす影響 (2019)
  • Author(s): 生川由貴、柏木陽一郎、森本千晶、沢田啓吾、竹立匡秀、村上伸也
  • Organizer: 第62回 春季日本歯周病学会
• [Presentation] A MapReduce-like Deep Learning Model for the Depth Estimation of Periodontal Pockets (2019)
  • Author(s): Yusuke Moriyama, Chonho Lee, Susumu Date, Yoichiro Kashiwagi, Yuki Narukawa, Kazunori Nozaki and Shinya Murakami
  • Organizer: HEALTHINF 2019 12th International Conference on Health Informatics
  • Int'l Joint Research
• [Presentation] Clinical Evaluation of Periodontal Tissue Regeneration by ADMPC Transplantation (2018)
  • Author(s): Masahide Takedachi, Keigo Sawada, Chiaki Morimoto, Satomi Yamamoto, Asae Hirai, Junpei Shimomura, Yuki Narukawa, Yoichiro Kashiwagi, Tomoaki Iwayama, Masahiro Kitamura, Shinya Murakami
  • Organizer: 96th General Session and Exhibition of the IADR
  • Int'l Joint Research
• [Presentation] Therapeutic efficacy of autologous ADMPC transplantation for periodontal tissue regeneration (2018)
  • Author(s): Chiaki Morimoto, Masahide Takedachi, Keigo Sawada, Satomi Yamamoto, Asae Hirai, Junpei Shimomura, Yuki Narukawa, Yoichiro Kashiwagi, Tomoaki Iwayama, Masahiro Kitamura, Shinya Murakami
  • Organizer: 第66回国際歯科研究学会日本部会総会・学術大会