The effect of periodontitis on glucose metabolism in skeletal muscles

• Project/Area Number: 20K18527
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57030:Conservative dentistry-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Sasaki Naoki 東京医科歯科大学, 歯学部, 非常勤講師 (40848305)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 歯周病 / 骨格筋 / 糖代謝 / 糖尿病 / 代謝異常

Outline of Research at the Start

歯周病は様々な全身疾患の増悪因子になることが知られている。本研究では、歯周病原細菌であるPorphyromonas gingivalis(Pg)の嚥下及び菌血症モデルマウスを作製し、骨格筋におけるglucose uptakeを始めとした糖代謝への影響を調査する。また動物実験の結果に基づいてPg由来LPSのマウス筋芽細胞株への作用を調査し、腸内細菌叢および遺伝子発現変動を網羅的に解析することで、代謝異常のメカニズムを解明する。さらには糖尿病患者における骨格筋脂肪化とPg 血清抗体価、唾液中のPgの量及び、総細菌数におけるPgの割合との関連を検討する。

Outline of Final Research Achievements

Skeletal muscles have a high metabolic capacity, which play key roles in glucose metabolism. Although periodontal disease increases the risk of metabolic syndrome, the relationship between periodontal bacterial infection and skeletal muscle metabolic dysfunction is unclear. We found that anti-Porphyromonas gingivalis (Pg) antibody titers positively correlated with intramuscular adipose tissue content (IMAC) in metabolic syndrome patients. In C57BL/6J mice fed a high-fat diet, recipients of oral Pg (HFPg) had impaired glucose tolerance, insulin resistance, and higher IMAC compared to recipients of saline (HFco). The soleus muscle in HFPg mice exhibited fat infiltration and lower glucose uptake with higher Tnfa expression and lower insulin signaling than in HFco mice. Our findings suggest that infection with Pg is a risk factor for metabolic syndrome and skeletal muscle metabolic dysfunction via gut microbiome alteration.

Academic Significance and Societal Importance of the Research Achievements

この研究の成果は、Porphyromonas gingivalisの感染が骨格筋の代謝異常を引き起こし、メタボリックシンドロームのリスクファクターとなっている可能性、およびサルコペニアへとつながる可能性を示すものです。サルコペニアは筋肉量の低下を主体とし、機能的低下をも含む概念ですが、動作の俊敏性が失われ転倒しやすくなる身体的問題に直結します。本研究により歯周病のさらなる危険性が注意喚起され、健康寿命の延伸へとつながることが期待されます。

Research Products

• [Journal Article] Porphyromonas gingivalis Administration Induces Gestational Obesity, Alters Gene Expression in the Liver and Brown Adipose Tissue in Pregnant Mice, and Causes Underweight in Fetuses (2022)
  • Author(s): Yoshida S、Hatasa M、Ohsugi Y、Tsuchiya Y、Liu A、Niimi H、Morita K、Shimohira T、Sasaki N、Maekawa S、Shiba T、Hirota T、Okano T、Hirose A、Ibi R、Noritake K、Tomiga Y、Nitta H、Suzuki T、Takahashi H、Miyasaka N、Iwata T、Katagiri S
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 11 Pages: 1-15
  • DOI: 10.3389/fcimb.2021.745117
  • Peer Reviewed / Open Access
• [Journal Article] Association between periodontal bacteria and degenerative aortic stenosis: a pilot study (2021)
  • Author(s): Kataoka Akihisa、Katagiri Sayaka、Kawashima Hideyuki、Nagura Fukuko、Nara Yugo、Hioki Hirofumi、Nakashima Makoto、Sasaki Naoki、Hatasa Masahiro、Maekawa Shogo、Ohsugi Yujin、Shiba Takahiko、Watanabe Yusuke、Shimokawa Tomoki、Iwata Takanori、Kozuma Ken
  • Journal Title: Journal of Periodontal & Implant Science Volume: 51 Issue: 4 Pages: 226-226
  • DOI: 10.5051/jpis.2006040302
  • Peer Reviewed / Open Access
• [Journal Article] Endotoxemia by Porphyromonas gingivalis Alters Endocrine Functions in Brown Adipose Tissue (2021)
  • Author(s): Hatasa Masahiro、Ohsugi Yujin、Katagiri Sayaka、Yoshida Sumiko、Niimi Hiromi、Morita Kazuki、Tsuchiya Yosuke、Shimohira Tsuyoshi、Sasaki Naoki、Maekawa Shogo、Shiba Takahiko、Hirota Tomomitsu、Tohara Haruka、Takahashi Hirokazu、Nitta Hiroshi、Iwata Takanori
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 10 Pages: 1-12
  • DOI: 10.3389/fcimb.2020.580577
  • Peer Reviewed / Open Access
• [Journal Article] Porphyromonas gingivalis impairs glucose uptake in skeletal muscle associated with altering gut microbiota (2020)
  • Author(s): Watanabe K、Katagiri S、Takahashi H、Sasaki N、Maekawa S、Komazaki Ri、Hatasa M、Kitajima Y、Maruyama Y、Shiba T、Komatsu K、Ohsugi Y、Tanaka K、Matsuzawa A、Hirota T、Tohara H、Eguchi Y、Anzai K、Hattori A、Iwata T
  • Journal Title: The FASEB Journal Volume: 35 Issue: 2 Pages: 1-16
  • DOI: 10.1096/fj.202001158r
  • Peer Reviewed / Open Access
• [Journal Article] Association between periodontal bacteria and degenerative aortic stenosis: a pilot study (2020)
  • Author(s): Kataoka A, Katagiri S, Kawashima H, Nagura F, Sasaki N, Shiba T, Iwata T, Nara Y, Hioki H, Nakashima M, Hatasa H, Maekawa S, Ohsugi Y, Watanabe Y, Shimokawa T, Kozuma K
  • Journal Title: Journal of Periodontal & Implant Science (in press) Volume: -
  • Peer Reviewed
• [Presentation] Porphyromonas gingivalis administration induces obesity, modifies gene expression in the liver and brown adipose tissue in pregnant mice, and causes underweight in fetuses (2022)
  • Author(s): Yoshida S, Hatasa M, Ohsugi Y, Tsuchiya Y, Liu A, Niimi H, Morita K, Shimohira T, Sasaki N, Maekawa S, Shiba T, Hirota T, Noritake K, Nitta H, Katagiri S, Iwata T
  • Organizer: Europerio 10
  • Int'l Joint Research
• [Presentation] Endotoxemia by Porphyromonas gingivalis aggravates inflammation in brown adipose tissue (2020)
  • Author(s): Hatasa M, Ohsugi Y, Katagiri S, Hirota T, Yoshida S, Morita K, Niimi H, Shimohira T, Watanabe K, Sasaki N, Maekawa S, Nitta H, Iwata T
  • Organizer: The 106th Annual meeting American Academy of Periodontology
• [Presentation] Porphyromonas gingivalisによる菌血症は褐色脂肪の内分泌機能を変化させる (2020)
  • Author(s): 畑佐 将宏, 大杉 勇人, 片桐 さやか, 新見 ひろみ, 森田 和機, 吉田 澄子, 下平 剛, 佐々木 直樹, 前川 祥吾, 芝 多佳彦, 廣田 朝光, 新田 浩, 岩田 隆紀
  • Organizer: 第63回秋季日本歯周病学会学術大会